(MT 6326) IMMUNOSERO LEC COMPRE by 3DMT PDF

IMMUNOLOGY SEROLOGY LECTURE
1
SOURCES: PPT, A ch Cla LEGENDS: , lec e, b k
he ir s for pro ec ion ia
NI 1: IN ROD C ION O I AND HI ORICAL inhala ion
CONCEP E J
Smallpo accina ion (adminis ered
PRE- E 1798
in ram sc larl )
S ccessf ll pre en ed
1. Who disco ered he HLA? Jean Da sse
infec ion i h smallpo b
2. Variola ion is a form of imm ni a ion b inhaling dried
injec ing co po
po ders deri ed from smallpo lesions
3. Who in rod ced accina ion? Ed ard Jenner 1862 H E Phagoc osis
4. Who disco ered li e a en a ed accines for rabies? Lo is
L P
Pas e r
Li e a en a ed, chicken cholera and
5. The scien is ho firs e plained cell lar media ed imm ni
an hra accine
hro gh phagoc osis as Elie Me chnikoff.
Fa he of Imm nolog
Disco ered he firs a en a ed
IMM NOLOG & EROLOG accine
A e a ed = Red ced and
IMM NOLOG 1862
enforced effec (less ir len ) b
Resis ance o disease (infec io s disease)
applica ion of hea , aging or
S d of a hos s reac ions hen foreign s bs ances are
chemical means o lessen
in rod ced in o he bod
pa hogenici of microorganisms
Branch of biolog ha co ers he s d of imm ne s s ems
Obser ed ha older bac erial
in all organisms
c l res o ld no ca se
Consis s of:
disease in chickens
S d of molec les (an igens/an ibodies), organs
( ransplan a ion/compa ibili ), s s ems L P
responsible for he recogni ion and disposal of Therape ic accina ion
1885
foreign ma erial (RBCs & macrophages) Firs repor of li e a en a ed accine
Ho bod componen s respond and in erac for rabies
Desirable and ndesirable conseq ences of
E M
imm ne in erac ions
Cell la he fi i hro gh
Wa s in hich he imm ne s s em can be
phagoc osis
ad an ageo sl manip la ed o pro ec agains or
Cond c ed sing s arfish
rea disease
lar ae in hich i eng lfed
EROLOG
foreign ma erials
Scien ific s d of ser m and o her bod fl ids
1883-1905 Foreign objec s become
S d of he fl id componen s in he blood
s rro nded b mo ile
ameboid-like cells a emp ing
HI ORICAL BACKGRO ND o des ro pene ra ing objec s
Imm ni o disease as based
recorded ha indi id als
on ac ion of sca enger cells
ho had pre io sl con rac ed he
(inna e hos defense)
430 BC disease reco ered
He recogni ed heir imm ne s a s E B & K
H al he fi i or H moral
Chinese prac iced a form of
response proposed
imm ni a ion b inhaling dried po ders
AKA an ibod media ed
1000 AD deri ed from smallpo lesions
1890 imm ni
(1500s ( )
Aspec of imm ni hich is
acc di g Lesions ca sed b Variola ir s
media ed b he secre ed
S e e ) Va i la i - ma erials from
an ibodies
smallpo lesions/p s les are
Responsible cells B cells
gi en o people ho ne er had
DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D RE 2022

IMMUNOLOGY SEROLOGY LECTURE 2
Demons ra ed ha diph heria & Based on he ass mp ion ha

e an s o ins co ld be each an ibod m s ha e a
ne rali ed b noncell lar leas 2 ac i e si es, i sho ld be
por ion of blood of animals m l i alen . As he combine, a
pre io s e posed m l imolec lar la ice ill be
formed
R K
Demons ra ion of c aneo s P B M
(dela ed- pe) h persensi i i 1944 Fa he of T an lan a ion
M c bac e i be c l i H po hesis of allograf rejec ion
Indi id als ha ere e posed
J and A
1891 de eloped a locali ed 1949
De elopmen of Polio accine
inflamma or response
Righ af er he in radermal R
injec ion of he fil ra e 1951 Vaccine agains Yello Fe er (Li e and
(organism) here is a dela ed a en a ed)
manifes a ion
D . B
P E Graf - ers s-Hos reac ion
1900 An ibod forma ion heor (AKA side 1953 In ol es he donor's T
chain heor ) l mphoc es des ro s he skin
cells of he recipien
C P and P R
Immedia e-h persensi i i (T pe 1) B
A a h la i = se ere pe of allergic Cl al Selec i The
1902
response hich is an ac e reac ion ha E plains he single B and T cells
in ol es m l iple organs recogni es an an igen ha en ers he
1957
Fa al if no rea ed promp l . bod is selec ed from he pre-e is ing
cell pool of differing an igen
N M A
A I and J L
Ar h s reac ion of immedia e
In erferon
h persensi i i
Locali ed pe 3 J D
1958-1962
h persensi i i reac ion H a Le k c e A ige (HLAs)
(ar h s reac ion)
H C
I is locali ed since he imm ne
1964-1968 T-cell and B-cell coopera ion in imm ne
comple es are ac all
coopera ion
acc m la ed in he small
dermal blood essels G M. E and R R. P
1903 Iden ifica ion of an ibod molec le
A
From mos prodiman : GAMDE
Linked cell lar & h moral heor of
IgG, IgA, IgM, IgD, IgE
imm ni
➢ IgG - mos ab ndan
Cer ain h moral fac ors
1972 imm noglob lin in ser m
( i ) coa bac eria for
➢ IgM - highes molec lar
hem o be more s scep ible o
eigh
inges ion b phagoc ic cells
Based he eigh of he
Ser m fac ors incl de
an ibod b r nning i hro gh
an ibodies & ac e phase
an l racell lar cen rif ge
reac an s
G K & R. C M
J R M
Firs monoclonal an ibodies
1938 H po hesis of an igen-an ibod binding 1975
Monoclonal - deri ed from a
AKA Imm ne comple
single paren an ibod

prod cing cell ha prod ces I F

man clones 2005 De elopmen of H man Papilloma Vir s
(HPV) accine
J P. A
1985-1987
Iden ifica ion of genes for T-cell recep or
P D PO - E
1986
Monoclonal Hepa i is B accine
R. M
Th1 ers s Th2 model of T-helper cell
f nc ion
1986 Th1 = s im la es he cell lar
imm ne response (T-cell
Th2 = s im la es he h moral
imm ne response (B-cell)
A e :B-D-A-E-C
J H nd B
a B
1996-1998
Iden ifica ion of Toll-like recep or
FO P3 - The gene direc ing reg la or T-cell

2001
de elopmen

MMAR FOR RE IE
Yea Scien i Di co e
430 BC Th c dides Recogni ion of imm ne s a s
1000 AD (1500s) Chinese Variola ion (inhaling dried po er from smallpo lesions)
1798 Ed ard Jenner Smallpo accina ion
1862 Haeckel Erns Phagoc osis
Fa he fI l g ; li e a en a ed accine, an hra accine, chicken

1862
Lo is Pas e r cholera
1885 Therape ic accina ion; Firs li e a en a ed accine for rabies
1883-1905 Elie Me chnikoff Cell lar heor of imm ni
1890 Emil Von Behring & Shibasab ro Ki asa o H moral heor of imm ni
1891 Rober Koch Demons ra ed c aneo s (dela ed- pe) h persensi i i
1900 Pa l Ehrlich An ibod forma ion heor / side chain heor
1902 Charles Por ier & Pa l Riche Immedia e-h persensi i i anaph la is
Nicolas Ma rice Ar h s Ar h s reac ion of immedia e h persensi i i

1903
Almro h Wrigh Linked cell lar & h moral heor of imm ni
1938 John Richardson Marrack H po hesis of an igen-an ibod binding (imm ne comple )
1944 Pe er Brian Meda ar Fa he fTa la a i ; Allograf rejec ion
1949 Jonas Salk & Alber Sabin Polio accine
1951 Wal er Reed Yello fe er li e a en a ed accine
1953 Dick W. Van Bekk m Graf - s-Hos reac ion
B rne Clonal selec ion heor

1957
Alick Isaac & Jean Lindenmann In erferon
1958-1962 Jean Da sse H man le koc e an igen (HLAs)
1964-1968 Henr Claman T-cell & B-cell coopera ion in imm ne coopera ion
1972 Gerald M. Edelman & Rodne R. Por er Iden ifica ion of an ibod molec le
1975 George Kohler & R. Cesar Mils ein Firs monoclonal an ibodies
1985-1987 James P. Allison Iden ifica ion of genes for T-cell recep or
Pablo DT Valen ela Monoclonal hepa i is B accine

1986
Tim R. Mosmann Th1 s. Th2 model of T-helper cell f nc ion
1996-1998 J les Hoffman & Br ce B ler Iden ifica ion of Toll-like recep or
2001 FO P3 gene (direc s reg la or T-cell de elopmen )
2005 Ian Fra er HPV accine

S ce : PPT, S c Ca e , B a d e e e e ce
P ima f ac i i i n f
UNIT 2: HUMAN IMMUNE SYSTEM imm n c m e enc . In he ima
l m h id gan , nc mmi ed cell a e
an f med in l m h id cell (i.e.
PRE-TEST h m and b ne ma )
1. A componen of he inna e defen e em e ing a he Whe e ma a i n f B & T
e e nal p o ec i e hield of he bod again coloni ing l m h c e ake lace
mic obe Seconda e e a a " aining
a. In ac Skin g nd" f he c mmi ed l m h id cell
b. M c memb ane he ein he ld mee he an igen/
c. Phag c e
d. N mal fl a gani m f eign agen .
2. La ge l mphoid o gan Si e f final ma a i n and
a. A endi diffe en ia i n
b. S leen P ide l ca i n he e c n ac
c. Th m
i h f eign an igen can cc
d. L m h N de
3. I i bo h a l mphoid and endoc ine o gan impo an in 2 l m h id gan - T n il ,
he de elopmen of f nc ional T-l mphoc e l m h n de , leen and he
a. B ne Ma a cia ed i e (i.e. m c al
b. S leen and c ane a cia ed
c. Th m
d. L m h N de l m h id i e )
4. (T/F) The e i a g ad al dec ea e in he i e and Ne k f cell , i e , and gan ha ide he b d
ec e o abili ie of he h m a one age mechani m e i infec i n and di ea e
5. (T/F) The l mphoc e a e he main le koc e C mm nica e, c llab a e, and c llec i el k
e pon ible fo he f nc ion of he L mpha ic em ge he
6. T-l mphoc e a e in ol ed in ha pe of imm ne
e pon e? Rec gni e, ne ali e and de a h gen
a. Cell media ed imm ne e n e Iden if and de cance cell
b. H m al imm ne e n e Rem al f n cell and i e damaged b
c. B h Cell media ed and H m al imm ne e n e a ma di ea e
d. Inna e imm ne e n e
Sea ch f f eign/n n elf an igen ha d n
7. Diffe en ia ed fo m of B-l mphoc e
a. Ma cell bel ng he b d & de hem
b. Pla ma cell Main ain eillance e a ea ance f ne
c. Mac hage f eign an igen m cell & de hem
d. L m h bla hile lea ing n mal/ elf an igen n heal h cell
8. Which of he follo ing cell a e capable of ecogni ing
fo eign an igen nha med
a. B-cell M n a c dina ed imm ne e n e again he
b. Dend i ic cell f eign agen
c. Lange han cell R f he d f Imm n l g
d. Mac hage
e. All f he ab e FUNCTIONS OF THE IMMUNE SYSTEM
9. (T/F) Ac i e ac i ed imm ni of confe ed o an
indi id al ho ha e eco e ed f om an illne o di ea e 1. Defen e again infec ion
10. (T/F) Pa i e imm ni p o ide lifelong p o ec ion f om Deficien imm ni e l in inc ea ed ce ibili
a di ea e infec i n (i.e. AIDS)
Al ec i e again he f eign b ance
IMMUNE SYSTEM ha a e n n-infec i
Vaccina i n b imm ne defen e and ec
Refe he L m ha ic em again infec i n
L m ha ic e el 2. Defen e again neopla m o mo
L m ha ic fl id (l m h) ha fl f m he P en ial f imm n he a f cance
l m ha ic e el c ming f m i e . 3. Inj e cell and ind ce pa hologic inflamma ion
C m nen f he l m h a e i e imila Imm ne e n e a e he ca e f alle gic,
i h bl d la ma. a imm ne, and he inflamma di ea e
L m h c e a e c ncen a ed in hi a ea
L m h id Ti e and O gan
DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

Al h gh i i ec i e in na e, in me ca e i All imm ne cell ld be c ming f m a c mm n ance -

end e eac a a ic la a h gen hich hema opoie ic em cell
can lead i e inj de ci n
Thi can al m e he eac i n f he b d
again i elf-an igen elf-c m nen ha can CELLS OF THE IMMUNE SYSTEM
lead a imm ne di ea e
4. Recogni e and e pond o i e g af and ne l
in od ced p o ein
Imm ne e n e a e ba ie an lan a i n
and gene he a
Ti e g af - i e c ming f m a
diffe en e n an fe ed
Re n ible f ejec i n f all geneic gan/ i e
an lan & g af - e -h di ea e
CELLS of he IMMUNE SYSTEM
Cell f nd in e i he al bl d: monoc e, ne ophil,

eo inophil, ba ophil and l mphoc e
O he cell f nd in i e : ma cell , mac ophage ,
an igen-p e en ing cell , na al kille cell
PROFESSIONAL PHAGOCYTES
(l m h c e-like cell f inna e imm ni )
The e cell ec e e m lec le f l m lec la eigh Ne ophil Monoc e Mac ophage
c m ed f e ide /gl c ein kn n a c kine
C e eg la e he f nc i n f he imm ne Mic o copic
em (i.e. ind ce life a i n f he cell , Appea ance
eg la e he cell , and e e a me enge )
Relea ed b T l m h c e
I can al be d ced b he cell ch a
PMN hag c e M n n clea hag c e
end helial cell and fib bla
T pe of WBC G an l c e Ag an l c e
Di ib ion Ci c la i n and Bl d Ti e
Ma gina ing l ci c la i n (ha e ecific
name
de ending n
hei i e
di ib i n)
T pe of F a ed S ained Facili a e
Phagoc o i Phag c i Phag c i
Chemo ac ic 1. Bac e ial 1. T an f ming G h
Fac o li eich ic acid Fac
2. C e ide - C5a 2. M n c e Chem ac ic

3. Le k iene B4 P ein 1 Chem a in a e elea ed d e

4. Ma cell 3. RANTES (Reg la ed n he b eaking f he kin and en f
de i ed Ac i a i n, N mal T Cell he a h gen (i.e. C5A,
chem ac ic E e ed & Sec e ed) c m lemen 5A, e ence f
e ide CCL5 - Le c e ac a bac e ial/ i al ein , ein
5. Ne hil aee ed a e c ming f m he c ag la i n
chem ac ic a ca cade, & he c kine
e ide 4. Mac hage Inflamma ec e ed f m imm ne cell ).
(In e le kin 8) P ein P e ence f nin ece
Enhance hag c i b c a ing f eign
Op onin Recep o
b die (an igen) ld all ea de ec i n
Fc𝝲R IgG P e en P e en b he imm ne cell (i.e. hag c e )
Fc𝝲R IgG an ib d
CR1/C3b/C4b/ P e en P e en
CR1/C3b/C4b/CD45 C3b nin
CD45
(c m lemen c m nen )
CRP ece P e en P e en CRP Rece C- eac i e ein
(+ T ll like ece ) Reca n Monoc e
Recep o fo Ab en P e en La ge WBC e en and ld ha e a
T mo kidne -/h e h e- ha ed n cle
Nec o i Ha d ll g a i h bl e c la m i h a g nd-gla
Fac o (TNF) a ea ance
and IFN𝝲 P e ence f d -like g an le c n aining: l mal
g an le , -gl c nida e, l me, li a e
Life pan Sh li ed L ng li ed O he e en : acid h ha a e & a l
Addi ional no e f om i Al in: lfa a e (n alkaline h ha a e e en )
Reca n Ne ophil : S b e :
AKA l m h n clea ne hilic (PMN) le k c e C a ca /I a a m n c e
Maj i f hi e bl d cell f nd in he PB ec i ed he i e f inj infec i n
Main f nc i n = f a ed/facili a ed hag c i N -c a ca im an f i e e ai
ince in ce ain ca e , ne hil i nable and can be f nd in he lining f he bl d
c m le el eng lf he a h gen (Kamika e cell ) e el (end heli m)
T c m le el kill he f eign b d , i ha Af e a fe h ,m n c e ld mig a e
elea e i g an le i e and ld bec me mac hage
P ima /a hilic g an le ch a Mac hage a e m e en hag c e
m el e ida e (MPO), l me , c m a ed m n c e
ela a e, defen in Di ad an age: mac hage l in
S ecific/ ec nda g an le ch a m emen = le efficien
lac fe in, c llagena e, gela ina e, B h a e in l ed in ained/facili a ed
e ia b c m nen e c. hag c i
O he f nc i n : able nde g diapede i Reca n Mac ophage
( a e e he bl d e el & en e i e ) Mac hage = m e en han ne hil
P ce e f dia ede i cc : elec in Q ie l in m emen
a e ed f he lling and in eg in a ach T e :
ICAM Re de f nd in ce ain a fb d
The fi imm ne cell each he i e f Ta e can m e f m ne lace
inj i he ne hil an he
In ac e inflamma i n, ne hil ill be he C kine elea ed b mac hage :
ed minan cell T m nec i fac (TNF) - m e
M emen i media ed b he elea e f inflamma i n
chem a in . IL-1 - ind ce inflamma i n
Chemical me enge ha ca e IL-6 - m e ec e i n f C- eac i e ein
cell mig a e in a a ic la (CRP )
di ec i n IL-12 - ac i a e NK cell de i al

agen / m b ec e ing in e fe n 𝝲 Eo inophil Ba ophil Ma Cell

Mac hage f nd in diffe en a f he b d :
Mc a B ain
K e ce Li e
A e a ac a e L ng
S da ac a e S leen
H c e C nnec i e i e
O e ca B ne
Af e hag c i , i b eak d n he e ide be Ha hag c ic Smalle Re emble he
an an igen-p e en ing cell ac i n g an l c e Ba hil
Cell ha e MHC cla 2 m lec le Fi line f S im la e B cell F nd in
ed e en ce ed an igen defen e again d ce i e and
(deg aded malle l e ide m lec le ) helmin hic an ib die ha e
APC e en an igen T cell infec i n Lea in he l nge life
T cell ill n ec gni e an igen Alle gic e i he al bl d an
ha d n ha e MHC cla 2 eac i n C a e C me f m
m lec le Reg la e he ba hilic a diffe en
T hel e cell = CD4+ imm ne g an le lineage
Monoc e & Mac ophage e n e c e ing he Can enhance
Once he m n c e lea e he bl d e el , i Reg la e ma n cle and e
an f m bec me a mac hage cell he a in & he ada i e
T ll like ece able ec gni e ma ke f Im an hi amine imm ne
a h gen ( ecific hi fall nde he ac i ed c m nen : P e ence f IgE e n e
imm ni ) Maj ba ic ece and "Sen inel f
Ma ke a e c llec i el called a PAMPS ein c m lemen i e "
(Pa h gen a cia ed memb ane ein ) ece G an le
PAMPS a e f nd n he face f c n ain: ACP,
he f eign mic bial agen ALP,
In l ed in inna e imm ni ea e ,
hi amine
Ab ndan IgE
OTHER FUNCTIONS OF TISSUE MACROPHAGES ece
Inna e Imm ne F nc ion Adap i e Imm ne F nc ion Relea e inflamma media ha

facili a e alle gic eac i n in he kin,
1. Mic bial Killing An igen P e en a i n e ia , & in e ine
De f eign b die Once mac hage
b elea ing l mal inge f eign b die , i
ein , gen ld b eak i d n DENDRITIC CELLS
adical , e c. malle f agmen . The
F nd in l m h id i e & in e i ial egi n f he gan
De ing b ida i e f agmen ill be
C n i f l ng e en i e dend i ic c la mic ce e
b e e ed he face
ich in MHC cla II m lec le
2. In acell la Pa a i e Killing f he an igen- e en ing
P ofe ional An igen P e en ing Cell
3. An i- m Ac i i cell (in he f m f
P ce ed an igen in he f m f a e ide be
4. Inflamma i n e ide )
e en ed T cell (ei he hel e c ic cell )
5. The m eg la i n Pe ide a e a ached n
C o p iming: diffe en mechani m n
6. Healing (Ti e e ai ) he MHC cla 2
h i ce e and deg ade an igen
7. Phag c i P e en ed T-cell and
ince MHC cla 1 i de ec ed (f nd in
8. Sec e i n f cell media B-cell
n clea ed cell )
F m d la i n f Nece a f T cell
Onl cell ca able f c iming
inflamma ce e im la i n & ind cing
F i be e en ed, i h ld be a ached an MHC
cell-media ed imm ni
(maj hi c m a ibili c m le ) 2
Mo effec i e APC in he bod , he a e:

Mac hage , B-cell , Va c la End helial NATURAL KILLER CELLS

cell , Va c la e i helial cell , &
Me ench mal cell Thi d P la i n cell / La ge G an la L m h c e
P e e he m n mbe f MHC cla 2 m lec le Cla ified a G o p 1 Inna e l mphoid cell
am ng he he APC AKA ce - ab ence f face ma ke ha ld
Mo po en phagoc e iden if hem a T- B-l m h c e
Unde he mic c e, he ld jec l ng N C4 and CD8 ma ke in ead he ld
e en i n , hence, dend i e ha e CD16 and CD56 face ma ke
Ca e, T an and P e en an igen T l m h c e P imi i e T C ic cell
Ma e in he b ne ma
C n ain kidne - ha ed n clei i h c nden ed ch ma in &
minen n cle li
F nd mainl in he li e , leen & e i he al bl d
Can gene a e highl ecific mem cell ecific an igen
Wi h T mo icidal and An i i al ac i i
De i all infec ed cell & m h gh ind c i n
fa i
Al de e ed cell ( a iall damaged)
Inc ea e in e le kin and in e fe n = m e NK cell
➢ Cla ical/c n en i nal DC m ab ndan DC Kill a ge cell e en i h i e e b elea ing
➢ Lange han DC f nd in he kin g an me and e f in A i
Follic la DC - diffe in f nc i n ince i i able MHC - Un e ic ed C l i C ic eac i n
e en an igen B cell in ead f T cell An ib d De enden Cell Media ed C ici (ADCC)
M l f nd in ec nda l m h id gan
(c ical egi n f l m h n de ince B cell
e ide in he c e , hile T cell a e in he
a ac e )
➢ Pla mac id DC l k like la ma cell ; N ha
hag c ic b i im an in he elea e f T e 1 IFN (f
an i i al defen e)
E en all ma diffe en ia e in cla ical DC
➢ Inflamma DC
IMPORTANT RECEPTORS
Kille Inhibi o Recep o Kille Ac i a ion Recep o
1. KIR - Kille Inhibi ind cing a i he a ge
Rece cell ( i all -infec ed m
Reg la e he ac i n cell ):
f NK cell 1. CD16 - Fc ece f
P e en killing f elf IgG; f elec i e l i f
F m he i e he e DC enc n e ed he an igen, APC cell b de ec ing cell c a ed i h
ec nda l m h id gan e en i T-hel e cell he he he cell an ib die (im an in
In me ca e , APC ma e en hi he leen hen a ge ed b NK cell me h e en i i i
an igen a e e en ed in he bl d a e n mal/abn mal eac i n )
N mal cell ld 2. NKG2D
ha e MHC Cla I NOTE:
m lec le n he B h ece bind
face f he cell. If di ea ed and cance cell

he NK cell de ec (cell d cing e ADCC (An ibod Dependen Cell-media ed C o o ici )

ab ndan MHC 1, i ein )
ill n de he Abn mal e cell
cell. a ge ed b KAR: MIC A &
2. CD94 / NKG2A MIC B. Whe ein, CD16 &
Bind MHC Cla I NKG2D ld bind and
KAR i n ac i a ed m ea i
nce KIR ec gni e Rende l e MHC
MHC 1 cla 1 = n n mal
cell
N mal cell ha e
man MHC cla
ADCC i a maj mechani m f killing m cell b
he a e ic an ib die
In ADCC, he killing f NK cell i b an ib d -de enden
( nl eac a a ic la a h gen hen hi i coa ed i h
an ibodie )
CD16 ma ke n he face f he NK cell ill bind
he an ib die f nd n he face f f eign
agen
CD16 i a Fc ece hich bind Fc i n f he
an ib d
Once binding f CD16 + Fc i n f he IgG
an ib d ill e l he elea e f he en me
leading he de c i n ia apop o i
ADCC i n e cl i e NK cell
Thi mechani m f killing can al be een n
m n c e , mac hage , ne hil , and K- e
l m h c e
1. N clea ed cell c n aining MHC Cla 1 hen infec ed b a
i ld al e he cell and ed ce he MHC n i face
2. MICA and MICB ma ke a e d ced a a e l #1 T & B LYMPHOCYTES
3. Once NK cell ha ei ed he i all infec ed cell , i ill
n ice he e ence f MICA and MICB and a e l
am n f MHC Cla 1
4. Thi ld ac i a e he NK cell de he cell
ADDITIONAL NOTE:
If he n clea ed cell i n abn mal, ha an ab ndan MHC,
and n MICA and MICB, NK cell ill n de i
Thi i eg la ed b he KIR m lec le a ached n
he NK cell
NK cell a e al able ec e e IFN gamma m e he
ac i a i n f mac hage

Addi ional no e f om i Al in: P ec cell: l mphoid em cell

1. Onl cell ha e e he cl nall di ib ed an igen a. P h m c e (T-l m h c e ec )
ece hich i f nd n he face f he cell b. P -T cell (d ble nega i e h m c e )
TCR = T-cell ece c. P e-T cell (d ble ii e h m c e )
An ib d = B-cell ece d. Ma e T cell
2. Unde he mic c e, b h cell a e diffic l diffe en ia e. CD4+ T cell
B b ing an elec n mic c e, he face can be CD8+ T cell
iden ified a : Ma a i n ake lace e 3 eek
B-cell gh face In l e h mic mal cell (e i helial cell , mac hage ,
T-cell m h face fib bla , dend i ic cell ) in de el men
3. M e c mm n a di ing i h i ia face ma ke (CD In e ac i h ne an he (e eciall IL-7) f
cl e f diffe en ia i n) g h & diffe en ia i n
ONTOGENY OF T & B CELLS

Addi ional no e f om i Al in:
1. F m he BM, p ec o (LSC) ill mig a e he h m nde
he infl ence f c kine
C e e = la ge famil f c kine ha ha e
he abili ec i ecific cell a a ic la i e
2. Once i en e he h m (c ic med lla j nc i n), i ld
n bec me a p o h moc e
In hi age, i ill n a f m he T cell
ece (TCR)
3. Do ble Nega i e S age: In he c ical egi n f he h m , he
cell ill ac i el life a e and bec me a (--) h moc e nde
he infl ence f c kine (IL-7)
B h cell ld be c ming f m a ingle a en cell -
D ble nega i e h m c e - nega i e f b h CD4
c mm n l m h id ec in he b ne ma
and CD8 ma ke
On he B-l mphoc e lineage
D ing hi age, TCR i n e e ed e
B-cell ld emain in he BM ma e and
CD3/TCR c e - c m ed f eigh
e en all make hi ac i a ed, i ill m e he
chain incl ding al ha & be a chain
ec nda l m h c e mee f eign an igen
O he i chain n n ecific
On he T-l mphoc e lineage
CD3 i n; a i in ignaling
Diffe en ia e in he h m and ld m e f m
hen an igen bind T cell
he BM Th m
a. Del a-e il n
Thi ill mee he f eign an igen in he
b. Gamma-e il n
ec nda / e i he al l m h id gan
c. Ta - a
In he ec nda l m h id gan
Rea angemen f he gene ha c de f al ha
T-cell and B-cell ld an f m effec cell
and be a chain f he TCR ( ed minan in hi
S me effec cell mem cell
age)
S me B-cell la ma cell
Rand m gene a angemen all T cell
ONTOGENY of T - CELLS e nd diffe en an igen ha b d
migh enc n e
Be a chain ch m me 7
Al ha chain ch m me 14
Al ha & be a chain c n ain a iable
egi n ha ec gni e ecific an igen
A ea ance f be a chain igge
h m c e bec me CD4+ and CD8+
➢ Ga a de a T-ce - e e gamma & del a
chain in ead f be a chain
Remain nega i e f CD4 & CD8
P minen in kin, in e inal & lm na
e i heli m

F nd healing & ec i n d ced b med lla e i helial

Ca able f ec gni ing an igen ih cell
being e en ed b MHC ein Again, if he e i ng
4. Do ble-Po i i e S age: A i de el i ill diffe en ia e in a eak eac i n, he cell ill be
(++) h moc e elimina ed ia a i
D ble ii e e e e b h CD4 & CD8 All ha emain in b h elec i n , ld e e en a
Being ea anging gene c ding f al ha chain la i n f a f nc i nal T cell ha ing b h CD4+
Take n e: he CD ma ke a e al being and CD8+ (a 2:1 a da a )
e e ed in hi age (i.e. CD2, CD3, CD5, CD7) 5. CD4+ and CD8+ T cell a e c n ide ed a Ma e T cell
Wi h he e ence f CD3 hich i in l ed in he
- Bind MHC c a II m lec le n APC
f ma i n f TCR, indica ing ha in he DP age
he e i al ead he f ma i n f he TCR
1. T-helpe cell ( b e : Th1 and Th2)
TCR i ea anged d ce ein
Th1 d ce c kine ch a IFN
ece ha a e in a ian in hei an igen
gamma, IL-2, and TNF be a hich can
ecifici f he life an f he T
ac n in acell la pa hogen
l m h c e
Ac i a e mac hage and T
CD3 ein = a i in an d c i n f
c ic cell
ignal in e i f cell hen an igen bind
Facili a e dela ed- e
TCR
h e en i i i & d ci n f
Onl f nc i nal T cell a e able i e in hi
an ib die ih ni ing ac i n
age
Th2 d ce c kine ch a IL-4,
P e e ec i al f cell ha
IL-5, IL-6, IL-9, IL-10, IL-13 hich a e
d n ec gni e elf an igen . Onl he T
in l ed n e acell la pa hogen
cell i h f nc i nal TCR ill i e
( i h he hel f B cell ince an ib die
Take lace in he c e
a e a ached i )
B h h ld be i i e f CD4
H m al e n e
and CD8 (2:1 a i )
Reg la e B-cell ac i i
F nc i nal TCR h ld ha e an
Ac i a e e in hil
in e media e eac i n MHC 1
Di ec l n he i e he
2 (n ng n
an ib die (e : IgG)
eak). If he e i a e eak
CD4+ ➢ Th9 d ce IL-9 f inflamma
ng eac i n, i ill be
effec (a imm ne inflamma ion)
elimina ed ia a i . Da a
Wa d ff f ngi & e acell la
a a a a a ab b a
bac e ia a e i helial face
a ; Wa da aba a
S im la e g h f
a aa
hema ie ic cell
Binding i h elf-MHC an igen
➢ Th17 d ce IL-17 & IL-22 hich
b TCR en me ca cade ( i h
inc ea e inflamma i n & j in de ci n
kina e ) change cell ha e &
A cia ed i h he ma id
m ili inc ea ed cell i al
a h i i , m l i le cle i &
➢ MHC e c = elec i n f
inflamma b el di ea e
h m c e ha ill nl in e ac
i h MHC an igen n h cell
2. T- eg la o cell (Ma ke : CD25)
CD4+ in e ac i h MHC 2
Im an f balancing/ eg la e he
CD8+ in e ac i h MHC 1
imm ne e n eb e ing he T
Ne a e e ec dea h f cell ha
cell i elf-an igen ( ia ec e ing
ec gni e elf an igen . Th e ha
inhibi c kine )
i ed in he i i e elec i n a e
F imm ne le ance & e en ing
bjec ed hi
a imm ne di de
Take lace in c ic med lla
D i en b IL-2 ( ia CD25) & FOXP3
egi n & med lla
an c i i n fac
Te ed again i elf- e ide
( he han he MHC m lec le)

- In e ac i h MHC c a I m lec le he e CD4+ cell can al ac i a e CD8+ cell

1. T-c o o ic cell (mem T-cell )
CD8+
Di ec l kill he i all infec ed cell ia Mem T-cell Inac i e b hen he a h gen
a i a i e i ill hen be ac i a ed
Remembe : T-c ic cell in e ac i h cell ha ing MHC

cla 1 m lec le f di ec killing (a i )
ONTOGENY OF B CELLS
Ma e /diffe en ia e in he B ne Ma
B ne ma mal cell f m ecial niche
he e em cell & B-cell ec e ide (kee
B-cell ec l cali ed ecei e ignal f
diffe en ia i n)
In he BM, he e ill be he de el men f imma e,
imm n c m e en B-cell
Imma e cell a e in l ed in he an igen
Independen ha e f de el men
D n need he e ence f an igen de el
Once ma ed, hi ill be he ime he e he cell
ill ha e he an igen Dependen ha e (ha en in
he 2 l m h id i e )
Remembe : T-hel e cell ld nl in e ac i h cell ih Th ee Di inc Pha e f B-Cell De el men
MHC cla 2 m lec le ( e en in APC ) ia he TCR and 1. De el men f ma e imm n c m e en B cell
CD4 ma ke (An igen-Independen pha e)
Wi h he elea e f c kine (IL-2), n nde g e cl nal 2. Ac i a i n f B cell b an igen
e an i n (An igen-Dependen pha e)
Cl nal e an i n - dada 3. Diffe en ia i n f ac i a ed B cell in la ma cell
CD4+ T-hel e cell (effec al ead ) can ec e e hich d ce an ib die
IL ec i mac hage and ne hil . S me f

P ec cell: L mphoid S em Cell CD40 and MHC cla 2 im an f he

P -B cell in e ac i n i h T-hel e cell
P e-B cell Abe an imma e B cell ill be elimina ed ia
Imma e B cell a i
Ma e B cell Abe an B cell ha d ce an ib die
again elf-an igen
Addi ional no e f om i Al in: Ce a e a ce = elimina i n f B cell ha
1. LSC ill diffe en ia e in PRO-B CELLS in he e ence f bea elf- eac i e ece
g h fac (EBF, PAX5, IFR8, IL-7 e c.) and c kine 4. In he ec nda l m h id gan ( leen), i ill n bec me
Ma ke e en : CD34, CD19, CD10, CD21 a MATURE B CELL
Remembe : CD19 ne f he im an ma ke S a f he an igen-de enden ha e
iden if B-cell lineage IN THE SPLEEN
En me: i i e f TDT (im an f gene ac i a i n) Ma e B-cell ld emain in he leen and
In hi ha e, ea angemen f he gene needed f e med a ma ginal one B cell
he f ma i n f he hea and he ligh chain f Check f he e ence f an igen ha
B-cell ece ha en c ld a h gh he bl d
Gene needed f he d c i n f he B-cell Follic la B cell ill e ide in he l m h n de
ece , be e e ed n i face, and he ec nda gan
ha en d ing he P -B C n an eci c la i n h gh
Hea chain ch m me 14 ec nda l m h id gan
Ligh chain ch m me 2 & 22 Ma ke : CD19, IgM and IgD
C-ki ece in e ac i h em cell IgM & IgD ide ima ac i a ing ignal
igge he ac i a i n ce f hi B cell hen c n ac ed i h an igen
ea angemen f gene IgD ma l ng life an f ma e B cell
Onl -B cell ha cce f ll ea anged In hi age, l mphoc e capping cc
ne e f hea -chain gene g n bec me
e-B cell
2. Af e he ea angemen f he gene (hea & ligh chain ),
PRE-B CELL ill a i e f m hi
C m nen f BC ece : fi hea chain f med
(M chain)
In hi age, he M chain (hea ) can be
acc m anied b a em a / ae
c a (n e e manen c m nen f BCR)
e med a p e-BCR (p e-B cell ecep o )
In hi age, M chain can ill be e en in
he c la m a ide f m i e ence in he
face f he B cell
Ma ke : CD19, CD20, TDT, M chain
3. E en all i ill n bec me an IMMATURE B CELL
Di inc fea e: e ence f c m le e BCR
Pe manen hea and ligh chain
IgM i n e en n he face
N m e M chain in he c la m
Rea angemen f gene f ligh chain n
ch m me 2 22 ake lace cell can
d ce an ib die i h ecifici f a ic la
an igen
Ma ke : CD19, CD21, CD40, MHC cla 2 and
e ence f IgM in he face
CD21 im an f ce ain c m lemen
c m nen (i.e. C3D); enhance likelih d f
c n ac be een B cell & an igen

Once he ma e B-cell mee an an igen, i bec me

ac i a ed. If ac i a ed, i ill nde g bla age
Bla age - dada ac a ed beca e
e ed a a hen an igen bind face
an ib die
Once ac i e, diffe en ia e in la ma cell ha
ec e e an ib die and me ill emain be
mem B-cell
Mem B-cell can be eac i a ed nce
he mee he ame an igen again
Ha e face ece f c m lemen (CD21) and f he
Fc egi n f imm n gl b lin (CD19 & 20)
Ma ke of ac i a ed B-cell: CD25 SUMMARY OF MARKERS
S b e f B-cell: Tl m h c e
B1 = C mm n ma ke + CD5 All T-hel e cell CD2 (e e e)
Reac i h c mm n mic bial agen
B2 = C mm n ma ke + Di e e ma ke (f nd in C mm n ma ke f TCR CD3
m ad l ) T-hel e and T- eg cell CD4
M e di e e in d cing an igen
T-c ic CD8
ece and e nd m e effec i el
T-de enden an igen Bl m h c e
C mm n ma ke f B cell CD19
SUMMARY OF T and B LYMPHOCYTES
P -B cell CD19
P e-B cell M chain and CD41
Ac i a ed B cell CD25
Mem B cell CD27

P e-B cell : a ea ance f m chain
Inc m le e BCR (c m le e: hea and ligh chain in
he f m f IgM)
CD41 l m h n de i e IgD ma ed
(l m h c e ha )
Ac i a ed B cell : CD25 ( life a e , cl nal e an i n
Pla ma cell )
Pla ma cell - eciali ed B-cell ha ec e e
an ib die (n CD19 hich i a c mm n ma ke f
B cell )
C mm n ma ke : IgD m lec le , CD19, CD21,
mi gen ece
Mem B cell : CD27
P d ce an ib die : di ec l in l ed in h m al
TAKE NOTE:
imm ni
Nai e L m h c e ha ha e n me an an igen
Ac i a ed nce i eache he ec nda l m h id gan
ince he mee he f eign b d he e PLASMA CELLS
Ac i a ed l m h c e ld ha e a high f e enc f
eac i n a ecific an igen S he ical elli idal cell
T-c o o ic - ec e e c kine f c ic ac i i Eccen icall l ca ed n cle ( ag n heel, ke
Ac i a ed B cell ( la ma cell ) a e able ec e e f a bic cle a ea ance)
an ib die C n i f ab ndan c la mic imm n gl b lin and
li le n face imm n gl b lin

L ca ed in ge minal cen e in e i he al l m h id gan

b ne ma (l ng li ed in BM b mal cell )
Once B-cell a e ac i a ed, me f i ld bec me la ma
cell ca able f ec e ing an ib die
Sec e i n f Imm n gl b lin
Effec cell f B-cell
M f ll diffe en ia ed l m h c e
Di inc fea e: e ence f a ale a ea - Hoff egion
C e nd he g lgi a a a f ackaging
Ma ke : CD138, CD78, CD126 (IL-7 ece )
N CD19 ma ke (di inc nl f B cell ) and CD20
Memo cell
Can emain ie cen f l ng e i d b if he b d
ld mee he an igen he 2nd ime a nd, mem
PRIMARY LYMPHOID ORGAN
cell a e ac i a ed a idl
Ma ke : CD27+ BONE MARROW / MYELOID TISSUE
FOLLICULAR DENDRITIC CELLS Bi h lace f all hema ie ic em cell ( ed b ne ma )

Fill he c e f all l ng fla b ne
Di inc fea e :
La ge gan a bi h
L ng ce e
P ec cell life a e and ma e a ind ced b
P e en in he ge minal cen e f l m h id f llicle
C kine (E . C-ki , IL3, IL7, CSF , Fl -3 ligand)
Di la an igen ha im la e B cell diffe en ia i n
C- = em cell fac
No e: Thi i diffe en f m he dend i ic cell hich a e
IL3 = d ced b T cell
im an f APC he T cell
IL7 = ind ce T cell de el men
F llic la dend i ic cell - APC B cell hich i n
F -3 = a ge dend i ic and B cell
he al ca e f he dend i ic cell
L m h c e em cell f m BM a el he ima
Ca e Ab-Ag c m le e ing hei Fc ece
l m h id gan he e f he ma a i n ake lace
f nd n i face
S me l m h c e ec emain in he ma
ma e and bec me NK & B cell
FUNCTIONAL COMPARTMENTS
ORGANIZATION OF THE IMMUNE SYSTEM
A. S em Cell / Gene a i e C m a men
B ne Ma
B. P ima / Cen al L m h id
A ea he e imm ne cell ac i e
imm n c m e enc THYMUS
Si e f an igen inde enden l m h ie i Bil bed gan and i l ca ed ab e he hea & bel he
Th m ma a i n f T-cell h id gland
B ne Ma P d ce HSC and Child en ha e la ge h m b a eg lde i
ma a i n f B and NK cell h ink (a i )
C. Sec nda / Pe i he al L m h id Si e f de el men f f nc i nal T-cell
Si e f an igen de enden diffe en ia i n Each l be i di ided in malle l b le
Enca la ed Co e : Imma e h m c e and h mic c ical
Unenca la ed (e.g. C ane IS, e i helial cell
MALT)

Th mic c ical EC - able d ce IL-7 L m h fl l l h gh in e lined i h mac hage

f T-cell de el men (ideal f hag c i )
Med lla: Ma e T-cell & APC A. Co e : B-cell a ea and mac hage
Ha a c c e - c ncen ic c e P ima F llicle:
ha i ni e f he h m (c m i i n: N ge minal cen e and c n ain
h mic e i helial cell la le in C n ain Re ing / Nai e cell
diffe en ia i n f T cell ) Sec nda F llicle:
P d ce c kine ha can eg la e Wi h ge minal cen e ( he e B cell
dend i ic ac i i an f ma i n ake lace)
The : ca able f em ing a ic C n ain P imed B-cell
h m c e C n ain f llic la dend i ic cell
Onl a nd 3% f he imi i e h m c e bec me ma e E hibi la ge n mbe f ece f
an ib die
Hel ca e an igen e en T&B
cell
B. Pa aco e : T-cell a ea f he l m h n de
In-be een he c e and med lla
In e digi a ing cell : APC al e en in hi
a ea i h cl e imi T cell
C n ain dend i ic cell
H e d e a e e - en le he e
l m h c e ma en e he n de ia bl d eam
C. Med lla
P ima il c n ain me T cell , B cell and
mac hage
Med lla Co d: ab ndan la ma cell
SECONDARY LYMPHOID ORGAN

P ide an en i nmen he e imm ne cell can in e ac
i h f eign agen
An igen de enden diffe en ia i n
O gan in l ed:
Enca la ed gan : pleen and l mph node
N n-enca la ed: M c a-a cia ed l m h id
i e (MALT) and C ane -a cia ed l m h id
i e (CALT)
LYMPH NODE
Cen al c llec ing in f l m h fl id f m adjacen i e Addi ional no e f om i Al in:

L m h fl id = fil a e f bl d f m a age f a e Ge minal cen e f fleming f nd in he ec nda f llicle f
&l m lec la eigh l e in in e i ial ace he c e
C llec ed b l m ha ic e el P e ence f cen bla and cen c e
C nnec ed l m ha ic e el ia l m ha ic d c Ce b a - ac i el di iding B-l m h c e
N me nea j in & he e a m and leg j in he b d Ce c e - e en in he ge minal cen e ha
Fil e he l m h f i im i ie & i e f in e ac i n i h ha e al ead ed di iding; elec ed f f he
f eign agen diffe en ia i n
Ideal f gene a ing B-cell mem

R e f l m h fl h gh a l m h n de: LYMPHOCYTE TRAFFIC/RECIRCULATION

a. Affe en l m ha ic e el
Te m emembe :
b. S bca la in
H mig a i n f le k c e a a ic la
c. T abec la in
i e/ a i e f inj
d. Med lla in
M a /Rec e Bl d Ti e
e. Effe en l m ha ic e el
Rec c a Re ea ed h ming he ec nda
Nai e T cell ld en e he l m h n de ia high
l m h id i e and emain he e em a hen
endo helial en le
back ec nda
While l m h c e can en e ia he affe en
M emen f l m h c e f m he bl d he l m h id
l m ha ic e el
gan and back he bl d
SPLEEN M emen i media ed b c kine and adhe i n
m lec le n he e el he e he imm ne cell
P e en in he e lef ad an bel he dia h agm
c ld a h gh
S nded b hin c nnec i e i e ca le
Refe he mig a i n f l m h c e f m he cen al
Fil e bl d f i im i ie
l m h id gan i e , ia he bl d eam, in de
P ec he b d f m f eign an igen in he bl d
e f m hei f nc i n
Rem e effe e RBC, imm ne c m le e ,
Cell c n in l eci c la e h gh he b d eek
ni ed mic be f m ci c la i n
, ec gni e f eign agen
Ini ia e in e ac i n f imm ne cell bl d b ne
MECHANISM
an igen
Mig a i n f imm ne cell in l e in e ac i n f
La ge ec nda l m h id gan
m l i le adhe i n m lec le e en n cell
face i h hei ligand n end helial cell
2 Main T pe of Splenic Ti e
e mi affic f m he bl d eam in he l m h id
1. Red P l de c i n f ene cen RBC
i e and inflamma ie
C n i f m e han half f al l me
RBC en e f m a e i le & e i ia lenic ein
2. Whi e P l c n ain l m h id i e
Pe ia e iola L mphoid Shea h (PALS): T-cell
a ea a anged a nd he a e i le
P ima f llicle a e a ached he e
PALS
P ima F llicle: n im la ed B-cell a ea
Ma ginal Zone: Dend i ic cell a ea ( a an igen )
Med lla Co d: Pla ma cell a ea
N ce: leen d e n' ha e a high end helial en le, nl
he l m h n de ha e hi
1. The nai e T-cell f m he bl d a e h he high

NON-ENCAPSULATED LYMPHOID ORGANS end helial en le f he l m h n de
Cell la c m nen a e n gani ed in CT ca le Effec and mem T cell ill en e f m he
MALT (M co al A ocia ed L mphoid Ti e) bl d i e ia en le he i e f inj
B nch A cia ed L m h id Ti e (BALT) 2. A cell a h l m h id gan , l m h c e ld
T n il & Aden id c n ain chem kine ece (i.e. CCR7 in nai e)
G A cia ed L m h id Ti e (GALT) Tl m h c e ill in e ac i h adhe i n m lec le
A endi & Pe e ' Pa che f nd in he e el (i.e. elec in and in eg in)
CALT (C aneo A ocia ed L mphoid Ti e) 3. Once he nai e T-cell mee he an igen, he ill e i ia he
P e ence f Lange han cell (dend i ic f kin) effe en l m ha ic e el and g e he i e f infec i n
M cell (mic f ld cell ) f nd in MALT im an in ini ia ing In he pleen:
m c al imm ni and can ake an igen in he m c a M emen f T cell i n c m le el defined (n
and ill hen be an ed he l m h id gan in l emen f elec in and in eg in

NATURAL/INNATE/NATIVE IMMUNITY
Inhe en and al a e en in a heal h e n
I e n e i n n- ecific, gene al and anda di ed
I ece ( a e n ec gni i n ece = ha ec gni e
a h gen a cia ed memb ane ein and e en damage
a cia ed m lec la a e n ) a e iden ical and a e
e e ed b a a ic la e f cell
Pa e n ec gni i n ece can ec gni e
PAMPS een n he face f mic bial agen
Once he cell ec gni e he PAMPS, a
eac i n ill cc b i i ne- i e-fi -all
ince i i gene ic
Can al ec gni e DAMPS
C m nen a e ef med - e in lace a a e e c
I d e n eac again he n mal h
I mechani m f defen e e-e i he in a i n f he
f eign agen
N i e e i needed
Lack imm n l gic mem
Same ced e i h T cell eci c la i n b B cell ill ha e

a CXCR5 chem kine ece in ead f CCR7
IMMUNITY
MAJOR PILLARS OF IMMUNITY
Inna e Imm ne S em (Na al imm ni )
N n- ecific, in-b n imm ni em
Gene ic n eciali ed and eac he
agen nl a fe h
Fi e in h defen e again infec i n
If he inna e imm ni cann de he
f eign b d , ada i e imm ni ill en e
Adap i e Imm ne S em (Ac i ed imm ni )
C m le em ha m n a ecific imm ne
e n e a d f eign agen (an igen)
In l e he T can B l m h c e 2 P inci al e f eac i n f he inna e imm ne em:
Inflamma ion and An i i al defen e
LINES OF DEFENSE OF THE IMMUNE SYSTEM E e nal defen e mechani m
In e nal Defen e Mechani m

EXTERNAL BARRIERS TO INFECTION (1 Line) INNATE DEFENSE SYSTEM
E e nal Defen e S em - h ical, chemical, and

bi l gical ba ie ha f nc i n e en m infec i
agen f m en e ing he b d
PHYSICAL BARRIERS TO INFECTION
Skin (S a m c ne m)
P ide a h ile en i nmen nfa able f
bac e ial c l ni a i n and g h
S c al Fea e
Ke a in c m nen f he S a m c ne m
make kin im e meable m infec i
agen
Ce amide
Chemical Ba ie
Lac ic acid f m ea (acidic H kee m
mic gani m f m g ing)
Seb m, fa acid f m ebace gland Ph i l gic fac
Al ha & Be a defen in , Ca helicidin B d em e a e
P ia in = ein i h an ibac e ial effec O gen en i n
(e eciall G am-nega i e bac e ia) H m nal balance
C mmen al O gani m (mic obio a/no mal flo a) Ba ic l e ide - ac n mic be
N mall f nd a ecific b d i e and d n icall S e mine - inhibi G (+) bac e ia
ca e di ea e Defen in (al ha & be a) - c m nen f ne hil
Ca helicidin
INNATE DEFENSE MECHANISM S fac an A & D
In e fe n - m lec le ha limi ead f i e and i al
e lica i n
Bl ck an la i n f i al ein
T pe I IFN (al ha & be a) - d ced b la mac id
dend i ic cell and i infec ed cell , fib bla
C m lemen em c llec i n f ci c la ing and memb ane
a cia ed ein ha media e inflamma e n e
O ni a i n, cell l i , inflamma i n
Mechanical ba ie Pa h gen ec gni i n ece (PRR )
Pe i al i in he in e ine F di ing i hing a h gen f m n mall e en
V mi ing efle m lec le in he b d
Shedding f cell F nd n ne hil , m n c e , ma cell , T cell &
C ghing and nee ing e i helial cell
Fl hing ac i n f ine Binding i h an igen ac i a e hag c ic cell eng lf
P e ence f n mal fl a & elimina e mic gani m
Chemical ba ie Ac e ha e ein / eac an
Acidic en i nmen P d ced b li e a ench mal cell
L me = en me f nd in b d ec e i n ha Se m m lec le ha a e m e en i i e indica f
a ack cell all (e eciall G am- i i e) inflamma i n
RNA e and DNA e Inc ea e a idl beca e f infec i n, inj a ma
Lac fe in Facili a e c n ac be een mic be & hag c ic cell
Bind mic gani m & m e
adhe ence
INTERNAL BARRIERS TO INFECTION (2nd Line) Limi de ci n f e l ic en me f m WBC
In e nal Defen e S em - cell la e n e ha ec gni e M & ec cle im an ein af e hag c i
ecific m lec la c m nen f a h gen C kine : IL-1, IL-6, TNF-al ha

C-Reac e P e (CRP) - n n- ecific

1. F nd m l in m n c e ,
an ib d like b ance f nd in ace mac hage & ne hil
am n f e m. Significan ele a i n C n i f le cine- ich e ea
d ing inflamma i n; m idel ed (LRR )
indica f ac e inflamma i n ➢ TLR 1,2,4,5,6 cell face
Ca able f ni a i n, ➢ TLR 3,7,8,9 c la m
aggl ina i n, eci i a i n & (end mal c m a men )
c m lemen ac i a i n 2. C- e ec ece
2. Se A dA In l ed in hag c i f f ngi
C kine like ac i i and bac e ia & inflamma
Ac i a e m n c e and ce e
mac hage m e Bind mannan & be a-gl can
inflamma i n f nd in f ngal cell all
P e en in a he cle ic le i n , Dec in = f f ngal gl can
bac e ial infec i n , and cance Mann e ece
3. C e e - media i n f inflamma i n 3. NOD- e ece
F ni a i n, chem a i & C lic ece ha de ec
l i f cell PAMP and DAMP
4. A a1-a (AAT) - gene al Hel ec again in acell la
la ma inhibi f ea e ; "m - " an a a i e
effec f ne hil in a i n NOD-1 & NOD-2 ecific f
Reg la e e e i n f bac e ial e id gl can
inflamma c kine NLRP-3 f n ela ed mic bial
5. Ha b - an i idan ide c e a h l gic change
ec i n again ida i e damage f m 4. RIG- e ece
elea e f hem gl bin Rec gni e RNA d ced b
Bind f ee hem gl bin f m i e
in a a c la hem l i Ind ce inflamma c kine &
6. F b e - in l ed in e I in e fe n (inhibi i al
c ag la i n/cl ing e lica i n & ind ce a i )
Small i n clea ed b h mbin 5. C c DNA e
f m fib il fib in cl Rec gni e c lic i al DNA
7. Ce a -c e an
P inci al c e - an ing INFLAMMATION
ein in h man la ma A c m le eac i n ai inj i agen
C n e ic fe i n (Fe2+) B d e all eac i n inj f in a i n b infec i agen
n n ic fe ic f m (Fe3+) C n i f a c la e n e , mig a i n and ac i a i n f
Cell la ece f mic be and damaged cell le k c e , and emic eac i n
E e ed n hag c e , dend i ic cell and he cell
e
Can be e en n cell face in he a f he
cell
5 a a e f cell la ece
1. T - e ece
Rec gni e diffe en a h gen
(PRR)
TLR ha ec gni e mic bial
ein , li id , l accha ide
a e e en n cell face
(PAMPS)
TLR ha ec gni e n cleic acid
e en in he end me

Ca dinal Sign of Inflamma ion (ac e ch nic a he

b d e n e he mic bial agen ia elea e f c kine )
a. R bo (Redne ) - a dila i n
b. Calo (Inc ea ed hea ) - a dila i n
c. T mo (S elling) - inc ea ed a c la e meabili
Fl id g e f m he bl d e el he
nding i e
Acc m la ed fl id: edema
d. Dolo (Pain)
S elling che he ain ece
Pain media m e ain (i.e.
aglandin )
e. F nc io lae a (L f f nc i n)
P incipal Componen
Va dila i n leading an inc ea e in bl d fl he
infec ed a ea (hi amine )
Inc ea ed ca illa e meabili
Dia ede i f le k c e
Mig a i n f mac hage
S im la i n f hag c i b ac e ha e eac an
W a e a ce e e a a e e ed b
a e de e e a a e ec a e ?
ADAPTIVE IMMUNE SYSTEM

Al kn n a ACQUIRED IMMUNITY
S ecific ec i n ac i ed f m infec i n
in en i nal imm ni a i n
INNATE VS. ADAPTIVE IMMUNE SYSTEM
T e f e i ance cha ac e i ed b :
S ecifici f each indi id al a h gen mic bial INNATE
agen Fi line f defen e
Abili emembe i e e N n- elf ece a e ha d- i ed in he gen me (PRR)
Inc ea ed e n e ha a h gen n e ea ed Pa h gen- ec gni i n ece
e e An e am le: ll-like ece (TLR )
Made f highl peciali ed cell ha e e ed ni e P e-f med c m nen
an igen ece ec gni e and m n a de ci e N n- ecific e n e a d Ag
e n e again f eign agen S anda di ed magni de f e n e
B and T cell : m e ecific and eciali ed Lack mem
Thi d line f defen e f he imm ne em ADAPTIVE
3 d line f defen e; Reinf cemen
S ma icall gene a ed n n- elf ece
C m nen a e d ced f ll ing e e Ag
E hibi Ag ecificall
Im ed magni de f e n e n e ea ed e e he
ame Ag
Ha mem
SIMILARITIES
Di c imina i n
S me l ble fac
S me cell la fac

FORMS OF ADAPTIVE IMMUNITY: MAJOR ARMS OF ADAPTIVE IMMUNE SYSTEM

ACTIVE VS. PASSIVE
ACTIVE ADAPTIVE IMMUNITY

Pe n a ici a e in he d c i n f imm ne fac
(an ib die and en i i ed l m h c e ); l ng la ing
Ac i ed de el ed in an indi id al n e e a
f eign b d
Thi indi id al imm ne em i in ol ed in he d ci n
f imm ne fac (e.g. an ib die and en i i e
l m h c e )
F eign agen (an igen) = imm ne e n e
L ng-la ing c m a ed a i e
POST-TEST
PASSIVE ADAPTIVE IMMUNITY
In c n a ac i e imm ni , he indi id al ecei e he 1. (T/F) The i ola ion of l mphoid em cell and hei
de cenden f om he gene al ci c la ion i h o gh he
imm ne fac f ma e n h a e i l imm ni ed
blood h m ba ie
b he f eign an igen 2. In l mph node , e ing o nai e T and B cell a e able
Imm ne em i n in l ed in he e n e (i.e. o ecogni e and e pond o fo eign an igen b o gh
b aining an ib die ) and collec ed b he ____ f om pe iphe al i e
A. Bl d
B. Pla ma
Bo h Ac i e and Pa i e imm ni ma be de el ed b na al C. L m h
a ificial mean D. All f he ab e
Na all Ac i ed ac i e: ge he di ea e 3. (T/F) The ana omic o gani a ion of he componen of
Na all Ac i ed a i e: h gh b ea milk he imm ne em i c i ical in he apid deli e of
A ificiall Ac i ed ac i e: h gh accine inna e imm ne cell o i e of infec ion a ell a
efficien adap i e e pon e o an igen
A ificiall Ac i ed a i e: h gh la ma an f i n 4. Which of he follo ing fac o i no a componen of
c n aining an ib die an i en m he in e nal inna e defen e em?
A. C m lemen
B. Ca helicidin
C. Ce amide
D. CRP
5. The ___ i he fi line of he inna e defen e em a
i e e a he p o ec i e hield of he bod again
coloni ing pa hogen
6. A neona e ecei ing BCG imm ni a ion ill de elop
ha fo m of adap i e imm ni ?
7. L mphoid follicle ha ing ge minal cen e o ld
con ain ha pe of l mphoc e ?
A. Nai e B cell
B. Re ing T L m h c e
C. Ac i a ed B cell
D. P imed T cell

8. (Ide ) Collec i el , hi efe o he imm ne Ce l la min

componen a ocia ed i h he m co al lining of he Hallma k f ac e inflamma i n
b onch and he ga oin e inal ac Inc ea e in a c la e meabili b elea ing
9. Which imm ne cell i engaged in ADCC chem a in and a ac ne hil in he i e f
10. (Ide ) Thi ag an loc e i he majo imm ne cell of
inflamma i n
adap i e imm ni
P ed minan cell : Ne hil
N nl ne hil can eng lf cell b
RECAP ON UNIT 2 (02/06/2021) al he g an l c e b n ha
Inna e imm ni effec i e
Gene ic, e-f med
N imm n l gic mem
E e nal defen e:
In ac kin, m c memb ane and i
ec e i n & fl hing ac i n f ine
In e nal defen e
When he b d can n l nge handle he
a h gen e e nall ;
O gen en i n, b d em , ec e i n f
ce ain l e ide , elea e f
b ance b imm ne cell (c kine
ha ld infl ence he imm ne e n e
f he b d )
S im la e he d c i n f he
cell and c kine
In e fe on (IFN ) b ance ha
ld limi i al e lica i n
Ac i a i n f complemen em
b ance ha ld f nc i n a
ni a i n, l i , and inflamma i n.
Pa h a ac i a ed hen mic bial
d c a e e en :
Al e na i e a h a
Lec in a h a /
mann e-binding lec in a h a
Ac i ed imm ni
S ecific - e f an ib die
Cla ical a h a (imm ne c m le e )
Wi h imm n l gic mem
Anamne ic: ec nd ime he b d
enc n e an an igen, he e n ei
fa e and nge d e mem
B h ha e le ance
Mechani m aid he imm ne em
Fi e nd he e he e i a b each in he
ba ie Inna e imm ni
If i can' c n l he blem: Ac i ed ill
en e (mem cell )
Ac e ha e eac an - d ced b he a c e and a e
igge ed b inflamma i n
CRP : ma ke f de ec ing f ca di a c la
di ea e
P imi i e an ib d
Se m am l id
Al ha-T in

S c : PPT, a c c d , B a d c
ece h dc e e he ha e f he
UNIT 3: ANTIGENS, IMMUNOGENS, & MAJOR iga d (g d e f fi ) c cia f affi i
HISTOCOMPATIBILITY COMPLEX
ANTIGEN
PRE-TEST Ca be a b a ce ( ec a , a f a ec e,
ga i ) ha ca be ec g i ed b he i e e
1. I i a b a ce ha ca eac i h a c e di g
ia ece f he ce (i.e. BCR, TCR a d TLR )
a ib d ha a a e i a i e e e
2. (T/F) The ec e he a ige i , he e i i C a ed BCR a d TCR, TLR a e c ide ed
i ge ic a ge e ic ( i ca de ec a f eig b d ) a d
3. The ______ i he a e i f a a ige ha a i c ide ed a a i a e i i
c e di g ece ca ec g i e A b a ce NOT ade b he b d (Non- elf); f eig
4. (T/F) F ag e ed e ide f a ce ed a ige h d
be c e ed MHC be ec g i ed b a T-ce ece b a ce
5. ________ a e che ica b a ce added acci e S b a ce ha eac i h a a ib d e i i ed T ce
i c ea e a i ge i c ea e he i e e e Ma be ab e e ke a i e e e
6. The h a MHC i ca ed he _______ S b a ce ha he I e S e ca ecifica
7. MHC C a ________ i e e ed i a c ea ed ce
ec g i e i h he he f Ag ece e e ed
8. (T/F) A ige a cia ed i h MHC C a II a e e e ed
CD4 T-ce ec e ed b h c e
9. (T/F) The T-ce ca ec g i e a a ige a de d i ic ce Epi ope/de e i a i e - a e i f he
e e i he ab e ce f he MHC ec e a ige ha he ece ca ec g i e
10. The ge e c di g f he MHC a e f d he h a TLR - ge e ic ec g i i
f ch e _______
BCR, TCR - ecific ec g i i
★ NOTE: NOT ALL A ige a e ab e i aea i e
*RECAP OF TYPES OF IMMUNITY AND ITS e e
FEATURES Bi di g a ha e b i a a i ae
e e
Inna e Imm ni (Na al imm ni )
N - ecifica a d ge e a i ed e e he ce ai
FUNCTIONAL TYPES OF ANTIGENS
a e i he a h ge = N i gic e
➢ I ge a ige i aei e e e
Adap i e Imm ni (Ac i ed imm ni )
➢ Ha e a a ige ha ca i a e e e;
Cha ac e i ed i h ecific ec g i i agai a h ge
i c e e a ige
L h c e (T a d B) - ai i e ce
➢ T e ge e f-a ige ha e e a ce (b d
Ha i ci a e ecifici , di e i , a d
i eac hi a ige )
e f he ada i e i i
T igge ed b A ige ca ab e f e ici i g a
i e e e IMMUNOGENS
A ige ca ab e f i a i g he I e Re e
INTRODUCTORY CONCEPTS No e: ALL IMMUNOGENS a e ANTIGENS; N a
a ige a e i ge
CONCEPT OF LIGAND-RECEPTOR BINDING
Mac ec e ca ab e f igge i g a ada i e i e
e e (i d ce f ai f a ib die e i i ed T
ce i i c ee h )
T igge i e e e f h c e
Ca be Th m -dependen Th m -independen
A ige - Liga d ha a e ec g i ed b ece

e e i ce d ced b ce
I e ac i f iga d + ece = ac i a i f
e k c e e ea e f b a ce (c ki e )
A he c ide a i , he bi di g i de e de
hei c e e a ce . The ha e f he

Th m dependen Si ae e e i h he he f The e di a a ica he ce f he

T ce i ge i f he h , he e cce f i
A ca e f a ib die d ced (G,A,M,D,E) i a a i
ha e ca i chi g 4. Abili o be p oce ed and p e en ed i h MHC
Cla i ching - cha ge i he a ib d c a molec le
(i.e. f IgM IgG) F i i d ce a i e e e, a ige
Beca e f hi i e e i ce i g ake ace
ib e A ige ce i g b eaki g d i a e
High affi i - e i e + ece a ic e ( e ide ) a d i be c e ed
Th m independen A e i e f ca i ke e e ce ai ec e i c ea ed ce (MHC)
N ca ab e f c a i chi g i ce i ca O ce a cia i cc ( e ide +
d ce IgM a ib die MHC), hi i a he ec g i i f
N i gic e i e ce
BOTH Re i e he he f he B-ce
PROPERTIES OF IMMUNOGENS
1. Molec la Si e
he La ge he Be e ( he g ea e he ec a
eigh , he e e he ec e i a a
i ge )
A ea 10,000 da i ge
>100,000 - a e g d i ge
A e ge e a i ca ab e f i d ci g a i e C a 1 MHC = A c ea ed ce
e e BUT he c ed i h ch a ge C a 2 MHC = APC (de d i ic ce ,
e i ie ( ei ) he e i g c j ga e i d ce ac hage , ac i a ed B h c e ,
a i e e e (i.e. e ici i , ge e e, e d he ia ce )
a ii ) NOTE: If a ige i ab e be deg aded b
2. Chemical Compo i ion and Molec la Comple i c ea ed ce , i i a a g d a ige
M ec e ed b a ce = M e i ge ic 5. Acce ibili o Reac i e Si e
P ei : Be i ge If e i e a e ea i ee he face, i i
P ei a d accha ide a e he c ide ed be a g d i ge
effec i e i ge c a ed
ca b h d a e a d i id ( g d
i ge i ce e ea i g b a ce
ia= c e )
S he ic e ( ef & )
g di ge i ce e ea i g i
Ca b h d a e - e i ge ic ( a e &
i i ed be f ga c ea e c e )
P e c eic acid & i id - i ge ic b
he e e
Re e ca be ge e a ed he
a ached i ab e ca ie ec e
FACTORS INFLUENCING IMMUNE RESPONSE
Di e i fi ge
If 3D, a ige a d e i e a e e ed Re pon e of he Imm ne S em i ba ed on he
a d ea i ec g i e , he i i follo ing combina ion of fac o :
c ide ed a a g d i ge 1. U i e bi gica e ie f a i di id a
3. Fo eignne 2. Na e f I ge
Rec g i ed a - ef i ge ic 3. Ge e ic c di g f MHC
The e f eig /diffe e = e be e a a 4. I ge ce i g
i ge 5. I ge e e ai
i.e. he a a ei i i c a ed a a i a
i a e a be e i e e e

Biological A. Age ( ei ) he e i g
P ope ie of O de i di id a dec ea ed c j ga e i d ce a
an Indi id al e e a ige ic i ai i e e e
Ne a e d f e d EX. Pe ici i ,
i ge (i e e P ge e e, A i i
c e e de e ed) CHEMICAL
B. O e a Hea h Chemical Compo i ion
Ma i hed/fa ig ed/ e ed High MW a d C e
e ike S c a C e
cce f i e e e P ei a e be e ha
C. Ge e ic Va iabi i ca b h d a e , i id , a d
Li ked he MHC a d c eic acid
ece ge e a ed d i g T Comple i
a d B- h c e de e e 3D a e a d he be f
D. D e f I ge e i e
Do e - A ig ifica a i f Ro e of En and Do age
a i ge be e i ed Deg adabili and he Abili o be
i de f he ada i e P oce ed and P e en ed i h MHC
e e ake ace A ige - e e i g ce
I aei e fi deg ade he a ige h gh
e e ake ca e a ige ce i g bef e he
f a a f ca e e a ige ic e i e
a h ge hei face
The a ge he a i f he
FURTHER REQUIREMENTS FOR IMMUNOGENICITY
i ge , he highe he
i e e e i 1. Ge e ic edi ii f he i di id a ha i e ici
Ve a ge a ca e i i e e e
T & B-ce e a ce 2. B a d T ce e e i e f a i di id a
E. R e f I c a i 3. R e f ad i i a i
E a e :i a e , S bc a e
i ade a , bc a e , a I a e
De e i e hich ce O a ad i i e ed
ai i be i ed I a a a
Na e of he Ph ica a d Che ica Na e f

Imm nogen I ge ici HAPTENS
[I f i a e i h e ie f i ge ] N i ge ic a e ia ha he c bi ed i h a
PHYSICAL: ca ie , c ea e e a ige ic de e i a
Fo eignne S a b a ce ha a e -i ge ic i i e f
S b a ce ca be Ab e bi d a d eac i h a ib die ih a
i ge ic if hei e b a e ca ie ec e
ec a c e Wi i aei e e e beca e he
c ai c e ec g i ed a ae e a
N -Se f N i ge ic beca e he e i f ai f
Mac omolec la Si e a ice/c - i k ( i ce e a ga)
M be >10 kDa (10,000 Da) C e ed a ge ec e (ca ie ) be
100,000 Da: A e a ac i e i ge ic g di ge
i ge C e e a ige i f ci a a
<10 kDa (L MW): Ge e a i ge a d ca e ici a i e e e
i ca ab e f i d ci g a Wi d ce eci i a i agg i a i eac i b
i e e e he e e (ha a i g e de e i a ie ca f
BUT, he c ed c i k )
i h a ge e i ie Ma be j i ed a ificia a a

TOLEROGENS
A ige ha i d ce e a ce
Se f a ige a e e ge ic
T e a ce - e i e e f he i e
e i e f-a ige
P e ada i e i eU e i e e
T e eg I ge
E e a e ge d e a di i i h
he e e a he ha e ha ce
EPITOPES
O a a i f he a ige i ec g i ed b i
c e di g ece
Thi i ca ed he Epi ope (a ige ic de e i a )
M ec a ha e c fig a i ha a e
ec g i ed b B T ce
Ma be e ea i g c ie diffe i g ecifici ie
Ca be linea & e en ial (c f ai a)
L a / e e ia = f d a i g e chai
C a a=f f di g f e i e
chai
T e f c fig a i i a a fac he he he
i be ec g i ed b he i e ce
Fig e 2-4: Cha ac e i ic of Hap en B cell
Rec g i e b h i ea a d c f ai ae i e
(A): Ha e bi d B -cell ecep o , b he ece e ai e e he face f a i ge
i de e de c i k: N ac i a i ( i ge ic) NOTE: A e i e ha i c f a i a (ca ab e
fc - i ki g face Ig ec e ) ca igge B
(B) Ha e /Ca ie c e c -i k ece : B ce ae ce ac i a i
ac i a ed a d begi d ci g a ib die (i ge ic) T cell
Rec g i e e i e a a a f he c e
(C) A h gh ha e ca bi d he a ib d bi di g i e f ed i h MHC he face f APC
(a ige ic), a f he a ib d -ha e c e e e ai E i e ca be ec g i ed b T ce if he
i de e de : The eac i ca be i a i ed a e deg aded i e ide a d e e ed ge he
i h MHC ec e
(D) Whe b d ca ie , he ha e c ib e he f ai
f a i ec ec ed a ice, hich i he ba i f he eci i a i
a d agg i a i eac i
CONSIDERATIONS:
I a a ige a fi d e i e : (1) i h he
a e a ea a ce (2) i h he diffe e
ecifici
Diffe e a ib d bi d he e i e
de e di g he ecifici
A a ge e : If he e i e a e i c e i i
each he , ca be he f i ea de ec i f
c e di g ece

U e a ed b hei c ei i e i i a = ead
c eac i cc = ece ca
ec g i e he a ige
E a e: F a Ag, b d g A&B
a ige i h bac e ia accha ide
OTHER TYPES OF ANTIGENS
He agg i ge Ag e e i RBC
Agg i ge I b e Ag i ed i agg i a i
P eci i i ge S b e Ag i ed i ha e cha ge
he eac i cc (PH: be i b e)
Vi a Pa ic e Ac ed e a i i g a ib die
Fig e 2-3: Linea . Confo ma ional Epi ope A e ge I d ce a e gie
A a h ac ge A e ge i ed i a a h ac ic
(A) Li ea e i e c i f e e ia a i acid a i ge eac i
e ide chai . The e a be e e a diffe e e e T i e ab ic d c (e i ); e a i ed b
chai a i- i
(B) C f ai a e i e e f he f di g f a e ide
chai / , a d e e ia a i acid a e b gh i c e
ADJUVANTS
i i
S b a ce ad i i e ed i h a i ge ha i c ea e
a d ha e he i e e e
REMEMBER! :) U a added acci e f a ie ha e a
be e i e e e he acci e
U a e ha ce he effec f he i ge b :
I c ea i g he i e f i ge
I c ea i g he . f ac hage
W k b a ge i g APC a d ec i ge f
deg ada i (a ge e e i e a ac a ge
be f i e ce i jec i ie b e gh f
e e)
Lead a e effec i e i e e e
I c ea e he i ge ici f eak a ige
E ha ce eed a d d a i fi e e e
CATEGORIES OF ANTIGENS Si aea d d aeh a e e , i c di g
A oan igen : Be g he H a ib d i e
AKA e e e ed a ige Si a e ce - edia ed i i
N i ai fi e e e I ei d ci f c a i i
A i e di ea e - he a a ige E ha ce i e e e i i gica i a e
i aei e e e a ie , a ic a i fa
i.e. P ei e (e e) T dec ea e he d e f a a ige e i ed
Alloan igen : F he e be f he h ecie Red ce c a dei i ae i c e ie
Sa e ecie , b diffe e e /bei g e ie e f b e h
Si ae i e e e M e i i a ici h a
I.e. b d a ige , Ag i ed i i e E ample of Adj an :
a a Al m / Al min m al : C e a ed
He e oan igen : F he ecie adj a i he USA
Diffe e ecie ( a Ag h a ) C e e ihi ge i c ea e
He e ophile an igen : He e a ige ha e i i i e a d e e a id e ca e f
e a ed a a i a b a e ei he ide ica i e
c e - e a ed i c e ha a ib d e ca O he pe : F e nd Adj an
c - eac / he a ige f he he Made f i e a i , e ifie & ki ed
c bac e i

I de f he T-ce ec g i e a a ige , i h d be
ce ed a d b e d i e ide a d e e ce f MHC
*RECAP OF T-CELLS
3 MAIN SUBTYPES
MAJOR HISTOCOMPATIBILITY COMPLEX
T-Helpe cell DESCRIPTION & FUNCTION
ec g i ed b he e e ce f CD4 a ke Majo hi ocompa ibili comple (MHC) - e f
I ed i : (1) ac i a i g ac hage , T a d B ge e ha c de f ce - face ec e ( e i a ige
ce & (2) i f a ai ec g i i )
T-C o o ic cell B i g a ige i he b d he face f ce f
ec g i ed b he e e ce f CD8 a ke ec g i i b T-ce
I ed i : (1) di ec ki i g f he a ge ce Ca f c i a a ige he a a ed
T-Reg la o cell De e i ed he he a a ed i ei
ec g i ed b he e e ce f CD4 a d CD25 hi c a ib e
a ke M hic e f di h a
I ed i : e i g he i e e e BACKGROUND
agai e f a ige e e a eac i f he Di c e ed a a ge e ic c ha de e i e acce a ce
b d . ejec i f i e g af e cha ged be ee e
MHC ge e a e hic a d i a e e a e
PRINCIPAL FUNCTIONS OF T-CELLS c d i a e e ed, i.e:
Defe e f i ace a ic be Fa he : HLA A9, A10 / HLA B4 B8 / HLA CW CZ
I hibi i fi e e e M he : HLA A7 A13 / HLA B5 B9 / HLA CW CX
Ac i a i fi e ce (Mac hage a d B Ce ) Chi d: HLA A7 A13 / HLA B5 B8 / HLA CW CZ
S ec ed fa he i he bi gica
REMEMBER ABOUT T-CELLS fa he
★ De e i he Th U ed de e i e a e a i c i
★ F d i he L h N de , Th acic D c F id Me b a e ei e e APC ha di a ce ed
★ 60-80% f he ci c a i g h c e i he b d a ige be ec g i ed b T-ce
★ I ed i he ada i e i i :E d d c f De i e f he e ea ch a a ai ha a ed i
ac i a i f c ki e he id-20 h ce
★ An igen : CD2, CD3, CD4, CD8 The e a e die hich ided i igh he
★ Pe ide a e b d a d di a ed he MHC ec e f e g e i g he acce a ce ejec i f
APC i e ( Hi c a ibi i )
Re ea che ea fi di g h ha a id ejec i f
a a a de e i ed b a i g e ge e: MHC gene
La e die i dica ed hi ge e a i fac a Comple
A e f c e i ked ge e i he i ed a a i
Nece a f c f ce a i e ac i fi e ce
P d ci f ce ai e ei
HUMAN LEUKOCYTE ANTIGENS
Ce face a ke ha a i e ce di i g i h
ef f - ef
The e a ige e e fi de c ibed WBC ( e k c e )
a d a e c ded f b ge e i he MHC ca ed
Ch e6

O he h a f he ch e6 NOMENCLATURE
MHC ge e d c e e ide ified a e ib e f g af Defi ed e gica h gh e f a ba e f a ib die
ejec i HLA a ige a e a ed acc di g he d c
HLA: Te a c i ed b Da e beca e he e e e fi e e ed b he Ge e L c (Ca i a e e ) a d he A e e
defi ed b di c e i g a a ib d e e ci c a i g (N be )
WBC EX. HLA-A2
A-L c
Ch e 6: 2-A ee
INHERITANCE OF HLA
Haplo pe: C bi a i f i he i ed HLA A e e
T ha e ( ef each a e ) a e a ge e
Beca e f he a ge be f a e e i he MHC, a
e HLA ei a a i e a a fi ge i
U i e e i a be i a a ai
Ge e c di g f HLA i f d he h a
Sh a ha 4 aj a ea a d di ided i 3 diffe e ci
1. Cla I
F d A, B, & C
Nea e e ic a ea
I ed i a ige ec g i i
E e ed he face f a c ea ed
ce
O e ge e c de f each a ic a
ec e
2. Cla II
F d i D egi 2 KEY FUNCTIONS OF MHC IN ANTIGEN PRESENTATION
Maj ci: DP, DQ & DR egi
I ed i a ige ec g i i 1) T elec i el bi d e ide d ced he ei a e
E e ed he face f he APC ce ed i ide he ce f he h
O e ge e c de f a ha chai & e 2) T p e en e ide he face f he h ce a
e ge e c de f be a chai T-ce i h a c ec T-ce ece
3. Cla III
Be ee C a I & II ch e MHC II ec g i ed b T-c ic ce (CD8 a ke )
C de f C4B, C4A, a d C2 MHC I T-he e ce (CD4 a ke )
Sec e ed ei ha ha e a i e
f ci T-ce d e d h ce i he ab e ce f f eig
A c de f D c e e ei e ide
a d ge e c di g f i e ec i T-ce f c e di g i fec ed ce b ca
fac h MHC i a i a i e d h ce ha a e i fec ed
d ci f c ki e a d he ★ The ef e, MHC ha a i a e d i g he
b a ce diffe e ia i f T-ce i he Th (i a e T-ce )
NOT i ed i Ag ec g i i a d i he e e f a e T-ce
NOT e e ed ce face
N e e ed he ce b i a
i i e f c i ( ec e e ce ai
b a ce )
Ha e c e e diffe e c e
c a ed he ca e

O gani a ion ba ed on T ai nde hei con ol I ed i N i ed i

hei biochemical ki i g i fec ed di ec ki i g
compo i ion h ce I ed i
CD8 de i ai g
Cla I Ta a a i a ige a ge ce c ki e
A, B, C, E, F, G, H, X Se gica de ec ed c ki e ac i a e
e ba e he i e ce
A ige d ce he c ki e
Ce a a ge a ige f ce
edia ed h i STRUCTURE OF MHC CLASS I & II
Cla II I- egi e k c e a ige

DP, DQ, DR, DM, DN, T a d B ce i e ac i
DO I e e e
Mi ed e k c e eac i
T i ce ibi i
Pe ide T a
Ge e a i fc ic ei
Cla III Se ei ec e
C' c e , c e e e e
c ch e 450, C ki e
h d a e a d TNF P ei
MHC ha a c cia e i T-ce diffe e ia i i he h

T-ce i h ee i i Ag be diffe e ia ed
2 MAJOR SETS OF MHC MOLECULES

CD8 + T-ce e d Pe ide + e f-MHC C a I
CD4 + T-ce e d Pe ide + e f-MHC C a II
MHC C a I MHC C a II
F di c ea ed E e ed APC
ce Wi h he a cia ed
I e ac i h T-c ic e ide i e e i
ce (ce / CD8+ CD4+ T-ce (T He e
a ke ) ce )

CLASS I MHC Thi i he bi di g i e f he e ide i h 8-11

a i acid g
The e a e ec e ha bi d e ide (8-11 a i acid
Ea :e e ha ed ce ga i
g) de i ed f ei ca ab i ed i he c a
acid e id e f i fi i he
Pe ide a e a ed i he e d a ic
e ide-bi di g i e
e ic (ER) he e he i e ac i h e
B h e d f he c ef a e e c ed ike i a b ead
he i ed MHC C a I Be a-2- ic g b i
M hic c a ed i h a3 & be a-2
chai
egi
M ec e ha a e f d i ea e e c ea ed ce
3d a
face
Reac i h CD8 f d C ic T-ce
Di ib i f MHC C a I c ea ed ce a e
S ecific i e f CD8 a ke i e ac
e a
I e ac i fCa I ec e i e e
M e MHC C a I i h c e a d
e d ge a ige CD8+ T-ce
e id ce
E d ge Ag : i ace a ga i
O he ce ha e e MHC C a I :
(i c di g , a a i e , e c.)
i e ce , c e ce , e ce a d
Bi di g f e ide MHC C a I a d II i a ecific
e a ce
a bi di g f e ide he TCR beca e diffe e
CD8 + T-cell e pon e o Pep ide + elf-MHC Cla I
e ide a bi d a a ic a MHC ec e
E e ed ig ifica h c e a d e id ce ,
he ea e e ed / de ec ed he a c e , e a
NON-CLASSICAL CLASS I MHC ANTIGENS
ce , c e ce , a d e ce
De ig a ed a E, F, & G
HLA-A a d HLA-B a ige a e ch e e ed
A EXCEPT G a e NOT e e ed he ce face a d
ha HLA-C a ige ( e)
d f c i i a ige ec g i i b ha he ei
The ef e, HLA-A a d HLA-B a e i a
i e e e
a ch d i g a a ai
G an igen
I i a gl cop o ein dime ade f2 -c a e
E e ed fe a h b a ce d i g he 1
i ked e ide chai
i e e f eg a c ( he a ige c e i
C e :
c ac i h a e a i e)
A ha chai
He e e e a ce f he fe b ec i g
Be a-2- ic g b i
ace a i ef he ac i f NK ce
Pe ide-bi di g c ef
F NK ce a ge he fe
A3 d ai
Bi d NK i hibi ece a d ff NK
1. Alpha chain = 44,000 MW
c ic e e
1, 2, 3 domain : I e ed i he ce
E molec le - i i a e
e b a e ia a e b a e eg e
F an igen - k f ci
(h d h bic):
Each d ai c i f 90 a i acid
25 T a e b a e h d h bic aa
5 Sh e ch h d hi ic aa
30 A ch aa
2. Be a-2-mic oglob lin = 12,000 MW
S a e c e
E c ded Ch e 15, hic
N hic= e ai he a e ac a
diffe e e fCa I ec e
D e e e a e he ce e b a e, b i ha
a e e ia e i c ec f di g f he chai
N a ached he e b a e
I a i he c ec f di g f he a ha chai
Pep ide-Binding Si e:
AKA Pe ide-bi di g c ef
1& 2d a each f a a ha he i e i g
a a dee g e a he f he MHC C a I
ec e

CLASS II MHC de d i ic ce , i i be b e d i ide he

e ic e e e ed face f APC)
The e a e ec e ha i e ac i h e ide (12-17 aa
P ei ha a e b ke d i MHC C a I i i
g) de i ed f ei ake i ce a d ca ab i ed
i c hi e i C a II i i i he e ic e
i acid e ic e i APC
Wi i e ac i h T-he e ce
Phag c ic
T he e ce i ha e CD4 c - ece ha i
Cla II MHC molec le a e fo nd on APC :
bi d be a-2 d ai
B-ce
B h a ha a d be a chai a e a ch ed i he e b a e
M c e
Mac hage
NON-CLASSICAL CLASS II MHC ANTIGENS
La ge ha ce
C i f HLA-DM, HLA-DN, a d HLA-DO
De d i ic ce
Ha e a eg a e i a ige ce i g
M effec i e APC ha i g he highe
A. HLA-DM = M ec e i ed i adi g e ide
e e f C a II ec e i face
C a II ec e
Th ic e i he i
B. HLA-DO = C a ige bi di g
Majo Cla II Molec le (DP, DQ, DR)
C. HLA-DN = F c i e ai k
C i f2 -c a e b d e ide
chai ha a e e c ded b e a a e ge e i he
MHC C e
➢ HLA-DP
➢ HLA-DQ
➢ HLA-DR
A e he e odime beca e he c ai 2 diffe e chai
HLA-DR molec le
E e ed a he highe e e
Acc f ha f f a C a II M effec i e APC , ha i g he
MHC ec e a ce highe e e f C a II
DR be a ge e = high hic ec e i face
HLA-DP molec le
F d i he h e
D ai : -chain (34,000 MW) a d -chain (29,000 MW) CLASS III MHC PRODUCTS
N -c a e b d I c de :
He e di e C e e ei
C ai 2 diffe e chai TNF A ha & Be a
Chai i c e ge he f e ide-bi di g O he ei (e.g. Hea Sh ck ei )
c ef hich a e e b h ide (h d g de A e NOT a cia ed i h ce e ba e face (
beca e g b ead g h d g b a e e ed he face)
g c ef , e a b h e d ) N i ed i a ige ec g i i
Beca e he e ide-bi di g c ef f HC
C a II i e a b h e d , i ca
ROLE OF CLASS I AND CLASS II MOLECULES IN
acc da e ge ce ed a ige
IMMUNE RESPONSE
13-18 a i acid e id e
A c a II ec e ca e ge RECAP:
e ide ha c a I ec e A ige P e e a i : Mai e f MHC C a I II
Each chain ha 2 domain ec e
The 1 and 1 domain c e ge he f P ce b hich e ide a e deg aded & a ed i
he e ide-bi di g i e a a e b a e he e T-ce ca ee/ ec g i e he
Ca ca e ge e ide ha C a I MHC ★ R b ha T-ce ca e d a ige he
ec e a ige a e c bi ed i h MHC ec e
High c e ed i i a ca I ec e F T-ce e e be igge ed, e ide be:
P e e e ge a ige a h ge ha a e A ai ab e i ade a e f MHC ec e
e ace a (E . bac e ia hag c ed i e a i ed b bi d
Ab e be b d effec i e
Rec g i ed b a TCR

ERp57 - a bi d a -chai ha i i
ai ed i h 2- ic g b i
O ce a -chai i b d i h 2- ic g b i , Ca e i &
ER 57 i be e ea ed
Chape one : Cal e ic lin a d Tapa in
The e i j i he c e a d he
abi i i g he MHC ec e f e ide
bi di g
I ace a ei a e dige ed i he p o ea ome
P a - acke fe e f ed i a
c i de h gh hich e ide a a d a e
c ea ed
Pe ide be f ded bef e
e e i g c i d ica cha be
C ea ed e i e f de i e
ca I ec e
Cla I molec le Made f a c e e e ha deg ade ei
Mai e e e ide he i ed i hi he ce e e i he c a
T-c ic (CD8) ce Re ide i a ge c a ic c e e
Wa chd g f i a, a d a a i ic a ige The e ei ca be c ic ei f he
ha a e he i ed i hi he ce (agai f eig b a ce i ca a deg ade
ac a a h ge ) da aged/i e f ded ei a defec i e
Cla II molec le ibo omal p od c (DRIP )
P e e e ge a ige T-he e (CD4) ce P d c f ea e = e ide f ag e
E ge ei ake i he ce f N e: he d bec e i g e a i
ide & deg aded acid ec e
He a i e e e bac e ia Ta ed RER
i fec i he a h ge ide ce Pe ide a e a ed / ed f he c a
( ac a a h ge ) he e f he ER
Ho do he MHC molec le and he pep ide in e ac ? TAP1 & TAP2 (T a e a cia ed i h
MHC c a 1 df he e d ge ah a a ige ce i g) - ecia i ed a e
A ige c i g f i e , a d ei ha de i e e ide f ea e
a a i e a e a ead f d i ide he ce ( a ia ER
dige ed a d a ead f ed i he c a ) M i ab e f ATP-de e de
a f e ide he MHC C a I
CLASS I MHC-PEPTIDE INTERACTION ec e
M efficie a a i g e ide
ENDOGENOUS PATHWAY c i i g f 8-16 a i acid
Ca I ei he i ed i a e ce a c a I RER Whe e he bi d i h e ide
ec e ( h e d ge ) Ta a i b i g i i i he TAP a e
S he i ed i he gh e d a ic e ic a d he MHC C a I ec e
Whi e ai i g f he e ide ( ce ed a ige ), I edia e he i e ac i a d adi g f
c a 1 i e ai a ch ed i he RER he e e ide i he c ef C a I ec e
he i bi d i h he e ide Ra id a ed ce face ce a ha chai bi d
Calne in i h e ide
The 88-kd e b a e-b d ec e i he ER ➢ Cal e ic lin - a he i a cha e e
kee i g he chai a ia f ded hi e i i He i abi i i g he e f ed c a 1
b d i ec e a d he a ia e f di g f he
Thi i be he ca e hi e i i ai i g bi d i h ec e
he 2- ic g b i
"Cha e e" ei ha he i abi i i g he
MHC ec e

P ea e - deg ade e ide

i f ag e , he eb
b a i g he a f i he
ca e f c a 2; i ead c a 1
Pe ide a e di ec aded he
MHC C a I ec e i acid e ic e .
C e e a e he a ed he
ce face
Vi a a ige e e C RER
I RER, i i he a cia ed i h ( aded
Addi ional no e f om i al in: i ) MHC c a 1 a d i be a ed
NOTE: I e ca e , e ide ca be i e ga d he face ia a e ic e
MHC' c ef ca acc da e a d 8-11 A.A. E e ed a c a 1 i ead f c a 2
e id e beca e i i c e-e ded ( i a b ead a ea a ce). ka i d aa i a a ER
ERAAP - ER e ide a i e ida e e ib e ★ Remembe : Pag a k a ER, i i
f c i g a d ed ci g A.A. e id e e hibi a c a 1 ec e.
O ce i i aded i he c ef , i i ge Na al pa h a :
a cia ed i h Ta a i DC a e a ige e e i g ce a d d
MHC c a 1 c e i he i edia e e e he e ide i h a MHC c a 2 ec e
a ed i he g gi c e f ackagi g a d e e ed CD4+ T ce
O ce e ide i b d he -chai , he c e i a id C o -P e en a ion i an impo an pa h a in:
a ed he ce face f T-ce ec g i i 1) Ac i a i g CD8+ T-ce be ab e e d
MHC ec e d e di c i i a e he ei aded b i e ce ha a e ake he APC
e e ( ad b h e ide f f eig a ige a d 2) P a a i a ei e di g d i g ce
e f-a ige )
I i he T c ic he he i i
ec g i e he e e ed ce i h MHC c a 1
I ca e , i i be ec g i ed ka i baka
aka a i a a a g ce
CLASS I MHC-PEPTIDE INTERACTION:
CROSS-PRESENTATION OF EXOGENOUS ANTIGENS
Mai b Dend i ic Cell
The e ake ic be a d ic bia ei (b
hag c i / i c i f i fec ed / d i g ce )
a d he b eak he i iece
Ac i a ed ce e e face ec e ha a e
i a f T-ce ac i a i
Pa h a h he e e ide i e ec / C a
I ec e a e no f ll nde ood, b i
ho gh o in ol e:
T a fe i g f a ige f he
c a e i he c opla m be
ce ed b he p o ea ome . Pe ide
a e he a ed he RER, he e
he bi d i h he MHC C a I ec e ,
he he ce face
U a beca e APC ih
CLASS II MHC-PEPTIDE INTERACTION
MHC c a 2 h d be
ce ed i he c a b EXOGENOUS PATHWAY (MHC c a II)
i ead i a e d e. B i C a II ec e a ici a e i he e ge ah a f
hi ca e, i i a ed i he a ige e e ai
c .

E ge PATHWAY FOR LOADING ANTIGENS IN MHC CLASS 2:

A ige a e hag c ed e d c ed 1. Whe a cia ed i h i a ia chai , i i he be
Thi i he ce b hich ce i ge a ed he G gi a a a a d e c ed i a e ic e
e ace a ec e b e c i g he i a MHC c a 2 i ide he e ic e, he i a ia chai
a i f he a a e b a e i deg aded a d a a f ag e , CLIP
Wi hi he e d e ( e ic e), h d ic e e (c a 2 i a ia chai e ide), i ef
( e) dige e ge a ige i C a 2 + CLIP e e a f e i h he
e ide f 13 - 18 a i acid e d e c ai i g he ce ed e ide
Pe ide a e c ide ed ge ha i f ag e
MHC c a 1 CLIP e cha ged f e ge e ide
De d i ic Ce a e e ac i a f he T-ce ➢ Fa ed b H
E ce e a ca i g & dige i g e ge 2. A he f e ge he , HLA-DM (f d i c a 2) i aid i
a ige e i g he CLIP f ag e
S he i ed i he ER a d a cia ed i h he ei Ii B e a f c i , e ide i he e ic e a
(I a ia Chai ) a ach
Ii (In a ian Chain) HLA-DM aid a i adi g he e ide i he
P ec he bi di g i e f c a II ec e c ef
hich d e i bi di g f e d ge e ide
eg e i hi he ER 3. O ce aded, i i a ed i he face a ce ed
Bi d i h a c a II ec e h af e e ide a cia ed i h MHC c a 2
he i
Se e a a cha e e di ec he
he e di e a e d a , acidic
ei - ce i g ca i
He b i g a ha & be a chai ge he
i ER e & e he h gh
he G gi c e he e d c ic
e e ( he e dige ed a ige i f d)
Ca (a cha e e) da a i
i i g he chai fca 2
MHC
Whe Ii e c e he a ige ic e ide , i
ec he Ag-bi di g ide f he C a II MHC
ec e ha i i be aded i h a ige ic
e ide i he e d a- a ca i
Ii -de i ed CLIP (c a II i a ia chai e ide):
C a II i a ia chai e ide a ached he
e ide-bi di g c ef
Re ai af e deg ada i f i a ia
chai (b ea e) ce c a II
ec e e c e e ide a
e d c ic e e
S aka ck a g bi di g c ef beca e f
hi cha e e e e bi di g f
e ide ha c a 2 MHC a e c e ★ Remembe : Mai diffe e ce be ee MHC c a e i ha
i he ER a ige a e aded ca 1 ec e i he RER, hi e
Pag a a g c , a d a f ee e ide i adi g f c a 2 ec e ha e i he endo ome
he ER ba a ag bi d i aca 2a ( e ic e).
ba a hi di a f a gca 2 ah a
a agi g c a 1 i a

MHC I MHC II CLINICAL SIGNIFICANCE OF HLA

The MHC-I An igen e e a i ah a i ea i T an plan a ion
h gh f a a in ide-o pa h a b hich ei C a I & II ec e ca i d ce e e eadi g
f ag e f ec e he i ed b he ce a e de i e ed g af ejec i
a db d b he MHC-I ec e d i g i bi he i Ta a a ge if he HLA a ige f
I c a , he MHC-II An igen e e a i ah a i he eci ie a d he d a e c e a ched
be e c ea i a i ed a a o ide-in pa h a i HLA ide ica d f b e a
hich i ge ed ei a e deg aded b e e i he a a ai ed ce he f e e c f G af .
e d a- a e a d a e de i e ed he H di ea e
MHC-II ec e i ha deg ada i e c a e De elopmen of a oimm ne di ea e
P edi e e ce ai a i e
di ea e
E : HLA B27 ge e & a k i g d ii
Pla ele T an f ion
A h gh e e aee a f i i
ifac ia , a ib die C a I HLA a ige
a e he i a ca e f i e- edia ed a e e
a f i ef ac i e
Pa e ni Te ing
HLA L ci a e hic a d ec bi a i i
ae
HLA i he i a ce a e ca e c de fa he ih
a i a e 99% acc ac
Diagno i of Di ea e
N a i di id a h ha e a a ic a HLA
a ige ha e a di ea e, b a i di id a ih
ce ai di ea e e e a a ic a HLA a ige
EX. HLA B-27 a ige i a cia ed i h
Ank lo ing Spond li i ( e e e ai i he i e
a ea)
Di ea e A ocia ion
Fo en ic Medicine
An h opolog
Racial Ance and H man Mig a ion S die
De elopmen of Vaccine
Ma be ai ed ce ai MHC ec e
Re ea che ca ecifica de e acci e
c ai i g ce ai a i acid e e ce ha e e
a i d i a e i e
Ma aid i de e e f ib e acci e
ba ed MHC e
STRATEGIES FOR HLA DETECTION
Se ological App oach
L h c e Mic ici Me h d - a
e ed i h c a 1 ec e
S id-Pha e Te i g e h d
Cell la App oach
Mi ed L h c e Reac i - a e ed
ihca 2 ec e
F C e
Molec la Diagno ic
Phe e Ge e f a i di id a

OTHER DISEASE ASSOCIATION
POST-TEST
1. Which f he f i g b a ce i he i ge ic?
a. Li id
b. Tef
c. P ei
d. S ga
2. Se f-a ige a e ca ed?
3. (A a g ) A ige : _______ a A ib die : Rece
4. F a a ige be i ge ic i h d ha e a ec a
eigh f a ea ________ da
5. (T/F) A ha e i i e f i a a ige
Fo 6-10, e he follo ing choice

a. MHC C a I
b. MHC C a II
c. B h
d. Nei he
6. E e ed b a c ea ed ce
7. I ge e f c di g a e f d i ch e6
8. I aei i
9. P ce ed a ige i e c ed i a e ic e
10. MHC- e ide i ec g i ed b a CD8 + T-ce

Diffe ba ed ecifici . If a Ig eac a

UNIT 4: ANTIBODIES AND T-CELL RECEPTOR
a ige , ha i e ed a a a ib d . B if
S ce : PPT (Pa &F e ), S ch a d A ch e , hi ce ai Ig' ecifici i k he e e
PRE-TEST i a Imm gl b li .
High ec a eigh
1) D ble ii el m h c e m e hich f he
Gl c ein - ei ec e ed b a a ce i
f ll ing cl e f diffe en ia i n?
a) CD1 a d CD2 e e a a ige ic i ai
b) CD4 a d CD8 Pe e i ai b d f id
c) CD4 a d CD2 Reac ecifica a Ag ha a e e ib e f hei
d) CD8 a d CD16 f ai
2) Which f he f ll ing chain f he T-cell ece bind
i a ge an igen? P i a i ha ga a ba d he bjec ed e ec h e i
a) A ha a d Be a chai a H 8.6
b) De a a d E i Elec h e i : S e i g ei a ea i g
c) Ga aa dE i chai a he ga a ba d
d) A ha a d Ta chai High ec a eigh
3) A e f elec i n ce he e h m c e a e
e en ed i h elf-an igen and h e ha eac ill C m i i n:
nde g a i 82 - 96% P e ide
4) (T/F) The T-cell ece nl ec gni e an igen 2 - 14% Ca b h d a e
ce ed b MHC ein
5) Which f he f ll ing an ib die a ea n he face
f B cell ?
a) IgM
b) IgA
c) IgE
d) IgG
6) The e a e cell ca able f an ib d d ci n
7) In elec h e i ing H 8.6, an ib die mig a e
ha egi n?
8) H man egmen f an ib die ill be d ced hen
ea ed i h e l ic en me a ain?
a) 1 Elec h e i : S e i g ei a ea i g a he
b) 3 ga a ba d
c) 2
d) 4 I g b i aec ide ed be a ga a
9) S bcla f IgG ha i inca able f c ing he lacen a g b i
10) (T/F) IgM i c n ide ed a he be eci i in
11) Which f he f ll ing an ib die a e a cia ed i h a
an iece?
a) IgM
b) IgG
c) IgA
d) IgE
ANTIBODY
Mai h m al elemen f he ada i e e e
H a - b a ce d ced An igen-binding i e i e ed a a a a e
Te ed a a Imm n gl b lin C ed f fi e aj c a e (ba ed hea chai )
Imm gl b li - g c ei f di e IgG - ga a hea chai
i f he f b d IgM - hea chai
E e ia e i a ige ec g i i & i e IgA - a ha hea chai
e e( i ai &c e e ac i a i ) IgD - de a hea chai
C i e 20% f a a ei i hea h IgE - e i hea chai
i di id a
N e: A a ib die a e c ide ed Ig ; b a
i g b i a e a ib die

FUNCTIONS OF ANTIBODIES A ea af e i d ci a a ige

i.e. RH a ib die (IgG Ab)
C bi e i h a ige ce a face
Ne a i e ic b a ce I an ib die a a ib die
Faci i a e hag c i i ce a ib die ca ac a a P d ced af e i d ci f Ag f a e
i ecie
Acc di g
C a i g e ha ce hag c i ha e i.e. ABO a d RH a ib die
he S ecie
Fc i f a ib d i e ed he e he Fc He e hile An ib die :
hich P d ce
ece f he hag c e i bi d i A ib die d ced af e i d ci f
hem
Ag f a he ecie
CLASSIFICATION OF ANTIBODIES
He f i he diag i f ce ai ia
A. Acc di g Sedi e a i Ra e di ea e (i.e. i fec i c e i )
B. Acc di g Te e a e Reac i i
N e: f ffi e i h "-i " a e a ib die a d
C. Acc di g Occ e ce
"-ge " c e d a ige
D. Acc di g he ecie hich d ce he
Aggl inin
E. Acc di g i eac i i h a a ige
I ed i agg i a i
F. Acc di g hei i - i beha i
U a IgM a ib die
P eci i in
I ed i eci i a i eac i ( be
a ige ) he e ha e cha ge ha e
G d eci i i a e h e a a ib die
(IgG)
Aggl in id
Hea dified agg i i
S edbe g i (S) - U i ea e he Ab e bi d i h agg i ge b a e
edi e a i a e f Ab ia ca ab e f agg i a i
ace if ga i a high eed Hemaggl inin
Acc di g Sa e c ce i h agg i i ; b a e
Sedimen a i n Hea = Highe S
De e i e eigh , i e a d de i a ib die ha bi d i h agg i ge
Ra e e e i he ed ce
f Ig
La ge i IgM i h 900,000 MW a d 19 S He agg i a i eac i
edi e a i c efficie Acc ding i L in: Ca e i f a ige ic ce (c e e
IgA ca be ee a a e /di e Reac i n i h edia ed)
M n me - 7S a d 160,000 MW an An igen Bac e i i bac e ia
Dime - 9S a d 170,000 MW He i ed ce
Di e ic f f IgA i e ed a Le k cidi WBC
ec e IgA i ce he a e f d O nin
i b d ec e i f c a E ha ce hag c i
i i Ne ali ing (P ec i e) an ib die
I ed i i a i fec i b bi di g i
C ld An ib die i ha d e de i ha e
Reac a e e Alle gic an ib die
Acc di g
i.e. IgM c a I ed i h e e i i i eac i
Tem e a e
Wa m An ib die An i in
Reac i i
Reac a 37 C A ib die agai bac e ia e ab ic
i.e. IgG c a d c
Na al An ib die / Na all Occ ing C m lemen Fi ing an ib die
An ib die : i.e. IgM i a g d c e e fi i g
Acc di g A ea i h i a ib d beca e he c e e
Occ ence N a ee i a a/ e i ce c e i ab e a ach he Fc
i.e. ABO a ib die (IgM Ab) i f he a ib d , e de i g he
Imm ne An ib die : fi ed a d i ge be ab e bi d
he i ec e e

Bl cking Inhibi An ib die TETRAPEPTIDE STRUCTURE

C bi e i h he Ag b g 2 Hea Chain (H Chain )
de ec ed UNLESS he a e h b ck 2 a g a d 2 a hea
a eac i , e he ei ecie f MW: A . 50,000 Da
he Ab ca be ide ified AA: 440
N ge be ide ified de ec ed b E c ded Ch e 14
he a ib die T e :
Ga a( )
C m le e: AKA Bi a e , Sa i e ac i g
M ( )
The abi e a d beca e f i i e
A ha ( )
ca c he ace a
E i ( )
De ec ed i ea ha e f i i ai
De a (ɗ)
(i.e.IgM)
∗ Hea -chai e e ci g = de ae e e ce f
Inc m le e: AKA U i a e ,
Acc ding d ai i ia L chai
F c i a B cki g C g i a i g
hei In-Vi 2 Ligh Chain (L Chain )
a ib d
Beha i MW: A . 22,000 Da
The ab e a d ca c he ace a
AA: 200-220
A b i - eac i g a ib die i ce he
E c ded Ch e 2 a d 22
ha e a a i e, high ei a be
T e : Ha e a ide ica ca b e i a a d
added aid i i bi di g i h a ige
f c i b diffe i he e e ce f i A.A.
De ec ed i he a e/ ec da
Ka a (𝝟)
i i a i (i.e. IgG)
La bda (ƛ)
NOTE: A ka a a d a bda igh chai a e f di
ANTIBODY/IMMUNOGLOBULIN STRUCTURE a Ig c a e b 1 ei e e f each ( a
mi e; ei he ka a la g i a lamda)
E cida e b Ge ald Edelman, R dne P e , and Alf ed Ligh chain i i n: S a a i i 1 111 a d
Ni n ff (1950 -1960) N be P i e i h i g be i i he c a egi f he igh chai
Ge ald Edelman: Di c e ed he c ee c e (ca b g ii )
fi g b i i g ace if ga i Di c e ed i h Be ce J e ei (f di i e
H chai = 3.5S f a ie ih i e a) = L chai ec e ed b
L chai = 2.2S a ig a a a ce
Ba ed e f a ai (c ea e IgG i h ee
iece )
Ge e igi a c ded f 110 a i acid
Cha ac e i ed b 4 ba ic e ide ( e a e ide) chai
b db -c a e b d a d di fide b d
C i f a ge chai (hea chai ) &
a e chai ( igh chai )
C i f 1 a iab e egi ( i e each
a ib d ) a d 1 ec a egi
MONOMER
Ba ic c a i fa i g b i
DISULFIDE CHAINS: S abi i e 3D c e fi g b i
Each e ha 2 a ai ab e A ige ic Bi di g Si e = 2
(N e: -c ale b d al hel i abili i g he c e)
Fab egi
In achain S abi i e he d ai (g b a /ba ike
Valence N . f c bi i g i e
egi ) f he e ide chai
M e - 2 bi di g i e
In e chain B d f d be ee (1) Hea a d igh
Pe a e - 5 e 2 bi di g i e = 10 a
chai a d (2) T hea chai
An ib d Valenc N . f ece i e f a ige
E i e f d i he a ige hich i bi d he
ac i e i e f he a ib d
An igen Valenc N . f a ige ic de e i a hich
e e a bi di g i e f a ib die

2 MAIN REGIONS
Va iable egi n U e a f he a ib d
U ed f bi di g f he a ige
C i e a i - e i a e d f chai
C n an egi n L e a f he a ib d
U ed f bi gica ac i i ie f IG ( i ai ,
bi di g f b h ece a dc e e f ag e )
C i e f ca b - e i a e d f chai
Di ided i 3 egi hea chai
Gi e a a e f each i g b i e
N e: Hinge egi n A he f e ibi i f he N e: I he c a egi he e he ca b g i f d, he
i g b i beca e i i ich i i e ca b h d a e i i ca ed (be ee CH2 a d CH3 a ea)
Abi i be d e 2 a ige -bi di g i e eae Ca b h d a e f nc i n :
i de e de & e gage i a g a i 1) I c ea e bi i f he a ib d
F e ibi i a i i effec f c i (i c de 2) P ec i f deg ada i
i i ia i fc e e ca cade & bi di g ce ih 3) E ha ce he f c i a ac i i f he Fc d ai f
ecific ece f Fc i ) he a ib d
F d i be ee CH1 (c a egi f he 1 I a beca e g c a i a ea
d ai ) a d CH2 (c a egi f he 2 d d ai ) be c i ica f ec g i i b Fc ece
a ea (f d hag c ic ce )
Si e he e he e e ac
Regi n De c i i n Im ance
P e e i gamma, al ha, & del a chain
Ab e i &e i chai VH a iab e egi f H chai Bi di g i e f a ige he e
h e a iab e egi ae
Va iable egi n C n an egi n
f d (CDR1,2,3)
U e a f a ib d L e a f a ib d
VL a iab e egi f L chai Bi di g i e f a ige he e
C i f 110-120 a i acid f Ha i i a a i acid e e ce h e a iab e egi ae
b h H a d L chai ha a ie f ( i i 111 ad )a g each f d (CDR1,2,3)
ei g b i ca a he e Ig
CH1 c a egi he Bi di g i e f C4b
Se e ce f A.A. c i i g f Se e ce f A.A. c i i g f 1 d ai f H chai (c e e f ag e )
e ide chai change e ide chai i fi ed and
CH2 c a egi he Bi di g i e f C1
nchanging
2 d d ai f H chai ( ec g i i ec e)
Amin g (NH2) i e i a Ca b lg (COOH) i
CH3 c a egi he Bi di g i e f he Fc
e d e i a e d
3 d d ai f H chai ece f di c e
F ci : binding i e f Ag F c i : e a ed he bi l gic a d ac hage .
ac i i ie f Ig ec e A he e hag c e (B&T),
a a ce , he e g
Incl i n : VH a d VL, c ec i e Incl i n : CL, CH1, CH2, a d a ce a ach
e ed a Fab egi n (a ea he e CH3
a ige bi d ) CL c a egi f L chai -
DOMAINS AMINO ACID TERMINAL ENDS

G b a egi f e ide chai E i a f ded c ac g b a b i (ba ed
S abi i ed b i achai di fide b d f ai f ba - ha ed a each d ai )
S abi i ed b di fide b d
F Be a- lea ed hee
P e diffe e e e ce i a Ab i h diffe e
ecifici ie i h 3 di i c egi f h e a iabili
Imm n gl b lin f ld - c i d ica c ef f ded
d ai f H chai i i g i h L chai
Whe e a ige i ca ed b bi di g
h e a iab e egi each chai

H e a iable Regi n : Di c e e /f e i e
jec i g a d f he e i a e d f he a iab e L chai .
Thi i he i e he e he e i e bi d
CDR (c m leme a i de e mi i g egi )
Occ a i f d f a iab e egi
f b h chai
C i f CDR1, CDR2, CDR3
A ige bi d i idd e f CDR i h a ea f f
CDR i ed
Ag i ca ed i hi he f d b bi di g a he e
h e a iab e egi
ANTIBODY FRAGMENTS
Lef : Fab egi i c ed f he i g b i f d he e C alli able F agmen (Fc)

he h e a iab e egi i f d E c a e ha i f he i g b i
ec e f he ca b egi he Hi ge
POLYMER Regi /H chai
Ig c ed f e ha a i g e ba ic e ic i S a e c a i e a 4℃
M n me : 1 c a i (EX. IgG, IgD, IgE, Re ib e f c e e fi a i a d i a i
e IgA) i ai
Dime : 2 c a i (EX. Sec e IgA) C ed f CH2 a d CH3 f he i g b i
T ime : 3 c a i N a ige -bi di g abi i
Pen ame : 5 c a i (EX. IgM) hich i He d ge he b di fide b di g
ec e ed b a a ce F effec f c i f Ig ( i ai &
J ining Chain (J Chain): P e ide chai ha a c e e fi a i )
h d e ic IgG i 1 c e An igen Binding F agmen (Fab)
Sec e C m nen : S b a ce a ached a e ic E c a e he i fi g b i f
Ig f d i ec e i he Hi ge Regi he A i Te i a Regi
Pa ic a ee i ec e IgA a ib d ha i Re ib e f bi di g a ige
a f he c a ce Re e e 1 a ige -bi di g i e
Faci i a e a c a face C i f e L chai & e-ha f f a H chai
Ma k i e IgA ha d be he d ge he b di fide b di g
ce ib e ea e c ea age
ENZYME DIGESTION STUDIES
A ached Fc egi a d hi ge i f a ha
chai f IgA 1) PEPSIN En me
Sec e ed b a a ce Ta ge he HINGE Regi ( e ii e e e a ack)
H mi g - eeki g be i he ia i eb E e c ea age a ceed f NH2 e i a g i g
ac i a ed h c e COOH e i a (Ca b e i a ide f he i e chai
Ta c i - ce he e IgA a d SC ec di fide b d)
a e ake i ide he ce a d e ea ed he ie C ea e be he di fide b d ha i k he 2
face hea chai
Pe in Dige i n f an In ac Ig in 2 iece ; P d c
f med:
(Fab)2 + Fc
(Fab)2 + Fc

Red c i b Me ca e h a i e
Me ca e ha ha d f he
b eakd he a ib d b de i g
di fide b d
Re l : 2(Fab)2 + Fc
Fab 1 L chai a d H chai
Remembe hei c m i i n:
Fab 2 Ligh chai a d 2 ha e f Hea chai
Fc 2 ha e f he Hea chai
REARRANGEMENT OF HEAVY CHAINS

Gene f Va iable Regi n
1) VH (Va iab e) ge e
2) D (Di e i ) ge e
3) J (J i i g) ge e
Gene f C n an Regi n : C > C > C 3 > C 1 > C 1 >
C 2>C 4>C >C 2
Occ af e he i f -chai
Rea a ge e i i i a i h hea chai e ce he ack D
egi
2) PAPAIN En me T e f j ining f egmen :
Dige i e i 3 iece 1. DNA e e ( cc i -B ce )
Ta ge he i achai di fide b d b c ea i g he b d I i ia ed b RAG-1 & RAG-2 ( ec bi a e
ha i k he hea chai e e )
Pa ain Dig. f an In ac Ig: P d c f med: Rec g i e ec mbi a i ig al
2 ec e f Fab + Fc e e ce
Fd O e D & J ge e a d ch e & j i ed
Deg adab e f ag e b ec mbi a e e me i h de e i f
Red c i b e ca e h a i e i e e i g DNA
C i e f he a i e i a ha f f he V ge e j i DJ c e V(D)J ge e
e i a chai ( a iab e i fi) VDJ ge e = c de f e i e a iab e egi
F c i : bi d he a ige a d i f H chai
e ha ced b he igh chai 2. RNA e e - he e a iab e a d c a egi ae
N e: Fd i d ced b a ai dige i j i ed
a d ed c i C e e DNA f c a egi
★ I ac Ig i added i h Me ca e h a i e C a egi i iced VDJ c e
P d c i 2 Hea Chai a d 2 Ligh Chai d i g a ci i
C chai - fi he i ed
(c e J egi ) a ke f
e-B h c e
C chai - e a c ibed

Unlinked cl e f gene ha enc de H man Ig:

1) Ch m me 14 - c de f he a iab e egi he
Hea Chai
Ge e eg e ib a ie i ed ( eg e ):
V (Va iab e)
D (Di e i )
J (J i i g)
2) Ch m me 2 - c de f he Va iab e egi he
Ka a (𝝟) Ligh chai
3) Ch m me 22 - c de f he Va iab e egi he
Lambda (ƛ) Ligh chai
Gene egmen lib a ie in l ed in he n he i f

he Ligh Chain:
V (Va iab e)
J (J i i g)
REARRANGEMENT OF LIGHT CHAINS
P ceed af e chai he i
L chai - ack a D egi
Rec bi a i f eg e cc f igh chai
La bda (ƛ) Ligh chai = ch e 22
Ka a (𝝟) Ligh chai = ch e2
VJ i j i ed b c i g i e e i g DNA
V𝝟 a d J𝝟 eg e bec e e a e j i ed
Ta ci i a d ici g cc
RNA ici g - e e a a ged J eg e
L chai j i ed i h chai f c e e IgM a ib d
(fi a ea i i a e B ce )
ALLELIC EXCLUSION
DEVELOPMENT OF ANTIBODIES
P ce he eb he ce i c i ed he e e i fa
Acc di g : SUSUMU TONEGAWA a ic a V egi f i hea chai a d i igh chai
Ch e c ai i ac Ig ge e . Di e i i he Ig Occ f i g a cce f ea a ge e f he Ig DNA
ec e i ge e a ed a a e f a ic ec bi a i f eg e
ge e
I e ge e ea a ge e d ce ecific a ib die

IgG4 (4%) - accha ide a ige

IgG2 & 4 = edia fc e e ac i a i
Ba ed be f di fide b idge : IgG3 > IgG1 >
IgG2 > IgG4
Va iabi i i hi ge egi affec abi i each f
a ige & abi i i i ia ed i a bi gica
f ci
M lec la c e : M e
Di ib ed a e a be ee i a a c a &
e a a c a ace
High diff i c efficie a i e e e a a c a
ANTIBODY CLASS SWITCHING ace e eadi c a ed he Ig
AKA I e S i ching
Whe ei da gh e a a ce ca d ce a ib d f
a he e
FUNCTIONS
P ide i i e b a ib d ha ca c
ace a
Fi i g c e e ac i a i
C a i g a ige f e ha ced hag c i ( i ai )/
Faci i a e i ai
Ne a i a i f i a d i e
Pa ici a i i agg i a i a d eci i a i eac i
Be e a eci i a i eac i (i e a
b e a ic e ch a IgG)
ADCC
IMMUNOGLOBULIN G (IgG)
IMMUNOGLOBULIN M (IgM)
M ed i a /ab da i g b i ca
75-80% f e Ig Bigge i g b i (AKA Mac gl b lin )
*70-75% f a e Ig [acc di g S e e ] Half life: 6-10 da
Maj Ab i ec da i e e e M lec la c e: Pe a e
MW = 150,000 (7S) Highe i e i i a i e e e
L nge half-life (a 23-25 da ) 5-10% f e i g b i
S a e i g b i ec e MW = 970,000 (19S)
Ha 4 bcla e ( ai diffe i be & ii f 1 a ea af e A ige ic S i ai
di fide b idge be ee ga a chai ) C ai 10 f c i a bi di g i e
IgG1 (66%) - e d ei a ige I c de e ec a d ai f d ga a chai
G d a i i ia i g hag c i bi d F :
g Fc ece Pe a e ic = ec e ed i e
IgG2 (23%) - e d accha ide a ige M e ic = B ce face
Ca c ace a J (j i i g) chai
IgG3 (7%) - ei a ige H d ge he fi e e ic i
La ge hi ge egi ( be f G c ei ade i a a ce ha c ai
i e chai di fide b d ) efficie e e a c ei e e id e
a bi di g c e e Se e a i kage i f di fide b d be ee
G d a i i ia i g hag c i bi d adjace e
g Fc ece

Ma i i ia e e i a i & faci i a e ec e i a
c a face
O e J chai e e a e
M e efficie ha IgG i c e e ac i a i
F d i i a a c a a d i he b d f id
i e
Ca c he ace a
U ed diag e ac e i fec i
N e ce e i f IgM
M e efficie i agg i a i eac i
FUNCTIONS
C e e fi a i IMMUNOGLOBULIN A (IgA)
Agg i a i
O i ai Re e e 10-15% f a ci c a i g i g b i
T i e ai ai MW = 160,000 (7S)
S face ece f i a e B ce P ed i a Ig i ec e i
M efficie i ac i a i g he c a ica c e e ah a B d Sec e i - I a Di e
(i i ia e eac i f i e bi di g i e ) An i e ic Pain
Na a I he agg i i - ABO a ib die S he i ed a highe a e ha IgG
Ha 2 bc a e
1) Se m IgA / IgA 1
Mai e ic
P e ib e h gh c
2) Sec e IgA / IgA 2
P ed i a f i ec e i a c a face
S he i ed i a a ce f d ai i MALT
Ha 13 a i acid e ha IgA1
M e e i a e bac e ia
ei a e ha c ea e IgA1
Di e i h J Chai a d ec e c e
I e Re e A ea i b ea i k, c , a i a, ea &
ea
★ NOTE: IgA ca ab e f C a ica C ac i a i
An i-inflamma agen
D - eg a e IgG- edia ed
hag c i , che a i , bac e icida
ac i i a d c ki e e ea e
Pa c a face
Ne a i e T i
FUNCTIONS OF He e e bac e ia adhe e ce
SERUM IgA c a
Ca ab e f ac i g a i (bi di g
IgA- ecific ece e hi ,
c e & ac hage igge
e ia b & deg a a i )

Pa c a face a d ac a a fi
i e f defe e
Ne a i a i f i
P e e bac e ia a d i a adhe e ce
c a face
IMMUNOGLOBULIN D (IgD)
P ide a a a i e i i
e b h gh b ea feedi g Smalle c ncen a i n i e (a 0.001%)
Ca ab e f ac i g a i M aef d face f ai e B L h c e
Be ie e a a e i eg a i g B-ce a ai a d
diffe e ia i
Half life: 1-3 da
MW = 180,000
E e ed i a ed B ce face
Sec d e fi g b i a ea
FUNCTIONS OF Idea ea e de a ige
SECRETORY P a a e i B cell ac i a i n, ma a i n and
IgA diffe en ia i n
Ha a g hi ge egi e ce ib e
e i
D e bi d c e e , e hi ac hage
IMMUNOGLOBULIN E (IgE)
Lea ab ndan in e m (a . 0.0005%)
MW = 190,000 (8S)
N ca ab e f C fi a i , agg i a i , i ai ,
c i g he ace a
N i ance Ab
Reagi ic a ib d
Pa ici a e i i edia e h e e i i i ie eac i (EX.
A h a, A a h a i , Hi e )
P d ced b a a ce a g a d i ki
A ache he f i g af e he i h gh Fc R (CH3)
Ba hi
La ge ha ce
E i hi
Ti e a ce
M hea - abi e f a i g b i

Hea i g a 56 C f 30 i -3 h
c f a i a cha ge & e abi i bi d
a ge ce
Bi di g ca e deg a a i (hi a i e & he a i e ea e)
Ca e eIi edia e h e e i i i (a e gic
eac i ) ha fe e , a h a, i i g, dia hea,
hi e & a a h ac ic h ck
FUNCTIONS
Abi i ac i a e a ce & ba hi
P a a aj e i a e gic eac i
Vi a i e i i a i i a a i e , e ecia he i h
T igge ac e i f a a eac i ha ec i e hi
&e i hi ie fi fa ai
TYPES OF ANTIBODY DIVERSITY
Defi ed b he c a egi f he H
chai
The H chai ha i i e each Ig c a
U i e a i acid e e ce c
a Ig ec e f gi e c a i gi e
ecie
Ha e diffe e hea chai
Re e e c a e f a ib d
ISOTYPES
PROPERTIES OF IMMUNOGLOBULIN
Hea Chain C n an Regi n

A ha > IgA
De a > IgD
Ga a > IgG
M > IgM
E i > IgE

Ha e he a e c a egi ih
i ,b i gic diffe e ce
Ge e ic a ia i i he c a egi
Ba ed he diffe e ce i a i acid a a
a ic a ii he c a egi f
he H L chai
Occ i 4 IgG bc a e , 1 IgA bc a ,
a d i ka a igh chai
Diffe e i di id a ha e diffe e a e
Defi i i : A ige ic de e i a ecified

b a e ic f f he Ig ge e
S ce f a i-a ic Ab
L ca i
Occ e ce
EX. G , k
ALLOTYPES
E : G1 3 & G1 17 a e f ga a
chai
THEORIES TO ANTIBODY DIVERSITY

INSTRUCTIVE THEORY OF ANTIBODY PRODUCTION
Acc di g hi he , An igen la ed a cen al le in

Va ia i i a iab e egi ha gi e de e mining he ecifici f Ab m lec le
i di id a a ib d ec e ecifici A a ige i c he i c e e ce (i.e. he ce
C i f a iab e i i e did ha e a ge e ic i f a i ea ie he e e
ecific a ib die a a ige ) he i e c e e a b d
IDIOTYPES N e: The a ic a a ige d e ea a e ae
The e a e a ib die ha ec g i e
diffe e ecific e i e a d hich a ib d d f d. The Ab d he eb
Each idi ei c ed f e ea a e a c fig a i c e e a ha f he
idi e c bi i g ide a ige e ae

T in c i e he ie la ed a e a f ll : Thi i ac i a e he ece a d
1. DIRECT TEMPLATE THEORY he e i a e d ci f he
Fi a ed b B einl and Ha i (1930) a e e f ece ha
Pa ic a a ige a ige ic de e i a d ci c a e a a ib die
e ea a e a e agai hich a ib die d (C e a Mecha i )
f d T ke e i e :
The a ib d ec e d he eb a ea L ck-a d-ke c ce f
c fig a i c e e a a ige e ae he fi f a ib d f
2. INDIRECT TEMPLATE THEORY a ige
Fi a ed b B ne and Fenne (1949) A ige e ec ed ce ih
The gge ed ha he e f a ige ic b i -i ca aci e d
de e i a i he a ib d - d ci g ce i
i d ced a he i ab e cha ge i he e ce . A
Je ne (1955)
ge c f he a ige ic de e i a a
D i g he e b ic ife, i i
i c a ed i ge ea d a i ed he
fg b i ec e e e f ed
ge ce /
agai a ib e a ge f
SELECTIVE THEORY OF ANTIBODY PRODUCTION a ige
NATURAL The a ige , he i d ced
Acc di g hi he he i c e e ce ha e a
SELECTION THEORY he h , c bi e e ec i e ih
e ic ed i gica a ge
(1955) he g b i ec e ha ha he
A ige i a e he i c e e ce e ec i e
ea e c e e a fi
he i e a a ib d
The g b i i h he c bi ed
i.e. a he ge e ic i f ai i e e i he ce
a ige i a ed a ib d -f i g
bef e e c e i g he a ige
ce d ce he a e e f
The ce ee d ci g a ib d a e e b a ige ic
a ib d
i ai e i d ci f e ec i e a ib die
B ne (1957)
P i a ige e e, ce ai ce
I di id a h c e ae
a ead e ecific face
ge e ica e ga ed
ece
d ce e e f
O ce a ige i i d ced, i i
i g b i
e ec i a ia e ece
A ecific a ige fi d e ec
The bi di g be ee he a ige
h e a ic a ce ca ab e f
a d he ece ead b eaki g
e di g i , ca i g he
ff he ece a a ib die
ife a e
hich he e e he ci c a i
Ne ece df i ace
f b ke ff ece
CLONAL SELECTION
EHRLICH S HYPOTHESIS
SIDE-CHAIN (1957)
THEORY
(1898)
A a ge be f c e f
i gica c e e ce
I -c e e ce ha e bea i g ecific a ib d a e
face ece ha a e ca ab e ae d ced d i g fe a
f eac i g i h a ige , hich de e e b a ce f
ha e c e e a ide chai a ic ai fi gica
S ecific a ige fi he e
c e e a

c e e ce (ICC) agai a T e a a e ge e c de f he
ib e a ige c a a d a iab e egi f
A i di id a ICC e e e i g b i
RECOMBINATIONAL
e b a e ece ha a e The e c d be a a be
GERMLINE THEORY
ecific f a di i c a ige c di g f he c a egi a d
Thi i e ece a a ge be c di g f he
ecifici i de e i ed a iab e egi
bef e he h c ei
The b e ed e e i e i
e ed a ige
ge e a ed f a i i ed be f
Bi di g f a ige i ecific SOMATIC
i he i ed V- egi e e ce
ece ac i a e he ce a d VARIATION THEORY
The de g a e a i i hi B
ead ce a ife a i f
ce d i g he i di id a ife i e
c e , he i i g he a ib d
M idel acce ed he
P ide f a e kf MONOCLONAL ANTIBODIES
be e de a di g f
he ecifici , A ib die de i ed f a i g e a e a ib d - d ci g
i gica e , ce ha ha e d ced a i e , h f i gac e
a d he e f De e ed f diag ic e i g f B ce ha he i e
ec g i i f efa d e ecific a ib die
- e f b ada i e PRODUCTION OF MONOCLONAL ANTIBODIES
i i
D a back: c ide a i f ge e ic
ba i f di e i f a ib d
ec e
D e e & Be e (1965)
ed ha c a & a iab e
i c ded f b e a a e
ge e
APPLICATIONS
Diagn ic Te
Ab a e ca ab e de ec i a ( g/ L) f
ec e
EX. P eg a c H e
Diagn ic Imaging
Ab ha ec g i e a ige a e adi abe ed
i h i di e I-131
Imm n in
Ab c j ga ed i h i
mAb clea a h gen
HYBRIDOMA TECHNIQUE
De e ed b Ge ge K h e a d Ce a Mi ei ( 1975) -
di c e ed ech i e d ce a ib die a i i g f
i g e B ce
*H b id ma - f i f diffe e e f ce

U e f i f a ac i a ed B ce i h a e a ce ha ca
be g i defi i e i he ab a
HYBRIDOMA PRODUCTION
A ei i i ed i h a a ige
The ee i ha e ed a d c bi ed i h e a ce
ih e h e e g c (PEG) a fac a
PEG - b i g ab f i f a a ce ih
e a ce
Ce a e he aced i c e edi ihh a hi e,
a i e i , a d h idi e (HAT edi ), hich i e ec i e
f h b id a ce
HAT edi - e aae h b id a ce
(a i g g e ec i e & a i g f ed
e a ce f ed ee ce i e)
M e a ce ca he i e
c e ide die
N a B ce ca be ai ai ed PRIMARY and SECONDARY IMMUNE RESPONSE
c i i ce c e die
H b id a ce a e di ed a d aced i ic i e e PRIMARY IMMUNE RESPONSE
g L g ag ha e
Each e (c ai e c e) i c ee ed f e e ce f S e e ia i c ea e i a ib d
de i ed a ib d b e i g e aa Sh i ed e e
CLINICAL APPLICATIONS SECONDARY IMMUNE RESPONSE

I i ia ed f i i diag ic A a e ic e e
P eg a c e i g (a ib die f Be a chai f HCG) Sh ag ha e
De ec i f a ige A ib d i c ea e i e a id
Mea e e fh e e e L g i ed e e
The a e ic age
T ea e f ca ce
Ta mab (He ce i ) - e a a ic b ea
ca ce (Ab agai HER-2 ei )
Ri imab (Ri a ) - -H dgki
h a & he B-ce a ig a cie
( a ge CD20 de e e e i he a B
ce )
Ce imab (E bi ) - c ec a ca ce &
head a d eck ca ce
Be aci mab (A a i ) - c ec a ,
- a g & b ea ca ce
A ib d -d g c j ga e
Ib i m mab i e a (Ze a i ) - ca ce
B h c e
T i m mab (Be a ) - e -H dgki
h a
A i e di ea e
I fli imab & adalim mab - he a id
a hii &C h di ea e (b ck
TNF-a ha)

EVOLUTION OF HUMORAL RESPONSE
T-CELL RECEPTOR
O f d he T ce e ba e
C ed f 2 e ide chai , (a ha) a d (be a)
G c ei ec e i ade fac a a d a iab e
egi hich c i e he a ige -bi di g ie
S e TCR e e a (ga a) a d a (de a) chai
The e ha e ecifici f c e i a a ige ,
ch a hea a d h ck ei h h i id
T-CELL DIFFERENTIATION
Th m c e
L h c e i he Th
Ma ke : CD44 a d CD25
STAGES
1) D ble-Nega i e S age
Th c e ha ack CD4 a d CD8
P ife a e i he e c e de he
i f e ce f IL-7
2) D ble-P i i e S age
Whe he h c e e e b h CD4
a d CD8

T-HELPER SUBSETS
Th1 - Agai i ace a a h ge
Th2 - Aid B ce d ce a ib die
Th9 - Ha e i fa a effec
Th17 - I c ea e i f a a i a d j i de ci
T eg - S i ch ff i e e e
MATURE T-CELLS
S i f e ec i ce e
E hibi e e f a ke :
1) CD4 + T-cell
AKA T Hel e T Ind ce cell
I e ac i h a ige a d MHC II ei
2) CD8 +T-cell
AKA T C ic cell
I e ac i h a ige a d MHC I ei
ACTIVATION
POSITIVE OF T-HELPER
SELECTION OF CELLS
THYMOCYTES
B-CELL DIFFERENTIATION
P -B Cell
Ma ke : CD19, CD45R, CD43, CD24, c-Ki
P e-B Cell
NEGATIVE
Wi h chai i c a a d e i e i ce
SELECTION OF
face
THYMOCYTES
Ma ke : CD19, CD45R, a d CD24
Imma e B Cell
Di i g i hed b he a ea a ce f c e e IgM
ec e he ce face
Ma ke : CD19, CD45, CD24, CD21, CD40, a d
MHC II ec e

Ma e B Cell
Ha e IgM a d IgD i face f a ach e f
a ige
Ei he a gi a e B ce F ic a B ce
Pla ma Cell
Re e e f diffe e ia ed h c e
Mai f c i i a ib d d ci
Pla ma Cell
Ma e B Cell
BCR TCR
ISOLATION AND B AND T CELLS
ROSETTE
TECHNIQUE

POST-TEST
1) Which f he f ll ing e e a a ignaling ein
nce an an igen i a ached he TCR?
USE OF FICOL a) CD2
HYPAQUE b) CD3
c) CD4
d) CD8
2) (T/F) D ble i i e h m c e in he h mic c e
nde g a i nce he eac ngl
elf-an igen f MHC
3) Which f he f ll ing cl e f diffe en ia i n i ed
iden if T eg la cell ?
a) CD4 a d CD25
b) CD8 a d CD16
CELL FLOW
c) CD4 a d CD16
CYTOMETRY
d) CD8 a d CD25
4) T c ic cell all a ge hich f he f ll ing?
a) Vi a i fec ed ce
b) T ce
c) Bac e ia a ige
d) A a d B
5) (T/F) An igen m be ce ed b APC i
ec gni i n f B cell ece
6) A ce he eb an an ib d facili a e
hag c i f ea ie eng lfmen f he an igen
7) The m efficien an ib d cla ac i a e he
cla ical a h a f c m lemen em
8) The m ed minan an ib d cla ec nda
imm ne e n e
9) The nen f he cl nal elec i n he f
an ib d di e i
10) Which f he f ll ing c m nen i n incl ded in
he medi m f ha e ing h b id ma cell ?
a) H a hi e
b) A i ei
c) Th idi e
d) P e h e e g c

So rce : PPT, a nchrono lec re ideo, Book and o her reference
1980s cha ac e i ing b molec la cloningand e p e ing
UNIT 5: CYTOKINES indi id al c okine molec le and p od c ion of monoclonal
and ne ali ing an ibodie .
Pre-test CYTOKINES
1. Name fi e (5) diffe en c okine Group of proteins made b he imm ne em ha ac a
a. Chemokine chemical messengers.
b. In e fe on Allo ing cell- o-cell comm nica ion
c. In e le kin Reg la e he imm ne em, o che a ing bo h inna e and
d. L mphokine acq i ed imm ni , induction of the inflammator
e. T mo Nec o i Fac o response, the regulation of hematopoiesis, and ound
2. An ac ion of a c okine ha ac in conce on he ame cell healing.
a. Pleio op In hema opoie i elea e of c okine o ld
b. S nerg allo g o h and p olife a ion of diffe en blood
c. An agoni m cell depending on he need o he igge
d. Ca cading Wo nd healing in ol emen of non-imm ne
3. The follo ing a e nde he inna e imm ni ha gene a e cell , e.g. fib obla and endo helial cell
c okine e cep : The abili o inabili o gene a e ce ain c okine
a. Mac ophage pa e n of en de e mine he o come and clinical
b. Endo helial cell co e of infec ion
c. Fib obla P od ced b imm ne cell and (in ce ain ca e )
d. Natural Killer cells non-imm ne cell
4. An inna e imm ne e pon e ha p od ce pecific Majo immune cells ha elea e c okine :
in e le kin ha gi e capilla effec and ac i a e 1. T helpe cell
ne ophil 2. Dend i ic cell
a. IFN be a (Fib obla ) 3. Mac ophage
b. IFN alpha (Fib obla ) Non-immune cells
c. TNF (Macrophages) 1. Endo helial cell lining he blood
d. A and B e el
5. Beca e of hei imm nomod la o , an i- i al and 2. Fib obla connec i e i e cell
an i-p olife a i e p ope ie , c okine p incipall in e fe on e pon ible fo he p od c ion of fibe &
(IFN)- alpha and in e le kin (IL)-2 a e c en l ed fo : nece a in he healing p oce ( o nd
a. Treatment of immune-mediated medical healing)
illnesses Ind ced in e pon e o he binding im li h o gh he
b. T ea men of bac e ial infec ion ecogni ion of fo eign Ag b ho l mphoc e
c. T ea men of diabe e Ho c tokines initiate cell-to-cell signaling?
d. T ea men of Le kemia 1. Binding
NOTE: C okine o ld onl ac on cell
bea ing he pecific ecep o .
DISCOVERY AND CHARACTERIZATION OF Going back o he ligand ecep o concep ,
CYTOKINES he c okine o ld f nc ion a a ligand,
In ol ed an in e iga ion of infec io di ea e o of and a a ligand, i o ld bind and in e ac
an igen-ind ced imm ne e pon e. o a pecific ecep o .
1950 - 1970s in ol emen of n me o p o ein fac o The ecep o can be fo nd on
p od ced b diffe en cell media ed b f nc ion in he face of diffe en cell .
pa ic la bioa a an i i al in e fe on , fe e -p od cing The p od c ion of c okine a e ind ced
p ogen , and mac ophage-ac i a ing fac o ee b diffe en fac o o im li.
di co e ed. P e ence of foreign agents, e.g.
1970s in ol emen of he p ifica ion and bac e ial componen (LPS,
cha ac e i a ion of man indi id al c okine and p od c ion flagellin)
of ne ali ing an i e a. Other c tokines
CASTILLO, J. KHOO, J. MAGTIBAY, M. 3D REVS 2022

Once he c okine bind o he pecific Biological Effects of C tokines

ecep o , hi o ld igge he
signal-transduction path a s.
2. Triggering signal-transduction path a s
P oce he ein a ph ical o a chemical
ignal o ld be an mi ed o a cell
h o gh a e ie of molec la e en
In he ca e of c okine , hi i p ima il
protein phosphor lation i h he e of
diffe en b ance o en me
(e ample: Jan kina e )
Re l in a cell la e pon e
In ol e binding of ligand (c okine ) and
i ecep o p e en in he cell
3. Alter gene e pression in the target cells
E en all , he gene e p e ion o ld Macrophages o ld be e pon ible fo he p od c ion of
p od ce p o ein ha o ld lead o he he c okine : TNF (pa ic la l he TNF- ) and IL-1
biological effec of he c okine The mac ophage ill ec e e he men ioned
Ind ce fe e c okine beca e of he p e ence of bac e ial
Ind ce p olife a ion of diffe en p od c , o he c okine , o o in like LPS
imm ne cell TNF & IL-1 a e p ima il pro-inflammator c okine .
Do n eg la ion of o he LOCAL EFFECTS
c okine nega e o inhibi he Vascular endothelium
elea e of o he c okine The can p omo e he e p e ion of le koc e
The c okine ha a e elea ed a e onl adhe ion molec le
in er small amounts b o ld e hibi Effec on he a c la endo heli m o
high affinit o he ecep o . lining of he blood e el
P omo e f he p od c ion of IL-1, chemokine
Chemokines c okine nece a fo
chemo a i o diapede i o happen; fo
he ne ophil o each he i e of inj
Procoagulant and anticoagulant acti it
P omo e coag la ion o clo ing
Pla ele adhe ion = o gh e el =
e en all cell o ld adhe e o he
e el
E en all , he change in he a c la
endo heli m o ld p omo e inflamma ion.
Leukoc tes
Migration & acti ation of WBC
In ca e of ac e inflamma ion, ha o ld
be he ne ophil follo ed b
mac ophage
Re ea e f TNF a d IL-1 che e d c
e che a inflamma ion
Fibroblasts
P olife a ion
Collagen n he i
T igge he p oce of repair

SYSTEMIC EFFECTS Major Anti-Inflammator

Major Proinflammator
S emic Manife a ion of Inflamma ion C tokines
C tokines (fo do n eg la ion)
Fe e
IL-1 i e ell-kno n fo hi TNF- TGF-
Con ide ed a e d ge ge
IL-1 IL-10
fe e -ind cing c okine
Ta ge ing he h po halam o inc ea e he IL-6 IL-13
empe a e p omo e de c ion of pa hogen IFN- IL-35
Le koc o i
Ac e-pha e p o ein General Properties of C tokines
[De a e a PPT]
In he li e
Impo an ma ke of inflamma ion 1. C okine p od ced d ing he effec o pha e of na al and
Appe i e pecific imm ni and e e o media e and eg la e imm ne and
inflamma o e pon e .
Sleep
2. C okine ec e ion i a b ief, elf-limi ed e en . Con olled b
C tokine Families po - an c ip ion mechani m, ch a p o eol ic elea e of an
ac i e p od c f om an inac i e p ec o .
➢ Naming of he c okine can be ba ed on f nc ion and pe
3. Man indi id al c okine a e p od ced b m l iple di e e cell
of cell he e he e e fi i ola ed
pe .
1. Chemokines 4. C okine ac pon man diffe en cell pe pleio opi m
Impo an fo chemo a i (chemoa ac ion) o p od ced b le koc e ha ac pa ic la l on in e le kin .
happen 5. C okine of en ha e m l iple diffe en effec on he ame a ge
2. Interferons cell. Some occ im l aneo l , he ea o he ma occ o e
P e en o inhibi i al eplica ion, mo g o h diffe en ime f ame (i.e. min e , ho o da ).
In ol ed in an i i al e pon e 6. C okine ac ion a e of en ed ndan one c okine ha p o ed o
be ha ed p ope ie of e e al diffe en c okine .
3. Interleukins
E .: knock-o mice lack pa ic la gene e di pla
Sec e ed b le koc e and impo an fo abno mali ie on hei imm ne e pon e .
in e cell la ac ion 7. C okine of en infl ence he n he i of o he c okine leading
Ac a media o be een le koc e o ca cade in hich a econd o hi d c okine ma media e he
Va majo i of he e a e p od ced b TH cell biologic effec of he fi c okine.
4. L mphokines 8. Of en infl ence he n he i of o he c okine o niq e effec ,
Sec e ed b l mphoc e a kind of in e ac ion commonl efe ed o a ne g .
9. C okine , like o he pol pep ide ho mone , ini ia e hei ac ion b
5. Tumor necrosis factor (TNF)
binding o a pecific ecep o on he face of a ge cell.
P omo e l i /nec o i of mo
Autocrine action ec e e b he ame cell
6. Transforming gro th factor (TGF) Paracrine action a nea b cell
Ind ce g o h a e in mo Endocrine action a di an cell im la ed ia c okine
Do n eg la ion of inflamma o eac ion ha ha e been ec e ed in o he ci c la ion; emic
Mac ophage & T cell 10. The e p e ion of man c okine ecep o i eg la ed b pecific
7. Colon stimulating factor (CSF) ignal . Thi ignal ma be ano he c okine o e en he ame
Ac pon he cell of he bone ma o o p omo e c okine ha bind o he ecep o , pe mi ing po i i e amplifica ion
o nega i e feedback.
p olife a ion of diffe en blood cell
11. Mo cell la e pon e o c okine eq i e ne mRNA and
S ppo g o h of blood cell p o ein n he i
8. Monokines 12. C okine ac a eg la o of cell di i ion (g o h fac o )
C okine elea ed f om monoc e and ca ego i ed i h epi helial and me ench mal cell g o h
mac ophage fac o in o a la ge f nc ional g o p of pol pep ide
➢ C okine can al o be cla ified a pro-inflammator and eg la o molec le .
anti-inflammator . Functions of C tokines
The bod ill balance he elea e of he e
1. Media o of na al imm ni
c okine o gi e an app op ia e imm ne e pon e.
2. Reg la o of l mphoc e ac i a ion, g o h, and
Relea e of c okine o ld al o depend on he
diffe en ia ion, elici ed in e pon e o pecific an igen
pa hogen p e en o condi ion of he pa ien .
ecogni ion b T-l mphoc e ;
3. Reg la o of imm ne-media ed inflamma ion

ac i a e non- pecific inflamma o cell elici ed in

e pon e o pecific an igen ecogni ion b T
l mphoc e.
4. S im la o of imma e le koc e g o h and diffe en ia ion
p od ced b bo h im la ed l mphoc e and
o he cell .
5. Ma al o ac on cell o ide he imm ne em Cascade induction a c okine ec e ed b a pecific
Mechanisms of Action pe of cell can ac i a e a ge cell o p od ce addi ional
Pleiotrop A ingle c okine can ha e diffe en ac ion c okine .
and ha e diffe en a ge cell E .: TH cell IFN- ec e ion p omo e
E .: IL-4 p od ced b ac i a ed T helpe cell mac ophage p od c ion of IL-12 p omo e TH
(ha al ead me an an igen) and can affec cell o p od ce mo e c okine , e.g. IFN- , TNF,
diffe en pe of cell IL-2, and o he c okine
B cell ac i a ion, p olife a ion, and Can bo h be beneficial and ha mf l o he pa ien
diffe en ia ion Ad an age: apid gene a ion of inna e and adap i e
Th moc te p olife a ion e pon e
Mast cell p olife a ion Rapid e pon e elimina ion of
pa hogen o fo eign bod
De e mine he o come of clinical co e of
infec ion
In ce ain ca e , if he e i no eg la ion o
d f nc ion in he elea e of he c okine , hi can
lead o h e a of he imm ne e pon e.
Lead o h perc tokinemia, al o kno n
a he c tokine storm
O e p od c ion of c okine
Redundanc diffe en c okine can ha e he ame
E .: TNF- & IL-1
effec on he ame a ge (ac i a e ome of he ame
o e p od c ion (p o-inflamma o
pa h a and gene )
c okine ) inflamma ion
E .: TH cell p od ce IL-2, IL-4, and IL-5; he e
If he e oo m ch inflamma ion,
o ld all p omo e B cell p olife a ion ( ame effec )
he bod can no longe be in i
no mal a e and lead o
dele e io effec in he pa ien
O e helm he imm ne
e pon e
Al o ca e colla e al damage o
ho cell beca e of e ce i e
The e in e le kin o ld mo likel ha e he inflamma o e pon e
ame ecep o in he B cell , allo ing binding and Leading o ma i e fa ali ie
p olife a ion. Al o een in e e e i al
Pa he me age infec ion , ch a COVID-19
Addi ional e ample: IL-6 and IL-11 e gp130 c tokine storm i mo l he
b ni a pa of hei ecep o ca e of dea h
Some c okine ma ha e o e lapping effec Ti e damage
al e ac i i of man of he ame gene Do n eg la ion i done
o p e en he c okine
Antagonism one c okine ma counteract (inhibi , om
do n eg la e, o off e ) he ac ion of ano he c okine Gi ing an i-inflamma o
E .: IL-4 p omo e p olife a ion and cla i ching d g , c okine
of B cell o IgE b i h he p od c ion of an agoni
in e fe on gamma (IFN- ), i p e en cla Al o een in o he i al infec ion
i ching (infl en a) and bac e ial
di ea e ( la emia)

C okine o m can CHAIN OF CYTOKINE ACTION (cell-to-cell signaling)

ac all ca e dea h S im l C okine-p od cing cell C okine
S nerg /S nergism nei he c okine A o c okine B Recep o Ta ge Cell Biological effec ( )
ind ce a ong e pon e indi id all , b hen combined,
he ne e pon e i m ch g ea e han he m of he
indi id al e pon e .
Occ hen he combined effec of 2 c okine on
cell la ac i i i g ea e han he addi i e effec
of indi id al c okine
Concep of 1+1 = 3
E .: TH cell IL-4 + IL-5 p olife a ion + ind ce
he B cell o cla i ch o IgE f om IgM
C okine ac in ne o k effec complement
and enhance each o he
Autocrine action
Relea e of c okine o ld affec he gene a ing cell
( elf); p omo e p olife a ion o he ac ion of ha
pa ic la cell
E .: IL-1 inc ea e ac i a ion of
an igen-p e en ing cell
Paracrine action
Relea e of c okine o ld affec he nea b cell
Affec cell in he immedia e icini
E .: IL-1 can be elea ed b T helpe cell,
ac i a e ne ophil , decolo i e ne on
Endocrine action
Affec cell ha a e fa o emo e f om he
gene a ing/ ec e ing cell
C okine a e of impo ance in infec io di ea e fo o The c okine o ld pa h o gh he blood
con a ing ea on : e el fo ci c la ion o a d he a ge cell in a
The can con ib e o he con ol of infec ion emo e place
The can con ib e o he de elopmen of E .: IL-1 ec e ed in o he blood e el and
pa holog (i.e. ep ic hock). go o a d he h po halam o p omo e fe e ;
im la e he li e cell o p od ce ac e-pha e
eac an
C tokine Receptor
[Refe ab e a he e d f he e e e ]
FUNCTIONS:
1. Con e e acell la ignal , namel he p e ence of
pecific c okine , in o an in acell la ignal, ch a
ac i a ion of an en me ha can igge a a ge cell
e pon e.
2. The a e an memb ane p o ein , and he e acell la
domain bind c okine, he eb p o iding mean of
de ec ion of he e acell la ignal.

Pla ele adhe ion gaga a g a g blood e el

C tokine receptor famil members clo ing
TGF- an i-inflamma o , an agoni
INTERFERONS
The be e abli hed an imic obial c okine .
In e fe e i h i al eplica ion
i i he pe I IFN (IFN- and IFN- ) ha f nc ion
p ima il in hi manne
c c
De i ed in 1957 he e i infec ed cell ec e ed a
Multichain receptor comple es
molec le ha in e fe ed i h i al eplica ion in b ande
cell .
Th ee (3) pe : alpha, be a, gamma
T o pe of en me ind ced an i- i al a e:
P o ein kina e
2 ,5 -oligoaden la e n he a e
CYTOKINES IN THE INNATE IMMUNE RESPONSE

1. In e fe on alpha and be a
2. T mo Nec o i Fac o
3. In e le kin-1be a
4. In e le kin-6
5. T an fo ming g o h fac o be a
--------------------------------------------------------------------------------------------
Impo an fo he diffe en ph sical s mptoms a ib ed o 2 t pes: IFN- and IFN-
inflammation
P od ced b dend i ic cell and ind ce p od c ion of
In ol ed in induction of inflammation
p o ein and pa h a ha di ec l in e fe e i h i al
Ca dinal ign : Redne ( bo ), fe e (calo ),
eplica ion and cell di i ion.
elling ( mo ), pain (dolo ), p e ence of cell la
Help limi he infec ion o one ela i el mall a ea of he
infil a e (ne ophil ) a i e of inj
bod .
(Main f nc ion) Impo an fo recruiting effector cells o he
T pe I IFN ac i a e na al kille (NK) cell and enhance
affec ed a ea
he e p e ion of cla I MHC p o ein , h inc ea ing he
In ac e inflamma ion: ne ophil , mac ophage
ecogni ion and killing of i -infec ed cell .
Inc ea ed a c la pe meabili allo he fl id o
The pe I IFN a e al o ac i e again ce ain malignancie
leak f om he blood e el o he i e
and o he inflamma o p oce e .
P ( a a) can be p e en e da ion
IFN- i efficacio in ea ing m l iple cle o i
(fl id)
18 IFN- i ed o ea hepa i i C and Kapo i a coma,
Inna e IR i fa e b non- pecific, and i effec ill be een
le kemia and l mphoma .
i hin ho af e fi con ac i h pa hogen
Kapo i a coma a ocia ed i h HHV-8
P ocoag lan ac i i
IFN- and IFN- p od ce apidl i hin 24 ho of
Inflamma ion o ld p omo e coag la ion o clo ing
infec ion
C okine co ld a ge he lining of endo helial cell
& inc ea e pla ele adhe ion

IFN i mainl a T cell p od c and p od ced la e , and O e ec e ion can lead o ep ic hock
mo n ed NK cell . La ge amo n of TNF ec e ed in
In e fe on al o inhibi i a embl a a la e age, e pon e o g am nega i e bac e ial
con ib e o he an i i al a e: infec ion , ca ing a dec ea e in blood
Enhance cell la MHC pe e (h po en ion), ed ced i e
Ac i a e NK cell and mac ophage pe f ion, and di emina ed in a a c la
Inhibi i e i ho damaging he ho cell coag la ion
DIC ncon olled bleeding
dea h
P omo e a odila ion & inc ea ed a c la
pe meabili
TNF- ac i i i a lea pa iall eg la ed b
ol ble fo m of bo h TNF ecep o
The e ecep o ac o bind e ce TNF-
and, combined i h he ho half-life of
he ol ble fo m, e e o limi he
c okine ignaling ac i i TNF- ac i i
i a lea pa iall eg la ed b ol ble
fo m of bo h TNF ecep o
TNF- a ell a IL-1 a e p e en in he ma oid
no ial fl id and no ial memb ane of pa ien
i h he ma oid a h i i (RA)
TNF- i he cen al media o of
pa hological p oce e in RA and o he
inflamma o illne e ch a C ohn
TUMOR NECROSIS FACTOR di ea e, lce a i e coli i , and j enile
The p incipal media o of he ho e pon e o a hii
g am-nega i e bac e ia-lipopol accha ide componen
(LPS) in bac e ial cell all ha pla a ole in he e pon e TUMOR NECROSIS FACTOR RECEPTORS
o o he infec io o gani m . TNFR1
LPS in lo do e ac a a pol clonal ac i a o of B cell , P ima media o of TNF- an d c ion in mo
con ib e o he elimina ion of bac e ia. cell pe
High concen a ion LPS ca e inj , DIC, and hock Bind he ol ble fo m of TNF-
e l ing o dea h Sh art man reaction Con i i el e p e ed on mo i e and bind
Fi een and i ola ed f om he l mphoc e and ol ble TNF- .
mac ophage TNFR2
When he di co e ed hi , TNF ind ce Ac i a ed b he memb ane-bo nd fo m of TNF-
de c ion o l i of mo cell U all e p e ed in epi helial cell and cell of he
TNF- mo p ominen membe imm ne em
Con i of a lea 19 diffe en pep ide
E i in bo h memb ane-bo nd and ol ble fo m
and ca e a odila ion and inc ea ed
a ope meabili
T igge ed b LPS (lipopol accha ide G (-)
bac e ia)
Effec : a odila ion, a c la
pe meabili , and T cell ac i a ion
Sec e ed b ac i a ed monoc e and
mac ophage (fo nd in he memb ane )
Al o fo nd in ol ble fo m in ec e ion
Ac i a e T cell ind ce MHC Cla II
e p e ion, a c la adhe ion molec le , and
chemokine

INTERLEUKINS ph iological e pon e o IL-1

and n off he e pon e hen
Interleukin-1
no longe needed.
A pol pep ide de i ed f om monon clea phagoc e ha IL- i e pon ible fo mo of he ema ic ac i i
enhanced he e pon e of h moc e o pol clonal a ib ed o IL-1, incl ding fe e , ac i a ion of phagoc e ,
ac i a o (a co- im la o of T cell ac i a ion). and a ge hepa oc e fo ac e-pha e p o ein p od c ion.
Pro-inflammator c tokines p od ced b monoc e , Ind c ion of IL-1
mac ophage , and dend i ic cell P e ence of mic obial pa hogen , bac e ial LPS, o
A a media o of he ho inflamma o e pon e in na al o he c okine
imm ni O he f nc ion
Majo cell la o ce i he ac i a ed monon clea Endogenous p rogen (ind ce fe e ) effec on
phagoc e igge ed b : h po halam o inc ea e empe a e inhibi
LPS g o h of pa hogenic bac e ia and i e and al o
Mac ophage de i ed c okine (TNF, IL-1) inc ea e l mphoc e ac i i
Con ac b CD4+ T cell . H po halam he mo a of he bod
IL-1 and IL-1 a e p oinflamma o c okine p od ced b Production of ascular cell adhesion effec on
monoc e , mac ophage , and dend i ic cell ea l on in he he lining of he blood e el : ind ce p od c ion of
imm ne e pon e adhe ion molec le (impo an d ing he mig a ion
P od c ion ma be ind ced b he p e ence of mic obial of ne ophil f om he blood e el o he i e of
pa hogen , bac e ial lipopol accha ide , o o he c okine inj )
Famil con i of: Induction of IL-6
IL-1 alpha ❖ Chemokine and cell-adhe ion molec le
Remain i hin he cell a ac and a i le koc e o en e he
No elea ed in o he o nding a ea inflamed a ea h o gh a p oce kno n
If e e he a e elea ed, i i all af e a diapede i
cell dea h Production of CSFs in bone marro igge
IL-1 can be elea ed af e cell dea h and CSF o p od ce a pa ic la pe of blood cell,
can help a ac inflamma o cell o he eb inc ea ing he n mbe of cell needed o
a ea he e cell and i e a e being e pond o he damaged i e
killed o damaged
Interleukin-6
IL-1 beta
Re pon ible fo mo of he emic A ingle p o ein p od ced b l mphoid and non-l mphoid
ac i i cell pe .
Fe e , ac i a ion of phagoc e , L mphoid: T and B cell , monoc e , mac ophage
and p od c ion of ac e-pha e Non-l mphoid: endo helial cell , mo cell
p o ein Pa of c okine ca cade and i elea ed in e pon e o LPS
Ta ge li e cell o p od ce ac e pha e and ha an impo an ole in ac e pha e eac ion
eac an (APR) S n he i ed b monon clea phagoc e , a c la
Clea ed in acell la l o an ac i e fo m endo helial cell , fib obla , and o he cell in e pon e o
ha i hen ec e ed b monoc e IL-1 and TNF
Majo IL-1 p od ced E p e ed b a a ie of no mal and an fo med cell (T
➢ IL- and IL- a e p oinflamma o and B)
c okine p od ced b monoc e, Al o b : and a io mo cell
mac ophage , and dend i ic cell IL-1 p ima il igge i eac ion
IL-1RA (receptor antagonist) Pleio opic c okine
Al o p od ced b monoc e and Affec inflamma ion, APR, Ig n he i , and
mac ophage ac i a ion a e of B and T cell
C okine inhibitor IL-6 im la e B cell o p olife a e and diffe en ia e in o
An agoni o IL-1 do n eg la e effec pla ma cell ( ec e ing a pa ic la pe of an ibod ) and
of IL-1 o n off he e pon e hen no ind ce CD4+ T cell o p od ce g ea e q an i ie of bo h
longe needed p o- and an i-inflamma o c okine .
Block he IL-1 ecep o , hich IL6 Recep o Con i of IL-6R and gp130 e po ing
help o eg la e he o ine e id e in he in acell la po ion of he molec le

Onl one IL-6 ecep o ha been iden ified ha The e molec le ha e he abili o im la e he le koc e
con i of IL-6R ( he IL-6- pecific ecep o ) and mo emen (chemokine i ) and di ec ed mo emen
gp130 ( he common ignal- an d cing ecep o (chemo a i );
b ni ed b e e al c okine ). Reg la e he chemotactic acti it of le koc e
Binding of IL-6 o he IL-6R ind ce ( e pon e o infec io di ea e , a oimm ne
dime i a ion of gp130 i h he - b ni inflamma ion, cance , and homing l mphoc e o
Homodime i a ion confo ma ional l mphoid i e)
change in gp130 ha e po e o ine E .
e id e CCL2 o MCP-1 (monoc e chemoa ac an
Se ie of pho pho la ion eac ion ind ced ignal p o ein 1)
an d c ion b one of he Jan kina e (JAK): A ac ing monon clea cell o i e of
CRP ch onic inflamma ion
Complemen fi a ion (C3) CCL3 o mac ophage inflamma o p o ein 1-alpha
Fib inogen ac i a ion A ac ing mac ophage , monoc e and
IRF-1 ne ophil
T and B cell a e ned on CCL4 o mac ophage inflamma o p o ein 1-be a
U ed o a ac NK cell , monoc e and
o he imm ne cell
IL-8 o CXCL8
A ac ing ne ophil in ac e inflamma ion
Ac i a ing monoc e
CX3
Cell adhe ion ecep o capable of a e ing
cell
Cla ified in o 4 familie ba ed on he po i ion of N- e minal

c eine e id e :
Alpha (CXC), chemokines con ain ingle
amino acid be een 1 and 2nd amino acid
Beta (CC), chemokines ha adjacen c eine
e id e
C chemokines lack one of he c eine .
CX3C - ha 3 amino acid be een c eine
Pla d ing he ini ia ion and de elopmen of inflamma o
e pon e in n me o di ea e p oce e .
Other functions of chemokines:

Inc ea e affini of in eg in fo hei co e ponding ligand
in he endo heli m (ICAM-1, ICAM-2, VCAM-1)
CHEMOKINES P o ein in ol ed in adhe ion of ne ophil d ing
P od ced b bo h l mphoid and non-l mphoid cell pe . diapede i
Pa of c okine ca cade and elea ed in e pon e o LPS P omo e binding of in eg in o hei co e ponding ligand in
and pla an imp ole in ac e pha e eac ion . he endo heli m (ICAM1)
T igge ed b elea e of IL-1 Reg la e l mphoc e affic and o he WBCS
FUNCTIONS: Main aining no mal mig a ion of imm ne cell in o l mphoid
S im la e B cell p olife a ion and diffe en ia ion o gan o o he peciali ed cell
Ind ce CD4+ T cell o p od ce bo h p o and an i
inflamma o c okine
IL6 Recep o compo ed of IL-6R alpha and gp130
TNF alpha and IL-6 can ind ce chemokine p od c ion
S im la e an endo helial le koc e mo emen
Enhance mo ili and p omo e mig a ion of WBC

Selected chemokines and their receptors and he gene ha a e ned on in

e pon e o he im li
T pe of cell face ecep o
e p e ed b le koc e a e
of en de elopmen all eg la ed
EX.: T cell po e onl
he chemokine ecep o
ela ed o l mphoid
i e homing. Onl
ma e T cell e p e
he ecep o ha allo
hem o pa icipa e in an
ongoing imm ne
eac ion
HIV e he chemokine ecep o CXCR4
and CCR5 a co ecep o fo infec ion of
CD4+ T l mphoc e and mac ophage .
Ce ain pol mo phi m in he e
chemokine ecep o long- e m
nonp og e o
Remain a mp oma ic i h
E amples: no mal CD4+ T-cell co n and
In HIV-infec ed indi id al e CXCR4 and CCR5 a imm ne f nc ion a ell a lo o
co- ecep o of infec ion of CD4+ T l mphoc e and nde ec able i al load
mac ophage . Al e ed p o ein eq ence of he
CXCR4 and CCR5 ecep o block o dimini h he
Fo nd in a ge cell of HIV i abili o en e he cell
Vi need he e fo ind c ion i al en and he eb inc ea e he infec ed
Al e a ion of gene in hi ecep o HIV indi id al chance of i al
e i ance CCR5- 32 pol mo phi m i a 32
Pol mo phi m of hi kind emain long e m non-p og e o , bp dele ion in he CCR5 gene and
a mp oma ic i h no mal CD4+ co n and nde ec able i he mo impo an of he ho
i al load . e i ance fac o
TNF- and IL-6 ind ce he chemokine TRANSFORMING GROWTH FACTOR-

p od c ion; Composed of 3 isoforms:
Wi h cell adhe ion molec le , facili a e 1. TGF 1
e a a a ion of le koc e in o he 2. TGF 2
i e . 3. TGF 3
Integrins (cell adhe ion molec le ) a e
ac i a ed leading o fi m adhe ion o he Characteristics:
endo helial cell . (I S e e & M e , he ff. a e ed a cha ac e c f TGF- 3)
E p e ion of chemokine among Fac o ha ind ced mo g o h a e in mo cell
Cha ac e i ic
le koc e allo co-locali a ion of cell Reg la o of cell g o h diffe en ia ion, apop o i , mig a ion
in o he damaged i e. and he inflamma o e pon e
Chemokine g adien concen a ion Reg la o in he e p e ion of CD8 in CD4-CD8- h moc e
enable le koc e o mo e h o gh he and ac a an a oc ine inhibi o fac o fo imma e
endo helial cell o a d he inc ea ing h moc e
concen a ion of chemokine . Do n eg la ion of imm ne e pon e
Spec m of chemokine and c okine Block he p od c ion of IL-12 and ongl inhibi he
e p e ed in he inflamma o e pon e ind c ion of IFN-gamma
de e mine he pe of cell ha e pond

P od c ion b Th2 cell i no ecogni ed a an impo an CYTOKINES IN ADAPTIVE IMMUNE RESPONSE

fac o in he e abli hmen of o al ole ance o bac e ia
no mall fo nd in he mo h
In ac i a ed B cell , TGF- picall inhibi p olife a ion and
ma f nc ion a an a oc ine eg la o o limi he e pan ion
of ac i a ed cell
TGF-
F nc ion a bo h an ac i a o and an inhibi o of
p olife a ion, depending on he de elopmen al age of he
affec ed cell
Reg la e he e p e ion of CD8 in CD4-CD8- h moc e
Ac a an a oc ine inhibi o fac o fo imma e
h moc e
Inhibi he ac i a ion of mac ophage and g o h of man
diff oma ic cell pe
F nc ion a an an i-inflamma o fac o fo ma e T cell
Major proinflammator Major anti-inflammator

c tokines c tokines
TNF- TGF-
IL-1 IL-10
IL-6 IL-13 C okine f nc ion mainl o inc ea e ac e-pha e eac an
IFN-gamma
IL-35 and o ec i WBC o he a ea of infec ion
C okine in he adap i e IR a e mainl p od ced b T
helpe cell .
Wo ld affec T and B cell f nc ion mo e di ec l
Th ee main bcla e of Th cell : T helpe 1 (Th1), T
helpe 2 (Th2), and T eg la o (T eg) cell
T helpe 17 (Th17) cell a e a fo h b e of Th
cell .
Th17 cell affec bo h he inna e and
adap i e
Once he T-cell ecep o (TCR) cap e an igen, clonal
e pan ion of ho e pa ic la CD4+ Th cell occ
Diffe en ia ion in o Th1, Th2, o T eg cell lineage i
infl enced b he pec m of c okine e p e ed in he
ini ial e pon e (Fig. 6 5)
Th1 lineage i d i en b he e p e ion of IL-12 b dend i ic
C tokines in the Innate I.S. cell and i p ima il e pon ible fo cell-media ed imm ni
APC ec e e a pecific combina ion of pola i ing c okine Th2 cell d i e an ibod -media ed imm ni and a e
ha di ec na e T helpe (Th) cell o diffe en ia e in o de elopmen all eg la ed b IL-4
b e . T eg cell de i ed f om nai e T cell in e pon e o
Each T-cell bpop la ion e e imm ne f nc ion and TGF-be a
elea e of effec o c okine coo dina e an app op ia e Help eg la e ac i i ie of Th1 and Th2
imm ne e pon e again he pa hogen.
The nai e CD4+ T-cell a e ho e de ined o become T
[Refe ab e a he e d f C e he ada e IR] helpe cell
Nai e CD4+ T cell in e ac i h an APC (e.g. mac ophage ,
dend i ic cell , B cell ) clonal e pan ion of nai e CD4 cell

P incipal molec le p od ced b Th1 cell ,

affec he RNA e p e ion le el of mo e
han 200 gene
D i en b IL-12 elea ed b dend i ic cell
in he p e ence of APC
T pe II INF
Ac i a ing mac ophage in ol ed in
phagoc o i
S im la e e p e ion of MHC Cla I and
II
P incipal mac ophage-ac i a ing c okine
Boo hei mo icidal ac i i
S im la e phagoc ic and
c o o ic abili ie of he e cell
pe mac ophage
S im la e e p e ion of MHC Cla I
and II molec le ; co- im la e APC
Interferon
Majo f nc ion: im la ion of Ag
Gamma
p e en a ion b cla I MHC and
cla II molec le on APC
Interferon-
Inc ea e he likelihood of
(IFN- )
an igen cap e and in ol emen
of addi ional l mphoc e
APC o ld ha e p oce ed an igen a ocia ed
Reg la ion and ac i a ion of CD4+ Th1
i h MHC Cla II
cell , CD8+ c o o ic l mphoc e , and
Relea e of c okine
NK cell
C okine elea e b pe / bpop la ion of T cell
Diffe en ia ion of na e CD4+ T
Each T cell bpop la ion o ld e e diffe en
cell o Th1
pe of imm ne f nc ion, a ell a diffe en
Inhibi Th2 cell p olife a ion
c okine
T mo icidal ac i i
C okine o ld be pecific o he a ge pa hogen
P omo e IgG bcla
o o gani m
i ching in B cell
The bod o ld elea e diffe en bpop la ion
S im la e c ol ic ac i i of NK
depending on he pa hogen (in a- o e acell la )
cell
The e o ld al o be bpop la ion ha a e
An agoni ic o IL-4
impo an fo he eg la ion of he o he
RECALL: IL-4
bpop la ion
Ind ce nai e Th cell
CYTOKINES OF Th1 o become Th2
Dend i ic cell in damaged i e p od ce IL-2 in e pon e AKA T-cell gro th factor
o ce ain im li: m cobac e ia, in acell la bac e ia, and D i e g o h and diffe en ia ion of bo h T
i e and B cell and ind ce l ic ac i i in NK
Al o p od ced b mac ophage and B cell cell
Ha m l iple effec on bo h T cell and NK cell Ho NK cell a ge he infec ed
IL-12 bind o i ecep o on na e T cell e p e ion of cell
a ne e of gene , incl ding ho e ha de e mine IL-2 and IFN-gamma ind ce Th1 cell
Interleukin-2
ma a ion in o he Th1 lineage. de elopmen
(IL-2)
Ac i a ion of Th1 cell high le el e p e ion of Ac i a ion of mac ophage and
IFN-gamma dela ed pe of h pe en i i i
IL-12 inc ea e c ol ic abili of NK cell Ac i a e p olife a ion of Th2 cell , aid in
Se e an impo an link be een he inna e and gene a ing IgG1, IgG3, and IgE-p od cing
adap i e imm ne e pon e b enhancing cell
defen e again in acell la pa hogen . E en ial o f nc ion a op onin
and complemen fi a ion

Th1 cell im la e he p od c ion of IgG1 CD80 Fo nd on he face

and IgG3 op oni ing and complemen of diffe en imm ne cell (e.g. B
fi ing an ibodie b an igen-ac i a ed B cell , monoc e , and APC )
cell . CD86 impo an fo T cell
Clonal e pan ion of ac i a ed Th cell ac i a ion and i al; al o
fo adeq a e imm ne e pon e fo nd in he face of B cell
T an c ip ion of he gene fo IL-2 and Co im la molec le
IL-2R begin i hin 1 ho of binding o Al o im la e he p od c ion of IgG2a
he TCR and IgE
IL-2R con i of: , , and / IL-5 d i e diffe en ia ion and
b ni ac i a ion of eo inophil (alle gie and
and b ni inc ea e he pa a i ic infec ion)
affini of he ecep o fo IL-2 Ha e ame p ope ie i h IL-13
and a e e pon ible fo mo of Bo h ind ce o m e p l ion
he ignal an d c ion h o gh Bo h fa o IgE-cla i ching
he ecep o IL-13 an i-inflamma o ole b
chain i al o ha ed b he inhibi ing ac i a ion and c okine
ecep o fo IL-4, IL-7, IL-9, ec e ion b monoc e
IL-15, and IL-21 P od ced b monoc e , mac ophage ,
chain demon a ed in indi id al CD8+ T cell and Th2 CD4+ T cell
ho ha e m a ion in hi chain Inhibi o effec
X-linked e e e combined An i-inflamma o , pp e i e
imm nodeficienc nd ome and lack Interleukin-10
effec on Th1 cell .
f nc ional T & B cell (IL-10)
Inhibi an igen p e en a ion b
RECALL: Th1 a ge in acell la i e and bac e ia mac ophage and dend i ic cell
TNF- o ld al o be elea ed Inhibi IFN- (an agoni o
P od c ion of he e c okine b Th1 o ld lead o he do n eg la o )
p olife a ion of mac ophage and T c o o ic cell (effec o In ol ed in e acell la pa hogen bac e ia and pa a i e
cell ) IL-4, 5, 9, 10, 13
Lead o cell-media ed imm ni and inflamma ion An ibod -media ed
CYTOKINES OF Th2 Th2 in e ac i h B l mphoc e
E acell la pa hogen Affec ma cell , B cell , and eo inophil
Bac e ia and ome pa a i e H mo al imm ni and an ipa a i ic effec
An ibod media ed CYTOKINES ASSOCIATED WITH T reg
In e ac ion i h B l mphoc e Ha he CD4 ma ke and CD25
B cell , eo inophil , ma cell (effec o cell ) Impo an in pp e ing he imm ne e pon e o
C okine p od ce: IL4, IL5, IL13, IL9, IL10 elf-an igen
Ha e ecep o p e en on effec o cell Tole ance o a ide a ie of elf-an igen , alle gen , mo
Recep o a e p e en in he l mphoc e an igen , an plan an igen , and infec io agen .
and non-hema opoie ic cell pe Limi a oimmni
T n ON he gene ha gene a e Th2 Fo nd in an plan ed i e
cells Help e abli h ole ance o he g af
Reg la ing imm ne e pon e: De i ed f om nai e T cell ha e e p od ced in e pon e
Interleukin-4 alle gie , a oimm ne di ea e , o TGF-
(IL-4) and pa a i e Do n eg la e he ac i i of o he T cell pop la ion
T n OFF he gene ha p omo e Th1 TGF- Ind ce e p e ion of Fo p3
Impo an in d i ing he an ibod e pon e Fo p3 an c ip ion fac o ha ca e T eg cell
Ind ce p od c ion of MHC-1, IL-4, IL-5, o pp e he ac i i of o he cell
IL-13, co im la o molec le CD80 and Re pon ible fo ind cing IL-10 and TGF- e p e ion in
CD86 adap i e T eg la o 1 (T 1) cell in he pe iphe al
ci c la ion

T 1 cell a e CD4+ T cell ha a e ind ced f om Ke c okine ha diffe en ia e T cell o main ain hem a
an igen-ac i a ed na e T cell in he p e ence of IL-10. Th17 cell a e TGF- and IL-6
E e pp e i e ac i i ie on bo h Th1 and Th2 In e le kin-23 p od ced b mac ophage and dend i ic
b p od cing mo e IL-10, TGF- , o IL-35 cell
IL-10 Pla a ole in finali ing he commi men o Th17
Ha p ima il inhibi o effec on he imm ne cell
em IL-17 po en p oinflamma o c okine and ind ce
P od ced b monoc e , mac ophage , CD8+ T e p e ion of TNF- , IL-1 be a and IL-6
cell , and Th2 CD4+ T cell p od ce p oinflamma o media o f om m eloid
Ha an i-inflamma o and pp e i e effec on and no ial fib obla and pe pe a e he
Th1 cell inflamma o p oce in RA
Inhibi an igen p e en a ion b mac ophage and IL-17A fi IL-17 iden ified
dend i ic cell O he IL-17 famil membe incl de IL-17B, IL-17C, IL-17D,
T-cell pp e ion occ h o gh IL-10 IL-17E, and IL-17F.
inhibi ion of p oinflamma o c okine Mo of he IL-17 c okine famil membe a e po en
and inhibi ion of co im la o molec le p oinflamma o c okine and ind ce e p e ion of TNF- ,
e p e ion on APC . IL-1 , and IL-6 in epi helial, endo helial, ke a inoc e,
Inhibi IFN-gamma p od c ion ia he pp e ion fib obla , and mac ophage cell .
of IL-12 n he i b acce o cell and he IL-17A and IL-17F ind ce epi helial cell , endo helial cell ,
p omo ion of a Th2 c okine pa e n and fib obla o p od ce CXC ligand 8 (CXCL-8)
An agoni o IFN-gamma C cial fo ec i men of ne ophil o he i e of
Do n eg la o of imm ne e pon e inflamma ion.
TGF- Ac oge he i h g an loc e mac ophage CSF o
Do n eg la e he f nc ion of APC and block p od ce CXCL-8 in mac ophage ignal
p olife a ion and c okine p od c ion b CD4+ T ne ophil o he i e
cell D eg la ion of Th17 cell b e and ec e ed c okine
IL-35 pa hogene i of e e al inflamma o and a oimm ne
Imm no pp e i e effec on Th1,Th2, and Th17 condi ion
P omo e T eg A hma and alle gie : inc ea ed Th17 cell and IL-17A
Do n eg la e imm ne e pon e and p e en IL-17A di ec l ind ce IgE p od c ion b B cell
ch onic inflamma ion Highe amo n of IL-17A and IL-17F mo e
e e e a hma
O he pe :
Ind ced T eg (iT eg )
HEMATOPOIETIC GROWTH FACTORS
Can de elop f om ma e T cell in he pe iphe
IN INNATE AND ADAPTIVE IR
TR1 cell
Effect of colon stimulating factors on gro th and
differentiation of blood cells:
Th17 CYTOKINES IN INNATE AND ADAPTIVE IR
G o h of hema opoie ic em cell (HSC) eq i e em cell
Bo h inna e and acq i ed Imm ne e pon e fac o (SCF) i h h ombopoie in (TPO).
Th17 ec e e IL-17 famil of c okine SCF (c-ki ligand) In e ac i h c-ki
C cial in bac e ial and f ngal infec ion , e peciall Needed o make BM em cell e pon i e o o he
in he m co al a ea CSF
Upon enco n e i h bac e ia o f ng SCF in i elf canno im la e BM
APC ec e e c okine diffe en ia e p ogeni o cell
Th17 b e of cell . Impo an ole in main aining iabili and
Th17 cell in ade he infec ed a ea and p olife a i e capaci of imm ne cell ch a
ec e e IL-17 c okine nece a fo imma e T cell and ma cell
con in o ec i men of ne ophil Colon Stimulating Factors im la e fo ma ion of
Th17 in local i e, ma ha e an impo ance in long- e m colonie of cell in he bone ma o
main enance of an imic obial e pon e o IL-17 c okine P ima media o of hema opoie i
im la ion, ec e e an imic obial pep ide . IL-3: ind ce BM em cell o fo m T and B cell
GM-CSF: diffe en ia ion o o he WBC pe

Enhance he f nc ion of ne ophil and

affec he i al, p olife a ion, and
diffe en ia ion of all cell pe in he
ne ophil lineage
Dec ea e IFN-gamma p od c ion
Inc ea e IL-4 p od c ion in T cell
Mobili e m l ipo en ial em cell
IL-3 in conj nc ion i h GM-CSF d i e
he de elopmen of ba ophil and ma
cell
Addi ion of IL-5 o IL-3 and GM-CSF
d i e he cell o de elop in o eo inophil
M-CSF: ac i a ion lead o cell o become
mac ophage
Inc ea e phagoc o i , chemo a i , and
addi ional c okine p od c ion in
monoc e and mac ophage
Er thropoietin (EPO)
Ho mone-like b ance impo an in
eg la ing RBC p od c ion
P ima il p od ced in he kidne
No mal: 5-28 U/L
G o h of common m eloid p ogeni o (CMP) depend
pon IL-3.
Diffe en ia ion i d i en b g an loc e-mac ophage colon
im la ing fac o (GM-CSF) o e h opoie in (EPO).
Common g an loc e/monoc e p ec o (GMP) a
diffe en ia ed in e pon e o g an loc e-CSF.
The pecifici i p o ided b IL-3 o IL-5.
Mac ophage-CSF (M-CSF) p omo e de elopmen of
monoc e
IL-3 i a m l ilineage CSF ha ind ce bone ma o em
cell o fo m T and B cell .
IL-3 ac on bone ma o em cell o begin he
diffe en ia ion c cle
The ac i i of IL-3 alone d i e he em cell in o
he l mphoc e diffe en ia ion pa h a
A hii
Defec in he IL-1RA
Unde e p e ion p omo e f he inflamma ion
Inflamma o Bo el Di ea e
C okine in ol ed a e a ocia ed i h p omo ing
inflamma ion
Dem elina ing nd ome
The m elin co e ing he ne e fibe a e de o ed
o ed ced

CYTOKINE AND ANTI-CYTOKINE THERAPIES Add ano he bio in la ed pol clonal Ab ha i

labeled ( pecific o he c okine of in e e )
An ic okine he apie a e done o di p he in e ac ion
Wa hing i done again, and ano he eagen o ld
be een c okine and hei pecific ecep o in di ea e
be added hich o ld help o i ali e he e l
U e of monoclonal an ibodie ha f nc ion a c okine
(en me conj ga e alkaline pho pha a e
an agoni
conj ga ed o ep a idin)
Bind o c okine o p e en i ac ion
An nbo nd b ance i hen a hed again, and
E . Infli imab (Remicade) fo C ohn Di ea e
a colo ed p ecipi a e can be een.
o RA
Spo ha a e een af e he final a hing indica e
a chime ic an ibod con aining h man
he a ea he e he c okine a e locali ed/ een
con an egion and m ine
Each po co e pond o a
an igen- pecific a m ha bind h man
c okine- ec e ing cell
TNF- .
Co n ing a e eomic o cope o an
Block ac i i of TNF- in RA and
ELISpo eade
C ohn di ea e i h apid on e of
he ape ic ac ion af e admini a ion
De elopmen of a cla of h b id p o ein con aining
c okine ecep o binding i e a ached o Ig con an
egion
E . Etanercept (Enrebrel) fo RA, ank lo ing
pond li i , p o ia i , pedia ic a h i i
Con i of he e acell la domain of
he pe 2 TNF ecep o f ed o he
hea -chain con an egion of IgG1. The
f ion p o ein can bind TNF- and block
i ac i i .
I ha a 4.8-da half-life in e m. 2. Multiple ed ELISA e of e e al de ec o an ibodie
Red ce ign and mp om , di ea e bo nd o mic o ell o an ibod mic oa a
ac i i , and d abili Ad an age: allo im l aneo de ec ion of
IL-17 Blocking An ibodie c okine
E . I eki mab (fo me l LY2439821 f om allo fo he de ec ion of 12 o 25 p o- and
Eli Lill ) - RA an i-inflamma o c okine in one
Can al o be ed in p o ia i eac ion
IL-23- enhance he diffe en ia ion of Th17 l mphoc e In he mic oa a fo ma , each ell on he lide
con ain a mic oa a of po ed an ibodie , i h
Clinical Assa s
po fo each of he c okine pl addi ional
1. ELISpot Assa ELISA on in- i o ac i a ed pe iphe al po fo po i i e and nega i e con ol .
WBC The eplica e po allo fo acq i i ion of
Monoclonal o pol clonal an ibod a ached o he eliable q an i a i e da a f om a ingle
mic opla e ample
The e o ld ha e pecifici ie o ce ain 3. Microbead assa s m l iple de ec ion of c okine in
c okine of in e e . ingle be
WBC a e hen added hich can f nc ion a ei he Each bead pe ha i o n fl o e cen
a + o - con ol a eleng h, hich, hen combined i h he
Po i i e (+) con ol an igen and fl o e cen econda an ibod bo nd o a pecific
mi ogen im la ed c okine
Nega i e (-) con ol NSS im la ed Allo fo de ec ion of p o 100 diff anal e in 1
The e con ol a e hen pipe ed in o he ell be
Mic opla e i placed in o a CO2 inc ba o a 37 C Sim l aneo mea emen of a m l i de of
D ing he inc ba ion ime, he immobili ed Ab bioma ke : ac e-pha e eac an ch a CRP;
a ached o he pla e o ld hen bind o he p oinflamma o c okine ; Thl/Th2 di ing i hing
ec e ed c okine c okine ch a IFN-gamma, IL-2, IL-4, IL-5, and
Wa hing i done o emo e nbo nd b ance IL-10; o he non pecific ac ing c okine ; and CSF
Ab fo de ec ion a e a ached o a mic obead

The mic obead ill be placed in a be, he ample

ill be added, c okine in he ample o ld bind
o he Ab, and a colo ed p od c i p od ced
The p od c can be q an ified
4. PCR
5. In acell la aining
6. Bioa a
7. ELISA

d. P olife a ion of he imm ne e pon e b ind cing

POST-TEST IL-4
9. Th17 cell affec he inna e imm ne e pon e b ind cing
1. Which of he follo ing c okine i al o kno n a he T-cell
p od c ion of hich c okine ?
g o h fac o ?
a. IFN- and IL-2
a. IFN-
b. IL-4 and IL-10
b. IL-12
c. IL-2 and IL-4
c. IL-2
d. TNF- and IL-6
d. IL-10
10. Which of he follo ing o ld e l f om a lack of TNF?
2. Which of he follo ing ep e en an a oc ine effec of
a. Dec ea ed abili o figh g am-nega i e bac e ial
IL-2?
b. infec ion
a. Inc ea ed IL-2 ecep o e p e ion b he Th cell
c. Inc ea ed e p e ion of cla II MHC molec le
p od cing i
d. Dec ea ed i al of cance cell
b. Mac ophage ignaled o he a ea of an igen
e. Inc ea ed i k of ep ic hock
im la ion
c. P olife a ion of an igen- im la ed B cell
d. Inc ea ed n he i of ac e-pha e p o ein
h o gho he bod
3. The abili of a ingle c okine o al e he e p e ion of
e e al gene i called
a. ed ndanc .
b. pleio op .
c. a oc ine im la ion.
d. endoc ine effec
4. A lack of IL-4 ma e l in hich of he follo ing effec ?
a. Inabili o figh off i al infec ion
b. Inc ea ed i k of mo
c. Lack of IgM
d. Dec ea ed eo inophil co n
5. IL-10 ac a an an agoni o ha c okine?
a. IL-4
b. TNF-
c. IFN-gamma
d. TGF-
6. Wh migh a colon im la ing fac o be gi en o a cance
pa ien ?
a. S im la e ac i i of NK cell
b. Inc ea e p od c ion of ce ain pe of le koc e
c. Dec ea e he p od c ion of TNF
d. Inc ea e p od c ion of ma cell
7. Which c okine ac o p omo e diffe en ia ion of T cell o
he Th1 bcla ?
a. IL-4
b. IFN-
c. IL-12
d. IL-10
8. Wha i he majo f nc ion of T eg la o cell ?
a. S pp e ion of he imm ne e pon e b
p od cing TNF
b. S pp e ion of he imm ne e pon e b ind cing
IL-10
c. P olife a ion of he imm ne e pon e b p od cing
IL-2

CYTOKINES
FACTOR SOURCE ACTIONS
IL-1 / Mac ophage Inflamma o
IL-2 T cell T and B cell p olife a ion
IL-3 T cell Pl ipo en g o h
IL-4 T cell T and B p olife a ion, ac i a ion of mac ophage
IL-5 T cell Eo inophil diffe en ia ion
IL-6 T cell B cell diffe en ia ion
IL-7 T cell B and T cell p olife a ion
IL-8 T cell PMN ac i a ion
IL-9 T cell Ma cell g o h
IL-10 T, B cell , Mac ophage Inhibi ion of TH1 c okine p od c ion
IL-11 BM S omal cell Ind c ion ac e pha e
IL-12 Monoc e Ind c ion of TH1 cell
IL-13 T cell Inhibi of TH1 cell
IL-16 CD8 T, CD4 (no p efo med) Chemo a i CD4 T cell and eo inophil
IFN M l iple An i i al
IFN M l iple An i i al
T cell An i i al, ac i a ion of mac ophage & inhibi ion of TH12 cell
IFN
NK cell MHC ind c ion
TFN Monoc e C o o ici , cache ia, fe e
TNF T cell C o o ici , cache ia, fe e
TGF T cell / Mac ophage Inhibi ac i a ion of NK cell , and T cell , mac ophage ,
inhibi p olife a ion of B and T cell
GM-CSF T cell Go h of g an loc e and monoc e
G-CSF Mac ophage Go h of g an loc e
M-CSF Mac ophage Go h of monoc e
S eel fac o BM S omal cell S em cell di i ion (c-ki ligand)

Summar of C tokine receptor families and its functions

FAMILY LIGANDS INVOLVED FUNCTIONS
IL2 IL-7, IL-15, Ha e con e ed mo if in hei e acell la

IL-3, IL-9, GM-CSF amino-acid domain,
IL-4, IL-11, G- CSF p ophan- e ine-X- p ophan- e ine (WSXWS),
IL-5 IL-12, lack in in ic p o ein o ine kina e ac i i .
T pe I c tokine
IL-6, IL-13, S bdi ided in o 3 b e ba ed on he abili of
(hema opoie in ecep o )
famil membe o fo m comple e i h 1 of 3
diffe en pe of ecep o ignaling componen
(gp 130, common , and common chain of IL2
ecep o .
IFN / IL-10 IL-26 Compo ed of he e ogeneo b ni , In e fe on mainl fo

IFN- IL-20 in e fe on ;
IFN- IL-24 Sha e c al imila i ie in hei ligand-binding
domain.
T pe II c tokine receptors
Ha e e e al con e ed in acell la eq ence
mo if ;
F nc ion a binding i e fo he nicell la effec o
p o ein JAK and STAT p o ein .
IFN / BAFF Ne e Seq ence a e homologo o he Fa p o ein, and

LT Ap il go h B cell face molec le CD40.
Tumor necrosis factor
CD40 O 40 fac o Adhe ion molec le o le koc e and kill mic obe .
receptor (TNFR)
Fa L GITR S im la e o he monon clea phagoc e and
o he cell o p od ce c okine .
IL-1 IL-18 Ac a media o of he ho inflamma o e pon e

IL-1 receptor famil in na al imm ni .
So ce of ac i a ed monon clea phagoc e
Se en transmembrane Chemokine Sha e he abili o im la e le koc e mo emen

G-protein-coupled (chemokine i ) and di ec ed mo emen
receptors (chemo a i )

CYTOKINES IN THE ADAPTIVE IMMUNE RESPONSE

SECRETED BY CHEMOKINE INVOLVED FUNCTIONS
In e fe on- Ac i a ion ind ce high le el e p e ion of IFN-gamma.

(IFN- ) IL-12 inc ea e he c ol ic abili of NK cell ;
Se e a link be een he inna e and adap i e imm ne e pon e b
enhancing defen e again in acell la pa hogen
Th1 In e le kin-2 D i e he g o h and diffe en ia ion of bo h T and B cell and ind ce
(IL-2) l ic ac i i in NK cell .
Ind ce he de elopmen of Th1 cell ,
Ind ce mac ophage ac i a ion and
Dela ed pe h pe en i i i .
In e le kin-4 Help d i e an ibod e pon e in a a ie of di ea e .

(IL-4) E p e ed on l mphoc e and on n me o nonhema opoie ic cell
pe .
IL-4 ac i i on nai e T cell n on he gene ha gene a e Th2 cell
and n off he gene ha p omo e Th1 cell .
Re pon ible fo eg la ing man a pec of he imm ne e pon e, (i.e.
alle gie , a oimm ne di ea e , and pa a i e .
Ind ce p od c ion of MHC-I, IL-4, IL-5, IL-13, and he co im la o
molec le (CD80 and CD86)
Th2 In e le kin-10 Inhibi o effec on he imm ne em.
(IL-10) P od ced b monoc e , mac ophage , CD8+ T cell , and Th2 CD4+ T
cell
Ha an i-inflamma o and pp e i e effec on Th1 cell .
Inhibi an igen p e en a ion b mac ophage and dend i ic cell .
Ac a inhibi ion of IFN-gamma p od c ion ia he pp e ion of IL-12
n he i b acce o cell and he p omo ion of a Th2 c okine
pa e n.
IL-10 e e a an an agoni o IFN-gamma a do n eg la o of he
imm ne e pon e
In e le kin-17 La c i ical ole in bo h inna e and adap i e imm ne e pon e .

Th17 in inna e and (IL-17) Diffe en ia e T cell o main ain hem a Th17 cell a e TGF- and
adap i e imm ne IL-6.30 In e le kin,
e pon e P od ced b mac ophage and dend i ic cell ,
Pla a ole in finali ing he commi men o Th17 cell

S ce : PPT, a nch n lec e ide , B k and he efe ence
INTERMOLECULAR FORCES
UNIT 6: OVERVIEW OF ANTIGEN-ANTIBODY Ionic or Electrostatic occ be een oppo i el cha ged
REACTIONS IN-VITRO (po i i e and nega i e) pa icle
H drogen Bonds occ hen Ag and Ab a e in clo e
Pre-test p o imi
1. T/F: The binding i e in an an igen i called he pa a ope A ac ion be een pola molec le
2. T/F: P o one eac ion can lead o a fal e nega i e eac ion Van der Waals occ beca e of in e ac ion be een he
3. Avidit i he o e all binding eng h be een m l i alen elec on clo d of o cilla ing dipole
an ibodie and an igen H drophobic bonds occ be een non-pola molec le
4. T/F: Binding of Ag-Ab in i o i i e e ible All of he e in e molec la fo ce pla an impo an ole in
5. T/F: E ce an igen in ela ion o amo n of an ibodie i main aining he binding of he imm ne comple .
called po - one phenomenon Al o impo an in main aining he goodne of fi of Ag-Ab.
ANTIGEN-ANTIBODY REACTION
Imm ne eac ion occ ing be een he antigenic
determinant (Epitope) and Fab (Antigen binding
fragment) of he an ibod molec le
An an igen ma con ain onl one ( ni alen ) o
mo e han one epi ope (m l i alen )
Fab region de e minan fo nd in he an ibod
Re pon ible fo Ag ecogni ion
[RECALL]
Fc po ion of Ab biologic
p ope ie of Ab (e.g. binding fo
complemen )
The imple combina ion of a Ag and i
co e ponding Ab i called sensiti ation LAW OF MASS ACTION
Fo ma ion of imm ne o Ag-Ab comple
If he an ibod ha pecifici o he
co e ponding epi ope, he epi ope o ld
hen bind o he co e ponding Fab egion,
fo ming an imm ne comple .
K=e ilib i m o a ocia ion con an ; mea e of "goodne of fi "

k1 = a e con an fo he fo a d eac ion
k2 = a e con an fo he back a d eac ion
CHARACTERISTICS
Invisible and precise All Ag-Ab binding i e e ible (indica ed b do ble a o )
Reac ion i mall, e min e and i go e ned b he la of ma ac ion.
Canno be een b he naked e e Law of Mass Action
P eci e Binding i dependen on he F ee eac an (Ag and Ab) a e in e ilib i m i h
goodne of fi of he epi ope o he he bo nd eac an (Ag-Ab comple ).
co e ponding Fab The e ilib i m ill ha e a e con an fo he
"Lock and Ke " fo a d (k1) and e e e (k2) eac ion .
Reversible The e i al o an e ilib i m o a ocia ion con an
In ce ain condi ion , he binding of if o ge he o ien of k1 and k2, hich i deno ed
epi ope and Fab ma no an mo e occ b K.
beca e of ce ain fac o K = [AgAb]/[Ab][Ag]
he e [AgAb] = c ce a f he a ge a b d
Held oge he b weak intermolecular forces
c e ( /L)
Non-co alen bond [Ab] = c ce a f f ee a b d ( /L)
Go e ned b he law of mass action [Ag] = c ce a f f ee a ge ( /L)

Val e of K depend on he eng h of Fab egion ; mo e po en ial o bind o

binding be een Ag and Ab diffe en epi ope of a m l i alen Ag
The onge he binding, he e i a le In ome ca e , he affini ma no be ha high b can be
endenc of he imm ne comple o compen a ed b he a idi
di ocia e; he efo e, he molec le of he affini , a idi
imm ne comple o ld be main ained Wo ld ill hold he imm ne comple oge he
and o ld no di ol e.
The highe he al e of K, he be e i he AFFINITY
abili & he le e he chance o Ini ial fo ce of a ac ion ha e i be een a ingle Fab i e
di ocia e. on an an ibod molec le and a ingle epi ope o de e minan
When he al e of K i highe , he amo n i e on he co e ponding an igen
of an igen an ibod comple i la ge and A he epi ope and binding i e come in o clo e
he a a eac ion i mo e i ible o ea il p o imi o each o he , he a e held oge he b
de ec able. a he eak bond occ ing onl o e a ho
Ideal condi ion: high affini and high di ance of app o ima el 1 10 7 mm
a idi S eng h of a ac ion depend on he pecifici of an ibod
To op di ocia ion of he comple , e ha e o fo a pa ic la an igen
ake no e of he affini and a idi of he imm ne One Ab molec le ma ini iall a ac n me o
comple . diffe en an igen , b i i he epi ope hape and
STRENGTH OF Ag-Ab REACTIONS he a i fi oge he i h he binding i e on an
an ibod molec le ha de e mine he he he
bonding ill be able
Ma imal affinit if epi ope and binding i e ha e pe fec
lock-and-ke fi
When he affini i highe , he a a eac ion i mo e
en i i e beca e mo e an igen an ibod comple e ill be
fo med and i ali ed mo e ea il .
In an dea e g, he imm ne comple ho ld ha e a high

affini and high a idi .
In ac al p ac ice & eali , ha doe no happen.
The e a e ce ain Fab and Ag ha do no fi
p ope l .
Talk abo he eng h of binding of one epi ope o i
Fig e A on he lef o ld ha e a be e fi (highe K)
co e ponding Fab egion
beca e e ha e a ec ang la epi ope hich fi pe fec l
Bo h affini and a idi con ib e o he abili of he
in o he Fab ecep o of i co e ponding Ab.
an igen an ibod comple e
The in e molec la fo ce a e al o balanced hich
Affinit S eng h of binding of he epi ope (an igenic
con ib e o i be e fi , compa ed o Fig e B on he igh .
de e minan ) and a ingle an ibod
Fig e B The Fab egion i ec ang la b he an igen
1:1 eac ion be een a ingle epi ope and an ibod
ha a he agonal epi ope (h d a a a ); he
Avidit o e all binding eng h be een m l i alen
in e molec la fo ce a e no ha ong o hold on oge he
an ibodie and an igen
Lo affini ma happen in c o eac ion o
No j he 1:1 binding eac ion, b e ha e o
c o - eac ing an igen
con ide he o he binding i e of he Ag and Ab
The e a e ce ain an igen ha ma ill fi
m l i alen
in o a co e ponding an ibod beca e
The hole pic e
he ha e a imila epi ope i h ano he
Ma al o be dependen on he pe of Ab o a e
an igen b he affini i no ha ong.
ing
IgG . IgM IgM o ld ha e a highe
a idi beca e i ha 10 binding i e o

FIGURE 10 1 Aff de e ed b he h ee-d e a f a d ec a a ac

FIGURE 10 2 A d he f he f ce b d g ae a ge ae
be ee e a ge c de e a a d e a b d -b d g e. The a ge c
a b de .I ac a be ee IgG a d IgM, IgM ha he e a b d g
de e a he ef ha a be e f a d cha ge d b ha he e e he gh
e f a ge a d h he h ghe a d . N e ha he e IgM ca g
a d he ce ha e a h ghe aff .
d de b d e effec e
AVIDITY
Specificit The abili of an indi id al an ibod
combining i e o eac i h onl one an igenic de e minan
The abili of a pop la ion of an ibod molec le o
eac i h one an igen onl
A pecific Ab i o ld onl eac o a pa ic la
epi ope p e en in he Ag
The an igen can be compo ed of m l iple epi ope
ae e e
Tha epi ope p e en can be
O e all binding i e -de e a o -de e a
O e all eng h of an igen an ibod binding and i he m Uni-determinant all of ho e epi ope
of he affini ie of all he indi id al an ibod an igen o ld ha e he ame pecifici
combining i e Multi-determinant m l iple epi ope
S eng h i h /c a m l i alen Ab bind a m l i alen Ag i h diffe en pecifici ie ; no all ho e
Mea e of o e all abili of an Ag-Ab comple epi ope o ld bind o a pecific/pa ic la
A high a idi can ac all compen a e fo a lo affini Ab
Mo e bond be Ag and Ab = highe a idi en i i e, pecific
[RECALL]
Each monome of he an ibod o ld ha e 2 binding Fal e po i i e a e p e alen
ie . P obabl ha e c o eac ion
Compa ing he IgG Ab (10 6) . IgM Ab (10 10), he IgM o ld The Ab migh bind o o he Ag hich a e
ha e a highe a idi d e o i m l iple binding i e . i e imila o o iginal Ag
S onge comple Cross Reactivit
Le likel o di ocia e Impo an in affini
A idi ma al o be a ocia ed i h he fo ma ion of la ice, Abili of an indi id al Ab combining i e o eac
fo e ample, in aggl ina ion eac ion . i h mo e han one an igenic de e minan
The IgM Ab o ld be a be e /e cellen aggl inin The e a e ce ain ca e he ein he Ab i
compa ed o IgG beca e i o ld ha e mo e able o bind i h no j one pecific
binding i e o allo he pa ic la e m l i alen epi ope, b co ld al o bind o o he
aggl inogen o bind epi ope ha omeho ha e he ame
IgM ha he po en ial o bind o 10 diffe en Ag cha ac e i ic o pa ha a e i e
IgG onl 2 binding i e , malle in i e imila o ela ed
Al ho gh i i capable of binding o Ag, The mo e he c o - eac ing an igen e emble he
he e o ld be no i ible eac ion o o iginal an igen, he onge he bond ill be
aggl ina ion be een he an igen and he binding i e.
The abili of a pop la ion of Ab molec le o eac
i h mo e han one Ag

Fac o in Ag-Ab binding In ol e Ag-Ab combina ion h o gh ingle an igenic

If o an a pecific Ab, i ho ld onl de e minan on he pa icle and i apid and e e ible
bind o a pecific an igenic de e minan o Since Ag and Ab o ld ha e o he binding i e , e en all ,
epi ope he e o ld fo m he la ice f ame o k.
A m ch a po ible, if o an o make Affec ed b he na e of Ag on he aggl ina ing pa icle
he e e pecific, he e ho ld be If epi ope a e pa e o if he a e ob c ed b
le e chance of c o eac ion beca e o he face molec le , he a e le likel o
o ho ld no con ide en i i i of he in e ac i h an ibod
e onl , b al o pecifici RBC and bac e ial cell ha e ligh nega i e
Al ho gh o e can de ec mall face cha ge like cha ge epel one ano he
amo n of a pa ic la an igen b i no diffic l o b ing ch cell oge he in o la ice
pecific, i i ill no a good e ologic e . fo ma ion
LATTICE FORMATION
INTERMOLECULAR FORCES
An an igen can be:
The econd ep
Univalent/Monovalent 1 epi ope p e en
Fo ma ion of c o -link ha fo m he i ible agg ega e
Multivalent he e a e mo e han one epi ope p e en in
Rep e en he abili a ion of Ag-Ab comple e i h he
he Ag molec le
binding of m l iple an igenic de e minan
In mo clinical ca e / pecimen
A he la ice i fo med, he imm ne comple become
Uni-determinant m l iple epi ope ha e he ame
la ge , and e en all , a i ible e l can be een.
pecifici
La ice h po he i fo m la ed b Ma ack
Multi-determinant m l iple epi ope b do no ha e he
Fi a hi in p ecipi a ion eac ion
ame pecifici o a pa ic la Ab
Ba ed on hi a mp ion, each Ab molec le
ho ld ha e a lea 2 binding i e , and he Ag
LEFT m l i alen an igen,
m be m l i alen in o de fo he la ice o fo m.
m l i-de e minan epi ope
Fo e ample:
RIGHT m l i alen an igen,
Ab i h 2 binding i e + m l i alen Ag
ni-de e minan epi ope
Once he e bind, en i i a ion occ .
C cial o he
B ince he e a e o he binding i e a ailable,
acc ac of e ologic e
he o he binding i e of he Ab i ill a ailable, o
ano he Ag can bind he e.
SENSITIZATION O he binding i e of he Ag a e ill a ailable, o
ano he Ab o ld bind he e oo.
E en all , he la ice ill fo m and o can no
ee a i ible e l .
La ice fo ma ion o he i ible e l o ld al o be affec ed
b he n mbe of Ag and Ab p e en in he
ol ion/ pen ion.
In o de fo he la ice o fo m, he e m be a
p opo ional amo n of Ag and Ab (no e al, b
A men ioned, en i i a ion i he fi pha e, hen he
he p ope e m i p opo ional)
epi ope bind o i co e ponding Fab
Sen i i a ion can happen e en i ho he
Aggl ina ion, like p ecipi a ion, i a o- ep
p opo ional amo n of Ag and Ab, b he eac ion
p oce ha e l in he fo ma ion of a able
ma no be een.
la ice ne o k. The fi eac ion, called
Nagbab d, ag e- e e, e ce
en i i a ion
e he ba g Ag ba g Ab,

h d a a a-f g a ce, h d Ca ie pa icle RBC , la e , cha coal,

a a g eac .D a a a a g cla , e c.
a eac . B a aching he mall Ag o he ca ie ,
Addi ional No e: hen o add he co e ponding Ab, he
IgM : po en ial alence of 10; >700 mo e efficien in eac ion ill no be mo e clea l een.
aggl ina ion han IgG ( alence: 2) TESTS BASED ON Ag/Ab REACTIONS
IgM ong aggl inin beca e of la ge i e
All e ba ed on Ag/Ab eac ion ill ha e o depend on
Reac be a 4 C and 27 C
la ice fo ma ion o he ill ha e o ili e a o de ec
Na all occ ing an ibodie again he ABO
mall imm ne comple e
blood g o p belong o he IgM cla
All e ba ed on Ag/Ab eac ion can be ed o de ec
IgG cano b idge he di ance be een pa icle bco of
ei he Ag o Ab
mall i e & e ic ed fle ibili a he hinge egion p ohibi
Ag o Ab a he anal e anal e: a a g
m l i alen binding
h aha a , b g ab h , he a e p e en in he
U e enhancemen echni e
pecimen
Aggl ina e be a 30 C o 37 C
E .: in mo p ecipi a ion eac ion , he Ag i
FACTORS AFFECTING MEASUREMENT OF Ag/Ab RATIO all he anal e of in e e .
1. Affinit Kno n/ eagen : Ab o an i e a
2. Avidit E .: In aggl ina ion eac ion , he anal e depend
S eng h of imm ne on he e
comple can be Take no e of he e fo ma /de ign
compen a ed b hi if e.g. CRP (C eac i e p o ein) e he e
o ha e a lo affini i a apid e a ailable; he anal e of
3. Ag:Ab ratio in e e i he CRP (con ide ed a he Ag)
Sho ld be p opo ional and he kno n b ance/ eagen i he
fo o o ha e he Ab again CRP.
la ice fo ma ion and o The Ab i all a ached o a
clea l ee he eac ion (coincide i h he one of ca ie pa icle.
e i alence o e i alence poin )
Zone of e i alence o e i alence poin PRECIPITIN CURVE
poin in hich he e i a p opo ional
amo n of Ag and Ab p e en la ice
fo ma ion o ld be fo med
4. Ph sical form of Ag
Depend on he he he Ag i ol ble o pa ic la e
Pa ic la e
Be e ed in aggl ina ion eac ion , e.g.
ed cell
Wo ld all fo m i ible eac ion ih
an IgM Ab, hich a e good aggl inin
Sol ble
U all p ecipi inogen ol ble Ag i h
m l iple binding i e FIGURE 10 3 P ec c e. The ec c e h h he a f
ec a a e h a g a ge c ce a he he a fa b d
U all emplo an IgG Ab hich a e e c a . E ce a b d ca ed he e a d e ce a ge c ce a
be e p ecipi in ca ed he e.
P ecipi a ion eac ion pha e change When he ame amo n of ol ble an igen i added
f om li id o olid o ee he eac ion o inc ea ing dil ion of an ibod , he amo n of
5. Si e of the antigen p ecipi a ion inc ea e p o he one of
The e a e ce ain an igen hich a e mall; all , e i alence.
d e o hei mall i e, he canno be clea l een When he amo n of an igen o e helm he
Remed : a aching o comple ing he Ag n mbe of an ibod -combining i e p e en ,
o a ca ie pa icle p ecipi a ion begin o decline beca e fe e la ice
ne o k a e fo med

[RECALL] TYPES OF IMMUNOLOGIC REACTIONS

P ecipi a ion depend on he ela i e p opo ion of an igen
Specific ecogni ion and combina ion of
and an ibod p e en . Op im m p ecipi a ion occ in he
an igen and a co e ponding an ibod
one of e i alence
1:1 binding
If he amo n of Ag and Ab i no p opo ional, o
Mo e en i i e han econda eac ion
o ld ha e onal eac ion .
Ve p eci e and pecific
Pro one e ce Ab
Reac ion i in i ible nle he e i he
P o one phenomenon
addi ion of a label
Ag combine i h onl one o o an ibod
P oblem i ha e e alking abo
molec le and no c o -linkage a e fo med.
1:1 binding; a men ioned,
U all onl one i e on an Ab molec le i ed
en i i a ion i no een
and man f ee an ibod molec le emain in
Addi ion of label, all o an Ab,
ol ion
i done o de ec Ag-Ab binding
Fal e-nega i e
Labelled Immunoassa s
In ome ca e , he p e ence of e ce Ab i no
Ve en i i e e ha de ec
he onl ca e of a p o one eac ion.
ei he Ag o Ab, depending on he
P e ence of complemen in he e m ma al o be
e fo ma
a fac o
U e label a ached o he p ima
Nega i e o no eac ion
Ab (bind o he pecific epi ope of
In ome e , e need o inac i a e he e m
Ag)
ample o emo e complemen ha migh in e fe e
Label ma al o be bo nd o he
i h he e l .
econda Ab
P e ence of blocking an ibodie i al o a fac o
Ha pecifici and bind
Migh bind o Ag, p e en ing he ac al Ab
o he Fc po ion of he
o bind o he Ag nega i e e l
p ima Ab
U all IgG Ab
e.g. an ih man glob lin,
Course of Action: dil e he e m o adj he Primar
Ab again ano he Ab
amo n of Ab reactions
Label ed:
Zone of Equivalence poin in hich o can ee a i ible
En me , e.g.
e l; e ong eac ion
ho e adi h pe o ida e,
E e a ailable Ab i e i bo nd o Ag
alkaline pho pha a e
N mbe of m l i alen i e of an igen and an ibod
Radioi o ope
a e app o ima el e al
Fl o e cen d e
P ecipi a ion i he e l of andom, e e ible
E ample : RIA, EIA, IF
eac ion he eb each an ibod bind o mo e
Radioimm noa a
han one an igen and ice e a, fo ming a able
Mea e b ance (ho mone ,
ne o k o la ice
e m p o ein , and i amin ) ha
Post one e ce Ag
occ a e lo le el in blood
Po one phenomenon
pla ma
Small agg ega e a e o nded b e ce Ag
Radioac i e: ed a label
E e a ailable Ab i e i bo nd o a ingle Ag and
En me imm noa a : e en me a
no c o -link a e fo med
label ; al e na i e o RIA
Adj he Ag ed
Reac / i able b a e o
Fo e ample, o e ing RCS, o ha e o adj
p od ce b eakdo n p od c ha
he concen a ion of RCS o p e en he po one
ma be ch omogenic, fl o ogenic,
phenomenon
o l mine cen
Fl o e cen Imm noa a
Fl o opho e o fl o och ome ,
can ab o b ene g f om an inciden
ligh o ce and con e ha
ene g in o ligh of a longe
a eleng h and lo e ene g a

he e ci ed elec on e n o he Inc ba ion, cen if ga ion,

g o nd a e d a ion of inc ba ion and/o
An ibodie ed o iden if ch cen if ga ion, empe a e, pH
an igen a e highl pecific; hen
bo nd o an igen in he i e, he NOTE: De ail of he e ologic a a /imm noa a hall be
fl o e cen p obe a ached o he di c ed in he labo a o .
an ibod i de ec ed nde Read Chap e 10 of he e book!
l a iole ligh ing a fl o e cen P e e: D a a a g ga e h d a d he ff a
mic o cope d c a a ab :) A f a ead e ab a
Confo ma ion of Amino Acid chain d e o eac (Labe ed a a ), cha e 11.
in e chain h d ogen bonding
POST-TEST
Occ af e p ima eac ion ; C o linking
Secondar 1. Ionic bond a e al o kno n a ? Electrostatic
lead o fo ma ion of imm ne comple e
reactions 2. T/F: Sen i i a ion d ing Ag-Ab binding i i ible o he
Mo e i ible eac ion
E ample : Aggl ina ion, P ecipi a ion, naked e e
Complemen , Fi a ion and Hemol i 3. T/F: The ini ial enco n e of Ag and Ab i efe ed o a a
p ima eac ion
Occ a biologic eac ion and in ol e
4. Cla if he follo ing imm nologic eac ion (p ima ,
folding of pol pep ide chain h o gh
econda , e ia )
Tertiar h d ophobic and h d ogen bond
a. Aggl ina ion eac ion - Secondar
reactions E ample : Phagoc o i , Op oni a ion,
b. RIA - Primar
Chemo a i , Imm ne adhe ence, Cell la
deg ada ion
In ome efe ence , he men ion quaternar reactions.
In ol e a ocia ion of pol pep ide o fo m one
p o ein
IMMUNOASSAYS
Imm noa a a e ick and acc a e e ha can be
ed on- i e and in he labo a o
De ec pecific molec le and/o mea e he
concen a ion of a molec le in a ol ion h o gh he e of
an an ibod o imm noglob lin
Imm noa a el on he inhe en abili of an an ibod o
bind pecific c e of a molec le efe ed o a "anal e"
and hich chemicall in man ca e , a p o ein.
GENERAL CONSIDERATIONS
In an imm noa a , an an ibod molec le
ecogni e and bind o an an igen
Binding i ela ed o:
Concentration of each reactant ( onal
eac ion )
Specificit of antibod for antigen
A e he e an c o eac ion
ha o ha e o con ide o
make he e mo e pecific?
Affinit & Avidit for pair
Ho ong i he binding
be een he Ag and he Fab
egion
O e all binding
Environmental conditions

S ce : PPT, a nch n lec e ide , B k and he efe ence
Th m i e f ma a i f
l m h c e ha ld bec me T cell
UNIT 7: BIOLOGY OF THE IMMUNE RESPONSE
Sec da l m h id ga ga he e he
imm e cell mee he a h ge he a ige ;
Pre-test he e imm e cell ld ma e, diffe e ia e,
1. S c e d ced b mic be hich a e ec g i ed b a d be ai ed ha dle a h ge
i a e cell im la e he imm e em T il
a. PAMP Ade id
b. NOD-like ece L m h de
c. TLR S lee
d. DAMP O he l m h id i e f d i he g &
2. Which f he f ll i g c ki e e ed a he i ci al e ia ac
ac i a f mac hage ?
a. TNF be a MECHANISM OF IMMUNITY
b. T a f mi g g h fac H he IS e i c n agi /infec i di ea e
c. IFN gamma Di ided i : i a e ( a al) imm i & ada i e
d. RANTES (ac i ed) imm i
3. T e Fal e: I i ial ac i a i f ai e i gi T I a e imm e e e
l m h c e cc mai l i he ima l m h id ga . Bef e he a h ge e e he b d , he b d
4. Which cell f he ada i e imm e em ma f c i a ld ha e he fi li e f defe e
a a ige - e e i g cell? Ph ical ba ie ch a i ac ki
a. T hel e cell Mic bi me mal fl a ha e e
b. B l m h c e he life a i f a h ge
c. Mac hage Fl hi g ac i f i e a d he
d. De d i ic cell ec e i
True or False: If he e ba ie a e able e e he e f
5. P e e a i f e ide f a ige c m le ed i h a MHC he a h ge , e ha e he ec d li e f
m lec le i fficie ca e c m le e ac i a i fT defe e, de he i a e IR
l m h c e . I l e he diffe e imm e cell f di
6. E a i f cl e f T cell b e cc h gh he he b d ( hag c e , mac hage ,
ac i f IL-2 ai e T cell . e hil , NK cell )
7. The e e ce f a ige ece i a e he fi ig al f T U e f PRR ( a e ec g i i
cell ac i a i . ece ) hich a e - ecific a d bi d
PAMPS ( a h ge -a cia ed
[REVIEW]
Defense S stem memb a e ei ) hich a e a cia ed
Refe he Imm e S em i h mic be
I l e cell , i e , a d ga ha f c i TLR, NOD
em e fil e a d e d diffe e a h ge Elici a ge e ali ed a ach i
ha e e he b d e ali i g he a h ge
A e k f eciali ed ga ha fil e a d e d The b d ld al be elea i g
mic be ha e e he b d i e . a imic bial b a ce e e he
C i f a m bile f ce f m lec le , b a ce , a d life a i f he a h ge .
cell i he bl d eam ha a idl e d a a l C m leme ca be a f
challe ge ed b a h ge a d hei ic d c he i a e IR if ac i a ed b he
Ne ali e he ic me ab li e d ced b he e al e a i e he
a h ge ma e-bi di g lec i a h a
Phag c i
HUMAN IMMUNE SYSTEM B he ac i f c m leme a d he b a ce ,
C m ed f he f ll i g maj ga : ge he i h he imm e cell , i flamma i
P ima l m h id ga ld al be ac i a ed
B e ma ce f all imm e I flamma i b d e e a
cell ; he e B cell ma e; i e f i fec i age f eig ma e ial
hema ie i
CASTILLO, J. KHOO, J. MAGTIBAY, H. 3D REVS 2022

If he e mecha i m a e ill able de I l e i e ac i f liga d a d he

e ali e he a h ge ha e e ed, ha i he ime ha he c e di g ece
hi d li e f defe e he ada i e imm e e e ld Wi h i e ac i f liga d a d hei
c me i lace ece , ac i a i ill ha e
M e ecific T e f Ag i al im a i ac i a i
Ha e imm l gic mem c m a ed he he F e am le: T cell ld l
i a e IR (ge e ic e e) ec g i e Ag ha a e ce ed
2 imm e cell ha a e ac i el i l ed: a da cia ed i h MHC; T cell
Tl m h c e ld ec g i e hem beca e
Bl m h c e f TCR
Sl e i ac i c m a ed he i a e IR The e ld al be i e ac i
i h ce ai liga d a d
ece e e i he T cell
a d i he a ige - e e i g cell
hich ca ie he Ag
B cell ld ec g i e h le
a ige ia he BCR (Ab f d
he face f B cell )
C ld ec g i e T
de e de Ag Ag
ha eed T cell be
ec g i ed b he B cell
T i de e de Ag Ag
ha d e eed T
cell be ec g i ed
b he B cell; ca
ec g i e
l accha ide
he e ea i g
m lec le
Af e ec g i i & ac i a i , he e ill be he
ce f life a i
Relea e f c ki e ha m e
Adaptive Immune Response life a i f he T a d B cell
1. A ige ec g i i T cell de he i fl e ce f
Ag ec g i ed b he imm e cell ca be: IL-2 (T cell g h fac ) a d
P ce ed b ke d i malle ld diffe e ia e i :
f agme / e ide T hel e ec e i f
The e a e ce ai Ag ha ca c ki e hich ld
be ec g i ed b he imm e d eg la e all
cell if b ke d life a i f he
U all e e ed i h he MHC cell (Th1, Th2, Th17)
Wi h he i e ac i f he Tc ic di ec
ce ed Ag a d MHC, killi g f a ge cell ia
imm e e e ill ha e a i
Na al ce ed h le Ag T eg la
U all ec g i ed b he B cell d eg la e he
Ag ca al be ec g i ed b he imm e cell effec f T hel e & T
a ell c ic
2. Ac i a i , P life a i , a d Diffe e ia i Mem cell
O ce ec g i i i d e b c e di g T B i ac i e b if 2 d
l m h c e, ac i a i ha e . mee i g f Ag ha e ,
he e cell ld be

a idl ac i a ed F m he ime he imm e cell ec g i e he Ag,

life a e a d ac ac i a i , elimi a i f a h ge /Ag, de ci ,a d
he Ag f he 2 d ime d ci f mem cell
B cell Specific immune s stem recogni es antigen through:
Pla ma cell d ce 1. Antibodies (BCR)
a ecific Ab F d he face f B cell ec e ed b
Mem cell la ma cell
eac i a ed he 2 d ime Ba ic f c i al i m me
a d Y- ha ed a d ha 2 bi di g i e
Each m me i bi ale , ca able f
Two Major Arms of the Adaptive IR bi di g 2 e i e a he ame ime
H m al Rec g i ed he a i e/ a al ( ce ed) f m
I l e ec e i f Ab f he Ag
U de he B cell 2. T Cell Receptor (TCR)
Cell-Media ed P ima il b d a ached he T cell
I e ac i i h cell f IR ha e J am ale c e i h 1 bi di g i e f
U de T cell ha Ag
Ag h ld be ce ed, b ke d i
IMMUNE RESPONSE mall/ h e ide ami acid
Al a e ic ed b MHC
I cl de he a i bi l gic ce e ha c i e he
If he Ag i c m le ed MHC, he
e e f he imm e em he i d ci f he
TCR ill ec g i ed b TCR
f eig b a ce
F d he face f T cell
I d ced b c i ical i e ac i f innate s stem
c m e , ha e d m l a d - ecificall
he f eig age , a d h e a f he adaptive immune
s stem ha ecificall eac a d bi d e i e f
a ige .
Purpose of the immune response
Ge id f he f eig b a ce a ige
PHASES OF THE IMMUNE RESPONSE
H d e he imm ne em eac again he an igen?
1. Recognition of the antigen or pathogen
a. INNATE (ge e ali ed, ge e ic, - ecific)
T CELL RECEPTOR B CELL RECEPTOR
Pa h ge A ack elea e f a imic bial
(Ab)
e ide , c m leme ac i a i ,
Phag c i Cell face Cell face
Site of Ag receptor
I flamma eac i ci c la i
b. ADAPTIVE ( ecific & ha imm l gic mem ) Cell b d/ I he e acell la
Ac i a i , life a i , Diffe e ia i ce ed i hi fl id/ e d c ed
Effec f c i Source of Antigen
c l f m he la ma
memb a e
Li ea e ide Na i e a al f m
Form of Antigen
e e ce
MHC restriction MHC e ic ed N MHC e ic ed
Diagram showing the Phases of Immune Response

INVASION OF THE ANTIGEN PATHWAYS OF ACTIVATION OF T LYMPHOCYTES

ROUTES OF ENTRY 1. Endogenous pathwa
1. Inhalation Pa h ge a mi ed ia he ai d le Ag i al ead i ide he c l f he cell
2. Ingestion O all U all i l e i e
3. Puncture of the skin T a ma e.g. he a i i fec a cell, he
4. Through the blood (Bl db e di ea e ) Ag/ ei f hi i ill be ce ed
i ide he cell, a d he i fec ed cell ld
Mic be e e he b d b a i a mi i me h d e e he ce ed Ag ge he i h
M a h ge ha e ecific al fe MHC Cla I
1. Ski I l e MHC Cla I
2. Ga i e i al ac F d i all clea ed cell
3. Re i a ac 2. E ogenous pathwa
4. U ge i al a ea I l e MHC Cla II
5. Place a a mi i i e ical (m he F d i APC ch a de d i ic cell ,
bab ) mac hage , a d he B cell
ANTIGEN CAPTURE AND ROLE OF APC F e am le, APC like he de d i ic cell
mac hage e g lf a a h ge like m c bac e ia
O ce he a h ge e e he b d a d b a e he
If he mac hage e g lf he m c bac e ia, i ide
diffe e i i ial ba ie f imm e em, i ld he be
he mac hage, i ill be e e i he e icle
ca ed b ce ai imm e cell
a d ce ed/b ke d i malle f agme
e.g. de d i ic cell f d i a ide a ie f i e
a d ld be a cia ed i h MHC Cla II
& ga
The ce ed Ag ge he i h MHC Cla II ill
La ge ha cell i ki hag c i
be e e ed he face f he APC
f Ag, ce e i i ide he cell, a d
he ld f c i a a APC e e
he Ag he imm e cell , f e am le,
i he l m h de (if he a h ge i
f di c ec i e i e e i heli m)
If he a ige i f di e-e e ia
he bl d, i ill be fil e ed ca ed i
he lee
1. Si e f a ige e
2. Si e f i i ial a ige ca e
3. Si e f a ige c llec i a d ca e
Interaction of the APC with T cells

If e a e deali g i h APC , he ld i e ac i h CD4+
(Th) cell
MHC Cla II + ce ed Ag ld i e ac i h
Th cell
Bi di g ill ha e i h TCR b he e a e 2 e
i l ed:
Need f a c im la ig al f
ac i a i ha e
B7 e e i APC (B7-1 i
CD80; B7-2 i CD86 hich i
all m e me )
C e di g ece f B7
CD28 i T cell

Dapa ma bi di g ng MHC & 8. IL2 i a l m h ki e ha f c i a a T cell g h fac . I

TCR, a d B7 & CD28 e e i ac i a ge cell i a a c i e ma e .
Beca e f hi he e ill be a Th , IL2 a ache he CD25 ece ac i a ed T cell
elea e f c ki e like IL-2 ca i g he e cell de g life a i e l i g i he
hich ld m e T cell e a i f cl e f a a ic la T cell b e .
ac i a i A ci e i a g ma a, i a rin ang
Sig al 1 MHC II + Ag + TCR makikinabang
Sig al 2 B7 + CD28 9. E a ded Cl e f T cell b e he de g
diffe e ia i i effec cell
T Cell Effector Function
10. T l m h c e he diffe e ia e i effec T c ic
(CD8) effec T hel e (CD4) cell
11. Effec T cell bi d a ge Ag a d deli e hei Le hal
Hi i g diffe e killi g mecha i m . CD8/T c ic
12. A he a ge a ige eake , T cell de ache f m i
a ge bef e he a ige b de ci .
APC ld i e ac i h T cell (CD4+/CD8+)

Relea e f IL-2 (T cell g h fac im la i g life a i
a d diffe e ia i )
IL-2R IL-2 ece
O ce ac i a ed, life a i /cl al e a i ha e
W ld he diffe e ia e i a CD4+ (T hel e ) CD8+ (T
c ic)
Cl al e a i ca al all d ci f mem T
cell ha ld bec me i ac i e a d ea il eac i a ed he Three Major APCs
2 d ime a d Immune Cells involved in recognition and function as
Recognition of Antigen ANTIGEN PRESENTORS
1. De ec i a d U ake f Ag b APC, Mac hage B cell
(de e di g he e f a ige ) ANTIGEN PRESENTING CELLS
NATURE OF ANTIGEN
2. P ce i g f he A ige ( eili g f Ag e i e) ge he (APCs)
i h MHC De d i ic cell Pe ide , i al Ag , alle ge
3. Af e ce i g i hi e e i g cell , Ag e face a
Pe ide f agme c m le ed a MHC cla f m lec le Pa ic la e Ag , e acell la
4. Rec g i i f li ea e ide f Ag b T cell i ible Mac hage (bac e ial cell ) & i a e ic la
h gh i TCR-CD3 ece Ag
T Cell Activation
Bl m h c e S l ble Ag , i , i e
5. T ig al a e e i ed GENERATE he ac i a i
ce
1 ig al I e ac i f Ag e ide / TCR-CD3 NOTE
ig alli g e ide E ce f he B l m h c e , De d i ic cell a d
2 d ig al Bi di g f C - im la ig al B7 Mac hage ec g i e i e a a geme f chemical
(f m e e i g cell) i h CD28 T cell g (PAMP) f a h ge i g hei Pa e Rec g i i
memb a e Rece (PRP).
B7-1 B7-2 PAMP a d PRP I a e IR
6. F ll i g c m le i f he e i ed ig al , ac i a i fT B cell ld l ec g i e Ag b PAMP i
cell f ll he a h ge
7. O T cell ac i a i , he l m h c e: De d i ic cell a d mac hage ec g i e he
Relea e IL-2 PAMP beca e he ha e PRR (TLR, NOD)
E e e CD25 face m lec le Pathogen Recognition Receptors
The ece f IL-2 Hard- ired i he ge me

E e ed hag c e , APC, e i helial, C. Li ea e ide f he i Ag, a ed he ER

e d helial cell he a ach a c e di g bi di g i e MHC ( he
Rece f PAMP & DAMP (e.g. TLR, NLR) al ha chai f Cla 1)
Pathogen-Associated Molecular Pattern D. The MHC-Ag c m le e cl ed i hi e icle i ched ff
Highl cha ged face c e f m he ER a d E) affic he face, f e i h he
Wi h i e a ial a a geme f chemical la ma memb a e di la he MHC-Ag c m le
g ee h i e ecific T cell (i hi ca e he CD8+ T cell )
Antigen Capture and Processing b Dendritic Cell (Overview)
Highlighted in discussion:
1. A a h ge e acell la a ige i hag c i ed b a
I he e d ge a h a , he Ag i al ead b ke d
a ige - e e i g cell (i.e. de d i ic cell) a d laced i a
a df d i he c la m.
e icle. I ge ed a h ge a e dige ed b l me
Thi i f he ce ed b he ea me bec me a
e ac hei a ige
e ide.
2. The a ige bi d i h MHC ei ha e e he e icle
The e e ide a e he b gh he e d la mic
3. The MHC ei , ca i g he a ige , a e elea ed
e ic l m he e he ld be a cia ed i h MHC Cla I.
f m he e icle a d a el he e face f he cell
ERAP e me ha im he e ide f agme
memb a e
The e ide f agme ha ill be a ached MHC
4. The de d i ic cell i e e i g a ige , hich ill
Cla I h ld be ha l g beca e he Ag clef
ac i a e he T cell ha bi d i h he MHC ei (Cla II)
f MHC Cla I i cl ed ( e emble i a b ead)
If e ide f agme ae l g (10 m e),
ERAP ill im i fi he clef .
Pe ide ill he a h gh he G lgi a a a a dae
e e ed i he face.
[REVIEW]
MHC Cla I i f d i all clea ed cell a d
i e ac i h CD8+ T cell .
EXOGENOUS PATHWAY
Summar : De d i ic cell f c i a APC, e g lf a h ge , b eak

he e d i malle f agme , a d e e hi ge he i h
MHC Cla II m lec le . The MHC Cla II m lec le i h he Ag ca
be e e ed he CD4+ cell . De d i ic cell a e al ca able f
ce i g Ag a d a cia i g hem i h he MHC Cla I m lec le .
The a e al able ec g i e PAMP . * Thi a h a cc i a h ge ca able f e lica i g i hi
ENDOGENOUS PATHWAY mac hage e icle ch a he M c bac e ia a d Lei hmania
STEPS INVOLVED IN EXOGENOUS PATHWAY

A. Pa h ge f m he e i me i e d c ed i
e d c ic e icle . The e e icle ha e a acidic
e i me a d c ai e d e ida e ch a ca he i
B ha b eak d he a h ge i li ea e ide .
B. I he ER he e MHC m lec le a e d ced, i ha a
i a ia chai a ached i .
STEPS INVOLVED IN ENDOGENOUS PATHWAY C. Thi chai , ce e ma icall clea ed, f m a mall
A. Vi i ade clea ed cell , e ca e i c l a d ei , CLIP, i he bi di g i e f MHC m lec le . Ve icle
e d ce c ai i g MHC Cla II i h he CLIP b d ff f m he ER
B. Ne l he i ed i al ei e e cell e l ic ge he i h HLA DM.
fac ie (i.e. ea me ) he e he ill be b ke b D. Th gh HLA DM, he CLIP a em ed a d a he e icle
e d e ida e i i al e ide a d a ed i he i h he MHC f ed i h he e icle i h he Ag e ide,
ER b cha el f med b TAP1 & TAP2. I he ER, MHC HLA DM l ad he Ag f agme i he CLIP f ee MHC.
a e a embled i h he ei ch a a a i aid i E. The f ed e icle affic he cell face a d di la
he a embl ce . he Ag e ide-MHC Cla II c m le T hel e (CD4+) T
cell .

Highlighted in discussion: ANTIGEN RECOGNITION b T CELLS

A ige e e i g cell Rec g i i f Ag b T cell ill cc i he e e ce f
Phag c ed a ige a e b ke d i he cell h gh Li ea e ide f Ag al e i h MHC m lec le al e.
he l me Rec g i i ill ha e i he e e ce f b h Ag e ide
The b ke d Ag a e he e ide f agme f d a d MHC li ked a c m le m lec le
i he e icle ( ce ed Ag adhe e he e)
The Cla II MHC d ced i he gh e d la mic
e ic l m ill mee i h he e icle a d ill he be
e e ed i he face
Cla I m lec le i e ac i h CD4+ T cell
I l e i a ia chai . CLIP, e c.
TWO COMPARTMENTS OF THE CELL
Presence of two signals

1. Bi di g f Ag e ide-MHC cla f m lec le c m le
TCR-CD3
2. I e ac i f B7 CD28 lead f ll ac i a i fT
l m h c e .
➢ If b h ig al a e ac i a ed, he e i life a i &
C l C i ih cle ac i a i f T cell
Ve ic la em C i ihe acell la fl id (i.e.
ER, g lgi, e d me , l me )
Intracellular Intravesicular E tracellular

pathogens pathogens pathogens
Degraded in C l E d c ic E d c ic
(e d ge ) e icle e icle
(e ge ) (e ge )
Peptides bind MHC Cla 1 MHC Cla 2 Cla 2

to
B7 ca be f d:
Presented to CD8 T cell CD 4 T cell CD 4 T cell I he APC if MHC Cla II
I i fec ed clea ed cell e e i g MHC Cla I
Effect on Cell dea h Ac i a i kill Ac i a i fB
presenting cell i a e ic la cell ec e e O ac i a i f T cell , IL2, T cell g h
bac e ia/ Ig elimi a e fac , i elea ed hich i a a c i e
aa ie e acell la effec , bi d CD25 (IL-2R) e e ed
bac e ia/ i ac i a ed T l m h c e a d ca e he
g ha de a i f he ecific T cell T
b e.
NOTE: Pe ide de i ed f m I a e ic la a h ge ( i.e. Ag ha
All ac i a i , life a i , a d
ca i e i hi e d c ic e icle ) a e e e ed b Mac hage
CD8 diffe e ia i
CD4 T cell ecificall he I flamma CD4 + cell . (T2h1)
Activation

Sh i he Mecha i m b hich
Mac hage ca e , ce a d di la
Ag e ide MHC Cla II c m le f
ec g i i f Th1 cell
CD4 Ac i a ed CD4(+) T cell ecificall Th1 T CELL DELIVERS ITS LETHAL HIT ON TARGET CELL
Activation b e ca elea e c ki e ha ca
Cell i fec ed i h a i ha e eg la ed e e i f
ac i a e Mac hage ha b i g he e ic la
Fa
a h ge i hi i e d c ic e icle .
I l e Fa -Fa liga d ef i de a ge cell
C ki e f m Th1ca d ce i ic ide
Fa -Fa liga d
a d ge adical f killi g f a h ge .
Bi di g f Fa (membe f TNF famil )
Th1, Th2, Th17
f d i a ge cell
Diffe he c ki e d ced
Fa L f di Tc ic cell hich i
Th1 ec i me a d life a i
he Fa ece
f mac hage
Ac i a e a dea h d mai & a ge cell ill
Th2 IL-4, 5, 10 (i l i g B cell ;
be de ed ia a i
h m al imm i )
CTL i e ac i / Ag e ide-MHC ca e elea e f l ic
Th17 i l i g a h ge f d
g a le a d U eg la i f Fa L. E f g a le
i he m c al a ea
a ge cell l Fa -Fa L i e ac i i d ce a i
T CELL ACTIVATION, PROLIFERATION and Ac i a ed CD4(+) T cell ecificall Th1 b e ca elea e
DIFFERENTIATION of CD8 & CD4 T CELLS c ki e ha ca ac i a e Mac hage ha b i g he
e ic la a h ge i hi i e d c ic e icle . C ki e
f m Th1 ca d ce i ic ide a d ge adical f
killi g f a h ge .
Effector Functions of C toto ic T cells -

Granule E oc tosis Mechanism
1. C ic T cell bi d igh l he f eig a ge cell
2. C ic T cell elea e e f i a d g a me m lec le C ic T L m h c e (CTL) c ai i ac la mic
f m i g a le b e c i g a le (e.g. g a me & e f i ) hich ha e ef med
3. Pe f i m lec le i e i he a ge cell memb a e a d Fa L hich a e a idl e e ed hei face he
f m e imila h e d ced b c m leme hei TCR i e ac i h a ge cell . I e ac i f Fa ihi
ac i a i liga d Fa L i d ce APOPTOSIS.
4. Ga me e e he a ge cell ia he e a d deg ade
cell la c e
5. The c ic T cell de ache a d ea che f a he e

PATHWAYS OF ACTIVATION OF B LYMPHOCYTES
Perforin Killing or Use of Granules

1. Mac hage ca e , e g lf , a d dige a a ige
2. Mac hage e e f agme f he a ige i face
3. I e ac i be ee ei he mac hage a d
hel e T cell cc , ac i a i g he hel e T cell
4. Ac i a ed hel e T cell life a e i ei he T H1 TH2
cell , hich ec e e diffe e e f c ki e
A a f B cell ac i a i ld al i l e he T cell .
The e i a elea e f ic g a le i he f m f e f i Th cell c ld elea e c ki e ha ca al all B
a dga me . cell ac i a i a d life a i .
Pe f i elea ed b T c ic cell a d B cell ca al f c i a a APC f Th cell
ca e e he a ge cell Able ec g i e a i e a ige
Beca e f he e e , he g a me N eed ce b eak d Ag f B cell
ill ha e a a f e e i g he a ge ec g i e i
cell m ea i N eed f agme
Summar : Ag ec g i able b B cell ca be cla ified i 2:
Ca i g f he Ag T de e de eed Th cell a i a ce;
If ha e a APC, hi ld be e e ed he B cell ac i a i ih a i a ce
Th cell E am le : T i f di h he ia,
The CD4+ cell ld bec me he T hel e , he ified ei de i a i e f M.
ld be ac i a ed, elea i g c ki e i fl e ce berc lo i , i al hemaggl i i
he imm e cell T i de e de ca able f B cell
If ha e a T c ic cell, hi ld m e ac i a i ih a hel f m T cell
di ec killi g f he cell a d ld al be affec ed I l ec m e f bac e ia
b he c ki e elea ed b Th cell (ce ai l accha ide )
T e1&2
O ce B cell ec g i e Ag, i ld be ac i a ed a d ld
life a e
Af e life a i , hi ld diffe e ia e i la ma cell
ec e e a a ic la e f Ab
I l e B cell ha e e IgG ca diffe e ia e
f he i la ma cell a d beca e f he elea e
f ce ai c ki e , hi ld al all i e
i chi g
I e i chi g IgG m lec le ca bec me
diffe e cla e f Ab ch a IgA IgE de e di g
he c ki e bei g elea ed
✓ F T cell e e, ake e f he ece a d Same ecifici i h e i e b diffe e
c im la ig al . Ab cla
✓ B7 i e e ! Hea chai a /c a egi ill be
cha ged
S me ac i a ed life a ed B cell ld al bec me
mem B cell
Ha e he CD27 ma ke

I ac i e, b ce he Ag i me agai , he e ld ed mi a l IgM f l affi i ,

be ea il eac i a ed bec me la ma cell a d mem cell ge e a ed; ec g i ed b B1
ec e e Ab cell
TYPE 1 ma ha e i he e mi ge ic
e ; Ca i d ce l cl al ac i a i
f B cell / BCR e gageme
Bac e ial LPS, Br cella abor
T independent
Mi ge ca able f im la i g
antigens
life a i f a ic la B cell
TYPE 2 e li ea l a a ged
m l e ea i g a ige ic
de e mi a
P e m c ccal l accha ide,
de a , l c e, Salmonella
B cell ld ha e face imm gl b li Ab ha a e l me i ed flagelli
able e ali e a h ge Rec g i ed b B2 cell
Ab c ld bi d i e e ali e hem B cell ac i a i e i e a i a ce f m T
Si ce Ab a e c a i g he i al a icle , i e e a T dependent
hel e cell
a i antigens
Di h he ia i , PPD f M.
Thi ld he be hag c ed b he effec cell ch a berc lo i , i al hemaggl i i
mac hage
P ce f ADCC Th mus- Th mus-Independent
Effec cell c ld al elea e l ble fac like c ki e Dependent Antigen Antigen
im la e he imm e cell de c l he (B2) (B1)
a h ge
A ib die a e ca able f di ec l de i g he a ige ; P ei P l me ic Ag ,
he ca me el e ali e c a i (a a i ) f he e eciall
hag c e e g lf i . Chemical nature l accha ide , al
gl c li id a d cleic
T pes of B l mphoc tes acid
E e e Ag ece f limi ed di e i
FEATURES OF ANTIBODY RESPONSE
De i ed f m fe al li e HSC; be defi ed
i de Ye L le el f
Isot pe switching
S a e l ec e e IgM a ib die ha (IgG, IgA, IgE) IgG a d IgA
B1 cells eac / mic bial l accha ide a d
li id Affinit maturation Ye N
Gi e i e IgM a ib die agai ABO Secondar Ye Le
Bl d g Ag response (mem B ( l ee / me
T cell i de e de B cell (T e 1 2) cell ) l accha ide)
M f B cell a e hi e
De i ed f m fe al li e HSC; C e i al
B Cell Response to T Independent Antigens
B cell
Re ible f de el me f h m al
imm i
B2 cells
T cell de e de B cell
Cla /i e i chi g ca
ha e
E e all diffe e ia e i la ma cell
d ce IgA, IgG a d IgE a ib die
T pes of B cell antigens

O ce B cell ec g i e T i de e de Ag, imm gl b li Si ce B cell a e al i l ed i e e i g Ag T cell ,

ca i g ha e he e i B7-1 & 2 (c - im la ; CD80 & CD86)
All he ece f face Ab i he B1 cell ill be I e ac i h he ece e e i T cell hich i
c ce a ed e a cl e i g he CD28
Nag a ama- ama, nagdidiki -diki ong mga IgM Ab CD40 ecei e ac i a i ig al f m he T cell
e e he face f he B1 cell ec g i e he Rece : CD40 Liga d f d i T cell
T i de e de Ag CD19-21 i e ma ke f d i B cell
All c -li ki g f he e i e f he Ag i h he Mi ge ece all bi di g f bac e ial d c
Fab egi f he cl e ed Ab B CELL Activation b T-Dependent Antigen
E e all all ac i a i & life a i f B cell ,
Important roles of T helper (CD4+) cells on B cell activation
diffe e ia e bec me la ma cell , a d d ce
The Th cell a e e im a f B cell ac i a i
a ib die
I e ac i h B2 cell (T de e de )
T i de e de NO i e i chi g ( e a e)
T cell a ici a i i he d ci f a ib die m
B CELL Activation without T CELL HELP a ige i a im a e i eme
C m le e ab e ce f T-cell hel. TH cell i e i ed f B2 cell life a e, diffe e ia e a d
N i e ac i = N c ki e . d ce a ib die
A high c ce a i B-cell TH cell i d ce cla i chi g a d affi i ma a i
mi ge . Sim l a e T a d B cell c llab a i i ece a
ac i a i f BCR a d he C ki e d ced b TH a d he a he
ece B cell (i.e. LPS l m h c e e gage hei c m leme a face
bi di g ei /CD14/TLR4) m lec le i c cial a hi ide he ece a
i d ce he B cell life a e ig al f B cell ac i a i ha e
a d diffe e ia e B cell STEPS INVOLVED:
ac i a i . 1. The B cell ece ec g i e a a h ge
2. Pa h ge i b gh i he cell
3. Pa h ge i dige ed i mall iece ( e ide )
S gc li ki g f BCR b 4. The e ide i di la ed he face f he B cell i h a
e e i i e l accha ide MHC cla II m lec le
ei e i e . C ki e hel 5. A TH2 hel e T cell ec g i e he e ide a d elea e
ided b T, NK cell , e c. c ki e
TI-2 all d ac a CD40 a d CD154 (CD40 liga d)
l cl al B cell ac i a Note: I ge e al, A e e ed a e B cell a e i ac , f a i e
c f ma i a d ce ed b APC
B CELL SURFACE MARKERS
Marker Function
Surface Ig A ige ecific ec g i i
MHC, class II A ige e e ai
(HLA-DR/DQ)
B7-1 & 2 T-cell ac i a i
B Cell Activation b T dependent Ag
CD40 Recei e ac i a i ig al f m T and B Cell Interaction
T cell
B cell ec g i e a d ca e he Ag h gh hei BCR a d
CD19-21 U i e B cell ma ke bi di g f Ag he ece lead i e ali a i f he Ag
Mitogen receptor Bi di g a d ac i a i b bac e ial ( ia ece media ed e d c i ).
d c The TD Ag i ce ed i e ide a cia ed i h M Cla
Ma e B cell ld ha e face Ig (IgM & IgD) II a d di la ed he face f ec g i i b CD4 hel e
Si ce B cell i al ca able f bei g a APC, MHC Cla II i T cell
al e e he face

Ag e ide- MHC c m le i ec g i ed b TH cell bi d

B cell , a d i e ac i be ee c m le e l adhe i
m lec le i igge ed.
TH cell e e he CD40L a d bi d CD40 B cell
i i ia e he ac i a i f he la e cell .
Ac i a ed B cell elea e B7 hich i bi d CD28
T cell c - eci call im la e he TH cell .
Ac i a ed TH cell d ce IL 2 ( a a c i e T cell g fac )
a d IL4 & IL5 , hich a e g h a d diffe e ia i fac f
ac i a ed B cell . B cell response to antigen Significance
END RESULT: B h T a d B cell cl e e a d a d
E i cell c cle, mi i Cl al e a i
diffe e ia i
I c ea ed e e i f B7 Abili ac i a e hel e T cell
Stages of B Cell Activation c im la
I c ea ed e e i fc ki e Abili e d c ki e
ece d ced b hel e T cell
Mig a i f l m h id f llicle I e ac i i h hel e T cell
Sec e i fl le el f IgM Ea l ha e f h m al imm e
e e
Activation and Class-switching

1. APC e e a ige T-hel e cell
2. B7 i e e ed a d i e ac i h CD28, ac i a i g T-hel e
De e de he e f Ag (T de e de i de e de )
cell
B CELL ACTIVATION PATHWAY 3. Ac i a ed TH cell i e ac i h B-cell ia CD40 liga d,
F ll he ame ha e i l ed i he ge e a i f ac i a i g B cell life a e, diffe e ia e, a d ec e e
imm e e e a ib die
B cell ac i a i e ie ig al 4. TH cell ec e e c ki e ha de e mi e cla i chi g
Signal 1 I e ac i f l ble Ag Cla i chi g ld be de he i fl e ce f he
For B cell - BCR i e le ki d ced b T hel e cell .
T independent Signal 2 B cell ecei e c m e IL-4 IgE
Antigen f m i ci i g T-i de e de Ag ca e B IL-5 IgA
Interaction cell life a i a d diffe e ia i a d
ca e d ci f IgM antibodies onl .
Signal 1 I e ac i f ei Ag
BCR
Signal 2 C ki e f m Th ca e B
cell life a i a d diffe e ia i a d
ca e d ci f a ib die f diffe e
For B cell -
i e .
T Dependent Ig heav chain isot pe switching
T cell ide he ec d ig al
Antigen Development of functional diversit
ia liga i f CD40 b CD154 (
Interaction
CD40 liga d) a d h gh ac i Principal effector functions
f c ki e IgM C m leme ac i a i
IL-4 a d IL-5 i i l ed
IgG FcR-de e de hag c e e e ;
m e he d ci f diffe e (IgG1, IgG3) C m leme ac i a i ;
i e Ne a al imm i ( lace al a fe
Possible Outcomes of B CELL ACTIVATION IgE Imm i agai helmi h ;
Ma cell deg a la i (immedia e
h e e ii i )
IgA M c al imm i ( a f IgA h gh

e i helial)
Late events in T-cell dependent antibod responses

1. E e i e i e i chi g de e de c ki e
2. S ma ic m a i
3. Affi i ma a i
4. Ge e a i f Mem B cell
5. I d c i f l g-li ed la ma cell
NOTE: All e e cc i he ge mi al ce e .

S ce : PPT, a ch ec e ide , B ka d he efe e ce
O e a f de i g i ac i a i g he
UNIT 8: COMPLEMENT SYSTEM c m leme i he e m am le hea i g a
56 C f 30 mi e
GENERALITIES The e a e ce ai e ha e i e he am le
[RECALL]
I eg al a i media i g he imm e e e f he be i ac i a ed de he a i e c m leme
b d I me ca e , he a i e c m leme i
Na all f d i he bl d ( e m) he e m i e fe e i h ce ai e l gic
Al called a ale in i lde efe e ce e
Eh lich amed c m leme C m leme i al de ed c med af e
C m ed f c m le e ie f m e ha 30 ci c la i g a d age
memb a e-b d ei Im a link/bridge bet een innate and adapti e
P ima il a ei ace b a ce i he bl d imm i
P ima il he i ed (maj i ) b he li e a ell a ther A deficie cie he c m leme em:
cells Ma be e de ime al he a ie beca e
Imm e a d e i helial i e c m leme i a i eg al e e f eig
C1 d ced b i e i al e i helial age a h ge
cell I c ea ed ce ibili i fec i ,
Factor D d ced b adi e i e Bac e ial, i al, a a i ic
Properdin & C7 d ced b he P m e acc m la i f imm e c m le e
imm e cell ch a m c e , leadi g autoimmune diseases
mac hage , e hil , a d e e T P m e f he ac i a i f c m leme
cell a d e e all lead i flamma
Monoc tes and macrophages di ea e
addi i al ce f ea l c m leme A deficie c d f c i i he
c m e ( C1, C2, C3, a d C4) c m leme em ma lead
Ma be l ble cell-b d a imm e di ea e blem i
I e ac i e ecific a i flamma e e
C m leme ec g i e cell la deb i ch a a ic Al f d i l e f m f mammal
cell a d imm e c m le e , aggi g hem f em al b IgM a d IgG a e c m leme ac i a
i a e imm e cell . IgM e ame , ma bi di g i e (be e )
Beca e f i e ial f fa eachi g effec , C m leme bi d Fc i a
c m leme ac i a i eed be ca ef ll c m leme ca cade
eg la ed. IgG 1, 2, and 3 IgG3 i be
I ac i e ec P blem: m me , mall, a d l
Ac a a cascade ee e m cc bef e ac i a e c m leme i he e e ce f 2
a he ake lace IgG m lec le
O l ac i a ed i he e e ce f diffe e Nomenclature
igge i g fac
C1 C1 , C1 , C1
Am lifie i flamma e e
Comple ; la ge am g he c m leme
Proinflammator
c m e
Elici he ca di al ig f i flamma i
W ld l k like a b e f li b e f
I c ea ed a c la e meabili
fl e de he elec mic c e
Rec i me f e hil a d m c e
C1q li fl e
he i e f i j
C1r and C1s c e di g
T igge ec e i f imm eg la
he e fl e
m lec le ha am lif he imm e
Ca+ ca i ha abili e he c m le
e e
C cial i he c m leme
C m leme ei e e a a im a li k
I ac i a i em al f calci m
be ee i a e a d ada i e imm i
e e c m leme ac i a i ,
A acute phase reactant
a ic la l i he cla ical a h a
Heat-labile and easil inacti ated i he e e ce f high
C4, C2, C3, C5, C6, C7, C8, C9
em e a e

Nami g i NOT ba ed hei de i he e.g. C5a & C5b

ca cade, a he amed i he de i hich he C5a ca be a im a
e e di c e ed a a h la i ; m i g a a h la i a d
N ch l gic igge i g he imm e cell (ma cell &
Ma efe ed a " mogens" e i hil )
E me ec C5b all e ai ed i he a ge cell
O ce ac i a ed, he ill bec me e me a d ld bi d he he c m leme
"a" a d "b" added i de e clea age d c d c
O ce a c m leme c m e i clea ed b a Complement receptors
ce ai e me F d he diffe e cell f he b d
The e ld al ha e diffe e m lec la eigh Si e he e c m leme c m e ld bi d
Ge e all , he b clea age d c ld Named acc di g liga d c m leme
ha e a la ge m lec la eigh ; c m e (E : CR1, CR2, e c),
The ligh e d c i he a U i g CD em
The a i all di ib ed he he
a f he b d ( e m) & ha diffe e
bi l gic f c i .
TABLE 7-1 PROTEINS OF THE COMPLEMENT SYSTEM
Serum Protein Molecular Wt. Concentration Function

(KD) (mg/mL)
Classical Path a
C1q 410 150 Bi d Fc egi f IgM a d IgG
C1r 85 50 Ac i a e C1
C1s 85 50 Clea e C4 a d C2
C4 205 300-600 Pa f C3 c e a e (C4b)
C2 102 25 Bi d C4b f m C3 c e a e
C3 190 1,200 Ke i e media e i all a h a
C5 190 80 I i ia e memb a e-a ack c m le
C6 110 45 Bi d C5b i MAC
C7 100 90 Bi d C5bC6 i MAC
C8 150 55 Sa e f ma i memb a e
C9 70 60 P l me i e ca e cell l i
Alternati e Path a
Factor B 93 200 Bi d C3b f m C3 c e a e
Factor D 24 2 Clea e Fac B
Properdin 55 15-25 S abili e C3bBb-C3 c e a e
MBL Path a
MBL 200-600 0.0002-10 Bi d ma e
MASP-1 93 1.5-12 U k
MASP-2 76 U k Clea e C4 a d C2
Fc f agme c alli able; Ig imm gl b li ; MAC memb a e-a ack c m le ; MBL ma e-bi di g lec i ; MASP MBL-a cia ed e i e ea e

HIGHLIGHTED IN RECORDING
Wi h ega d he c ce a i fc e e c e :
M ab da i e m C3
Im a ke i e media e i all a h a f he c m leme
Th ee a h a : cla ical, al e a i e, a d lec i a h a
C e ge ce i f all a h a
All a h a ill e e all mee i hi c m e
Im a marker of inflammation
A e i flamma di ea e ha he a ie i e e ie ci g
Sec d m ab da i e m C4
Im a a f C3 c e a e
E me d ced ac i a e C3
Wi h ega d he i e ec a eigh f c e e c e :
La ge C1q
Rec g i i i
The C1 c m le i c m ed f C1 , C1 , a d C1 .
Ve c cial a f he C1 c m le
I bi d he Fc i / ece f IgM a d IgG Ab ha ld i i ia e he a f he c m leme ac i a i ,e eciall i
he cla ical a h a
The other complement components are also necessar for complement acti ation.
Bac e ial cell i h hi cell

FUNDAMENTAL FUNCTIONS
memb a e
G (-) bac e ia like N.
g h eae
N all a ge cell a e able be l ed b
c m leme
2. Opsoni ation
Ce ai c m leme c m e f ci a
i ; e am le gi e : C3b
Adhe e a ge cell/ a h ge
W ld be ec g i ed b mac hage
Diffe e effec f c m leme ac i a i /ca cade:
1. L sis i h he C3b CR1 ece ( ece f
E d e l f c m leme ac i a i he C3b ha a ached he a h ge )
I he e e ce f ce ai c m leme c m e All m e hag c i ; E g lf
ch a he C3b a d hag c e he cell
E e all ac i a e he e mi al Bi d a ge cell leadi g e ha ceme f
c m e (membrane attack comple hag c i
or MAC) f he c m leme 3. Acti ation of Inflammator Response
A he c m leme i ac i a ed, C3a & C5a
e e all , i ld f m he MAC Anaph lato ins i he bl d e el;
MAC a ach adhe e he a ge cell a a h lac ic eac i ; im la i g he
& ld lead m ic l i imm e cell (e.g. EOS & BASO)
H2O m e , he e ld be Chemota ins ec i di ec
l f elec l e , a d he cell e hil he hag c e he i e
be de ed fi j
Complement-mediated l sis 4. Clearance of immune comple es
[RECALL]
W k a ge cell ha ha e hi C m leme ac i a i ld ha e if he e
all /memb a e i he e e ce f imm e c m le e .
RBC C m leme ld bi d he e imm e
O he WBC c m le e , a d e e all , he e b d imm e

c m le e ld be e g lfed di ed f b
hag c e .
Tagged b C3b (opsonin)
Whe la ma cell elea e Ab
F ll i g cla ical a h a ei he be de ed
b l i i ed b mac hage
SLE ( e ic e he a )
i flamma i & de ii f imm e c m le i
diffe e ga
Fig e 1. O i ai
Figure 2-15. L cal i flamma e e ca be i d ced b he mall c m leme

f agme C3a a d C a. The e mall a a h la ic e ide a e d ced b
c m leme clea age a he i e f i fec i a d ca e l cal i flamma e e b
ac i g l cal bl d e el . The ca e i c ea ed bl d fl , i c ea ed bi di g f
hag c e e d helial cell , a d i c ea ed a c la e meabili , leadi g he
acc m la i f fl id, la ma ei , a d ell i he l cal i e . He c m leme a d
cell ec i ed b hi i flamma im l em e a h ge b e ha ci g he ac i i
f hag c e , hich a e hem el e b he a a h la i . C5a i m e e ha
C3a.
Anaph lato ins ac bl d e el i c ea e a c la

e meabili . T hi g ma ha e :
I c ea ed a c la e meabili all i c ea ed
fl id leakage f m bl d e el a d e a a a i
f c m leme a d he la ma ei a he
Fig e 2. O i ai i e f i fec i
C ac i f m h m cle
Relea e f hi ami e & he l ble
b a ce f m he ma cell &
ba hil
Mig a i fm c e a d e hil f m bl d
I i e i i c ea ed. Mic bicidal ac i i f
mac hage a d e hil i al i c ea ed
Chemota in elea e m e mig a i
Figure 2.10 C m leme ece hag c e igge he ake a d b eakd f
C3b-c a ed a h ge . C ale l a ached C3b f agme c a he a h ge face,
f e hil ie fi j
he e a bac e i m, a d bi d c m leme ece 1 (CR1) m lec le he hag c e OTHER FUNCTIONS
face, he eb e he i g he bac e i m he hag c e. I acell la ig al ge e a ed
b CR1 e ha ce he hag c i f he bac e i m a d he f i f l me Complement components and its functions
c ai i g deg ada i e e me a d ic m lec le i h he hag me. Ul ima el , he 1. Chemota ins C5a, C5b, C6, C7
bac e i m i killed.
2. For immune adherence C3b
3. Kinin acti ator C2b
Ac i a e kinins hich a e im a media f
i flamma i
4. Anaph lato ins C3a, C4a, C5a (m e )

5. Opsonins C3b (m all e c e ed), C4b, C5b Alternati e

Classical Lectin
6. For irus neutrali ation C4b (Properdin)
LPS
Imm e
S im la e B cell e e a d Ab d ci Acti ating (bac e ial Ma eg
c m le e
Al e a i e Pa h a C3d i ec g i ed b CR2 substance ca le) mic bial cell
(IgG/IgM)
IgA
e e i B cell ; e ha ce B cell e e
mic be Recognition C3, Fac B, MBP, MASP-1,
C1q, C1 , C1
unit Fac D MASP-2
F he d ci &e e i f Ab
C3
C4b2a C2bBb C4b2a
con ertase
C5
C4b2a3b C3bBb3b C4b2a3b
con ertase
MAC C5b6789 C5b6789 C5b6789
END RESULT CELL LYSIS
RECOGNITION UNIT
Classical
C1 c m le
C1q bi d he Fc i f he Ab
C1r & C1s a e m ge ha ld e e all
ge e a e e me ac i i begi he ca cade
Alternati e
HISTORY OF COMPLEMENT C3
Ehrlich le f "c m leme i g" a ib die i de i g Fac B
mic ga i m . Fac D
Bordet el cida e le f C' Lectin
Q i e imila he cla ical b ld be i g a
diffe e e m
MBP imila C1
MASP-1 & MASP-2 imila C1 a d C1

A a ge e al le, he classical path a i ac i a ed b he CLASSICAL PATHWAY

e e ce f immune comple es.
M died am g he diffe e c m leme ah a
Ag-Ab bi di g
I l e i e ei ha a e igge ed ima il b
Ab ha i all i l ed IgG and IgM
a ige a ib d c mbi a i
Ve effec i e ac i a f c m leme ,
Ab-directed mechanism f igge i g c m leme
e eciall IgM, d e i la ge i e
ac i a i
IgG all IgG b e a e ca able f
N all imm gl b li a e able ac i a e hi a h a
ac i a i g he c m leme ; IgG1, IgG2,
The imm gl b li cla e ha ca ac i a e he cla ical
a d IgG3 (m effec i e)
a h a i cl de IgM, IgG1, IgG2, and IgG3, b NOT IgG4,
IgG3 i he m effec i e d e he fac
IgA, IgE
ha i ha a l ge hi ge egi
IgM m efficie f he ac i a i g imm gl b li
IgG2 i he lea effec i e
Ha m l i le bi di g i e Take l 1 m lec le
IgG ld l ac i a e he
a ached adjace a ige ic de e mi a
c m leme if he e a e at least
i i ia e he ca cade
2 IgG Ab.
T IgG m lec le m a ach a ige
O he ac i a i g b a ce ma al be e e i
i hi 30 40 m f each he bef e
he cla ical a h a .
c m leme ca bi d
CRP, i e , bac e ia (e.g. M c a a
I ma ake a lea 1,000 IgG m lec le
a d E che ch a c ), a
e e ha he e a e cl e e gh
Alternati e or properdin path a
i i ia e ch bi di g.
Ac i a ed b he e e ce f bac e ial c m e
Rh g fa a a he cell able fi
(f eig cell b a ce ) ch a
c m leme
li l accha ide (LPS) hich a e e e i
Wi hi IgG g (m effec i e lea ):
G (-) bac e ia.
IgG3 > IgG1 > IgG2
O he bac e ial c m e ch a ca le IgA
O he b a ce ha ca bi d c m leme di ec l
Ab ma al ac i a e hi .
i i ia e cla ical ca cade: C- eac i e ei (CRP), i e ,
Antibod -independent
m c la ma , me a, a d ce ai g am (-) bac e ia
D e eed a imm e c m le be
(e.g. E.c )
ac i a ed
M i fec i age ca di ec l ac i a e ONLY
Lectin/mannose-binding lectin path a
al e a i e lec i a h a
M ece l ec g i ed a h a
Al ac i a ed b f eig b a ce
C m leme ac i a i ca be di ided i h ee mai
Mic bial d c ch a lec i e e
age , each f hich i de e de he g i g f
i he mic be
ce ai eac a a a i.
Ma e-bi di g lec i f d i bac e ial
1. Recognition unit - fi age; C1 i cla ical
face
ah a
Antibod -independent
C1 ill be fi ed
U de he i a e imm i ; fi e d alternati e
3 b i :
D e he e e ce f mic bial d c
C1 , C1 , a d C1
Lec i ld al be de i a e IR a d ld ac
Re i e e e ce f Ca2+
ec d
mai ai c e
Ac i ed ada i e imm i classical
C m le i made f e C1 b i
La ac d e he fac ha i i
a d each f he C1 a d C1 b i
antibod -mediated ( e e ce f imm e
2. Acti ation Unit - C4, C2, a d C3 (cla ical a d
c m le e )
lec i a h a )
L ge ime de el
3. Membrane attack comple (MAC) - C5 h gh
The lec i a h a e emble he cla ical a h a
C9; la i ; c m le e he l i f f eig a icle
Migh be a c i a i f he cla ical a h a

PATHWAY C1 ec g i e he f agme c alli able (Fc) egi f

adjace a ib d m lec le
A lea f he gl b la head f C1 m be
b d i i ia e he cla ical a h a .
A bi di g f C1 cc , C1 a d C1 a e c e ed i
ac i e e me
C f ma i al cha ge i C1 a ac i a i fC1
O ce ac i a ed, C1 clea e a hi e e b d C1 hich,
i , ac i a e i .
Ac i a ed C1 i e emel ecific
O l k b a e i C1 .
C1 limi ed ecifici
O l b a e : C4 a d C2.
O ce C1 i ac i a ed he ec g i i age e d .
RECOGNITION UNIT
1. C1 bi d a ige -b d a ib d . C1 ac i a e ACTIVATION UNIT
a -ca al icall a d ac i a e he ec d C1 ; both Begi he C1 clea e C4 a d e d / he d ci f C5 c e a e
acti ate C1s.
C1q (MW:410,000) c m ed f 6 a d ha
f m 6 gl b la head i h a c llage -like ail
Head f C1q a ha bi d he Fc
i f he Ab;
S alk c llage -like
S c e ha bee like ed a b e f
li / 6 bl m e e di g ad
[RECALL]
The Fc i f he Ab ha C H2 a d CH3.
If IgG i i l ed, he C1 ld 2. C1 clea e C4 a d C2. Clea i g C4 e e he bi di g
ecificall bi d he CH2 i f he i e f C2. C4 bi d he face ea C1 a d C2 bi d C4,
Fc egi . f mi g C3 con ertase.
If IgM i i l ed, he C1 ld C1 f c i a a e me clea e C4 a d C2.
ecificall bi d he CH3 i f he C4 2 dm ab da c m leme ei ;
Fc egi . 600 g/mL i e m
C1r & C1s m ge ( ei e ea e The ac i a i f C4 ld e e all lead
e me ); ge e a e e me ac i i a C clea i g f C4, f m C4a a d C4b.
ca cade C4a a 77-ami acid f agme ; i e
[RECALL]
The c m le i held ge he b Ca2+. a hi e e -c ai i g ac i e i e he
A l g a Ca2+ i e e i he e m emai i g a , C4b.
C1 a d C1 i emai a cia ed i h ★ C4a ld ha e bi l gic
C1 f ci ha a e elea ed he
The fi C1 ill be ac i a ed af e bi di g f C1 , bl d eam.
hich ld al ac i a e he ec d C1 i he C4b m bi d ei ca b h d a e
c m le . i he a ge cell i hi ec d f i
Ac i a i f C1 ld ha e b clea i g C1 be de ed deg aded.
O ce he C1 i ac i a ed, he ec g i i age ★ Ma eac ih ae f m
e d . iC4b ea il deg aded
★ C4b bi d mai l Ag i c e
/i a 40- m adi f
➔ Re e e he 1 am lifica i e i
he ca cade beca e f e e C1
a ached a ima el 30 m lec le f
C4 a e li a d a ached
B ki f :
C2 ld be ac i a ed bec me C2a a d C2b.
C1 clea e C2 f m C2a a d C2b

Ba g ad g f c g a a d b O l a mall e ce age
f ag e f C2. f clea ed C3 m lec le
C2b ld ha e he bi l gic f c i ; bi d a ige ; m
g e he bl d eam. a e h d l ed b ae
C2a ld al be a ached he m lec le a d deca i
face f he a ge cell; emai he he fl id ha e
a ge cell. ★ O ce C3b i b d C4b2a, i
★ C2 ge e i cl el a cia ed ld he me ge i h C4b2a
i h he ge e f Fac B f m C4b2a3b (C5 con ertase).
(al e a i e ah a )
ch m me 6
C4b and C2a ( hich ha he highe MW), i he
e e ce f Mg2+, ld f m C4b2a ( i e a :
i dica e ha i i a ac i e e me)
he C3 con ertase.
C m le i e able
Half-life: 15 3 mi
C3 m be b d icl
3. C3 c e a e h d l e ma C3 m lec le . S me
c mbi e i h C3 c e a e f m C5 con ertase MEMBRANE ATTACK COMPLEX (MAC)
[RECALL]
C3 : m ab da i he bl d 4. The C3b c m e f C5 c e a e bi d C5, e mi i g
Maj a d ce al c i e f all f he C4b2a clea e C5
ah a he i al i . ( la ma C5 c e a e ill li he C5 i C5a a d C5b.
c c. 1 - 1.5 mg/mL) C5a g e he ci c la i a d ha e
ALL f he a h a ld e e all he bi l gic effec
mee i he C3. ( i al i ) C5b emai i he a ge cell/Ag;
I he e e ce f C3 c e a e, C3 ill be a ache cell memb a e ( a f MAC)
clea ed i C3a a d C3b. C5b ld e e all bi d C6
Clea age f C3 (MW: 190,000) C3b S li i g f C5 a d he clea age f C3 e e e
e e e he m ig ifica e i he he m ig ifica bi l gical c e e ce f he
e ie ce f c m leme ac i a i c m leme em
★ l e ide chai , al ha ( ) C5b e emel labile a d a idl
a d be a ( ) i ac i a ed le bi di g C6
chai c ai a
highl eac i e hi e e
g .
C3a he bi l gic f c i
★ em ed b clea age f a i gle
b d i he chai , he hi e e
i e ed
C3b highe MW; emai a ge cell
face; f c i a a ef l i
★ C3b i a im a e i he
ce f C ac i a i . 5. C5b bi d C6, i i ia i g he f ma i f he
★ C3 i ca able f bi di g membrane-attack comple .
h d l g O ce C5b bi d i h C6, b e e bi di g f
ca b h d a e a d ei i he e mi al c m e fC ld ha e
immedia e ici i I cl de bi di g f C7, C8, and C9
★ If C3b i b d he a ge The e C ld ha e e ma ic
cell/Ag, i ld ha e a e h ac i i ; he ld j bi d he C6.
life. (half-life: 60 mic ec d )

All e e i m ch malle am i
e m
★ C6 a d C7 (MW each: 110, 000):
imila e ie
★ C8 (MW: 150,000): 3 di imila
chai i di lfide b d
★ C9 (MW: 70,000): i gle
l e ide chai
Af e he bi di g, he memb a e a ack-c m le
(MAC) ill be f med.
C m ed f C5b-C9
The h d h bic a f he MAC ld
a ach/a ch he a ge cell m el i b
elea e f a e
Ca b e mi al e d i h d h bic
Ami - e mi al e d i h d hilic A ea a ce f MAC de he e ec c c e
Relea e f ae l f elec l e
ALTERNATIVE PATHWAY
ab b a g a ge ce ae e e
a aba g e ec e a ge cell a e O igi all called he properdin s stem beca e he ei
de ed e di a h gh be he mai i i ia f hi
The c m le f C5b-C6-C7-C8 and C9 i k ah a .
a C5b-9 or MAC P e di maj f c i i abili e a ke
If he c m le i soluble i ci c la i , i i k e me c m le f med al g he a h a a d
a sC5b-9. ha he he f m f ac i a i a e m e
Mea eme f he le el f C5b-9 i a mi e .
i dica f he am f e mi al Properdin fi h gh be a
a h a ac i a i ha i cc i g. im a c m e (i i ia ) f hi
Whe f med, he MAC e e a e f 70 ah a ,b a f d l be a
100 ha all i a i a d f he abili i g fac f he C3 c e a e
memb a e P ei properdin, a c i e f mal e m
I fl f ae a dl f elec l e de ci i h a c ce a i fa ima el 5 15
f a ge cell g/mL.
P e e ce f C9 g ea l eed he l i Fi de c ibed b Pilleme i he 1950 60
Ab e ce f C9 Ca be ac i a ed i ih a imm e c m le e
fficie e ba i f he I f ci mai l a a am lifica i l f ac i a i
memb a e ca cc i he a ed f m he cla ical lec i a h a
ab e ce f C9 I me ca e , he i i ial ac i a i i b he
Deficie cie i C9 a ea la gel cla ical a h a .
be ig Al e a i e a h a ca c i e
e ha ce he ac i a i .
Al h gh e di ha bee c fi med bi d a d
i i ia e ac i a i , he ima f c i f e di
i abili e he C3 c e a e f med f m
ac i a i f he fac .
Se m ei Fac B a d Fac D a e i e hi
ah a
C3 ke c m e
C m e : C3, factor B, factor D, properdi
T igge i g b a ce :
Mic bial d c
Pa h ge
C m e f bac e ia, f gi, aa ie

O e a ic la a a i e ha igge I ac a he eed f ac i a i f he
al e a i e a h a a me al e a i e a h a .
Bac e ial cell all (LPS) 2. Fac B bi d C3a, e e i e ac ed b fac D.
F gal cell all Clea age ge e a e C3bBb, hich ha C3 c e a e
Yea ac i i
Vi e Factor B imila C2 i he cla ical a h a
O he f eig b a ce he - a h ge F m a i eg al a f a C3 c e a e
A ib die (IgG, IgA) O ce Fac Bi b d C3b, i he e e ce f
Ve m Fac D, i ca be clea ed (b Fac D).
He e l g e h c e Factor D
P l me Pla ma ei ha g e h gh
Ca b h d a e a c f ma i al cha ge he i
Vi all i fec ed cell bi d Fac B.
T m cell li e Se i e ea e i h MW f
Se e a i e f bi di g he c m le C2bBb 24,000
( e f he e d d c ) C ce a i i la ma i he
C e i f C3 fi e l e f all c m leme ei
Na i e C3 able i la ma ( 2 g/mL)
Wa e i able h d l e a hi e e b d, h Clea e Fac B i iece :
a e l ac i a i g a mall mbe f he e Ba (MW: 33,000) a d Bb (MW:
m lec le 60,000)
TABLE 7-1 I i ia f he al e a i e a h a f c m leme ★ Bb emai a ached C3b
ac i a i f mi g he i i ial C3 c e a e
PATHOGENS AND PARTICLES OF MICROBIAL ORIGIN
f he al e a i e a h a .
★ Ra idl i ac i a ed le i
1. Ma ai f g am- ega i e bac e ia
2. Li l accha ide f m g am- ega i e bac e ia
bec me b d a ie e
3. Ma ai f g am- i i e bac e ia f he igge i g cell la a ige
4. Teich ic acid f m g am- i i e cell all
5. F gal a d ea cell all ( m a )
6. S me i e a d i i fec ed cell
7. S me m cell (Raji)
8. Pa a i e ( a me )
NONPATHOGENS
1. H ma IgG, IgA, a d IgE i c m le e

2. Rabbi a d g i ea ig IgG i c m le e
O ce clea ed b Fac D, C3bBb ( ) i
3. C b a e m fac f med.
4. He e l g e h c e ( abbi , m e, chicke )
5. A i ic l me (de a lfa e)
C3 c e a e f he al e a i e a h a
6. P e ca b h d a e (aga e, i li ) Ca able f clea i g addi i al C3 i C3a
a d C3b
1. C3 h d l e a e l ; C3b f agme a ache E emel able le e di bi d
f eig face he c m le
Al e a i e a h a a i he C3 hich ill 3. Bi di g f e di abili e c e a e (C3bBb)
h d l e a e l f m C3a a d C3b F i ha e a l ge half-life
C3b f ma i ca be d e he I c ea e he half-life f C3bBb f m 90
a e h d l i f m he ec d e e al mi e
ac i a i f he cla ical lec i If he e i e di , C3 c e a e i ea il
ah a deg aded.
P ede g a d a g g O imal a e f al e a i e a h a ac i a i i
cla ical a h a . achie ed
O ce C3 i clea ed, C3b ill emai 4. C e a e ge e a e C3b; me bi d C3 c e a e,
he face f he a ge cell & C3a ill g ac i a i g C5' c e a e. C5b bi d a ige ic face
he ci c la i . C3 c e a e ge e a e C3a and C3b; me C3b
C3b (iC3) f med b a e h d l i bi d C3 c e a e bec me C5 c e a e
f m ac i a i f m cla ical lec i a h a (C3bBbC3b)

C3b bi d Fac B a d i fai l Ac i a ed b ec g i i f face m ie ie ha

ab da i he e m, a a le el f 200 aef d a h ge .
g/ mL. Addi i al li k be ee i a e a d ac i ed imm e
★ S me C3b a ache cell la face a d ac a e e
a bi di g i e f m e Fac B MBL i d ced b li e i ac e- ha e i flamma
Re l i a am lifica i l eac i
Ac i a i i i ia ed b he cla ical lec i N mall e e i e m b i c ea e d i g a
ah a i am lified le el f i i ial i flamma e e
bi l gical c e e ce. O ce MBL bi d a ge cell, e i e ea e (MASP-1,
➔ All C3 e e i la ma ld be a idl MASP-2) bi d MBL ac like C1
c e ed b hi me h d e e i f MBL-a cia ed e i e ea e (MASP )
he fac ha he e me C3bBb i 3 MASP ide ified: MASP-1, MASP-2, MASP-3
e emel able le e di bi d Simila i f c i i h C1 a d C1
he c m le
O ce e ha e he C5 c e a e, i ill clea e
C5 i C5a a d C5b.
C5a ci c la i
C5b emai he face f he a ge
cell a d ld e e all a ach f
MAC
1. Ac i a ed MASP-2 clea e C4 C4a and C4b. S me C4b

C3bBb ca clea e C5
bi d c ale l he mic bial face
I i m ch m e efficie a clea i g C3
2. Ac i a ed MASP-2 al clea e C2 C2a and C2b
S me f he C3b d ced emai b d he
3. C2a bi d face C4b f mi g he cla ical C3
C3 c e a e, he e me i al e ed f m
c e a e, C4b2a
C3bBb3bP
4. C4b2a bi d C3 a d clea e i C3a a d C3b. C3b bi d
C3bBb3bP ha a high affi i f C5 a d e hibi C5
c ale l he mic bial face, f mi g he MAC
c e a e ac i i
★ Ve imila he cla ical a h a , b diffe i he
C5 i clea ed d ce C5b, he fi a f he memb a e
ec g i i (C1 MBL, C1 & C1 MASP 1 & 2)
a ack i
★ Im a a a defe e mecha i m d i g i fa c
F m hi i he al e a i e, lec i , a d
D i g he ime he he i fa ha l ec i
cla ical a h a a e ide ical
c mi g f m ma e al a ib die
LECTIN PATHWAY Effec i e imm e ec i d i g he ime
be ee he l f ma e al Ab a d bef e
Lec i i a ei ha binds to carboh drate
de el i g a f ll-fledged Ab e e
N ecific ec g i i f ca b h d a e
c mm c i e f mic bial cell all a d
ha a e di i c cell face
Lec i a h a : 3 d a h a , m a cie f he h ee
A he Ab-i de e de mea f ac i a i g
c m leme ei
Q i e imila he cla ical a h a i e m f
c e a d fl
MBL (mannose-binding lectin) bi d ma e ma
bac e ial cell Classical and Lectin path a
Bi d ma e ela ed ga i a
Sha e he c m e C4 a d C2
calcium-dependent ma e i i ia e hi
O ce C4 a d C2 a e clea ed, he e f he a h a i
ah a .
ide ical he cla ical a h a .
Ma e-( ma a -) bi di g lec i (MBL)
C1 i cla ical i filled b 3 cla e f ec g i i
F d mai l i he all e c ai g f
m lec le i he lec i a h a : lectins, ficolins, a d
bac e ia, i e , ea , a d a
CL-K1

S c e f all h ee cla e f ec g i i
m lec le i imila ha f C1 all cla ed a
c llec i
2. A cia i f C4b a d C2a i bl cked b bi di g

C4b-bi di g ei (C4bBP), c m leme ece e I,
memb a e c fac ei (MCP).
Reg la f he C3 c e a e
C4b-binding protein l ble eg la
Cell-b d eg la
1. CR-1 or CD35
2. Membrane cofactor protein
(MCP) or CD46
3. Deca accelerating factor
REGULATION OF COMPLEMENT SYSTEM (DAF) or CD55
Nece a beca e i i nonspecific, e e al eg la CELL-BOUND REGULATORS
mecha i m a e i l ed ( he i e he e ld be a l f
"c lla e al damage") CR1 La ge l m hic gl c ei f d
(CD35) mai l i e i he al bl d cell ; bi d
A d f c i i c m leme ac i a i ca be C3b a d C4b
e da ge he b d Highe affi i C3b
Ca ca e i e damage Mai f c i : ece la ele
Ma c m e a e er labile/easil destro ed a d RBC ; hel media e a f
Ma eg la ei bl ck ac i i h gh bi di g C3b-c a ed imm e c m le e li e
a d lee
a ge Imm e adhe e ce- abili f cell
BEFORE assembl of con ertase acti it bi d c m leme c a ed a icle
1. C1 inhibitor (C1-INH) bi d C1 2S2, ca i g di cia i MCP B d i all i all e i helial a d

f m C1 (CD46) e d helial cell e ce RBC
M efficie c fac f
C1-INH gl c ei d ced b he li e & i Fac -I-media ed clea age f C3b
me e , al b m c e Se e a c fac f clea age f C4b
Reg la e c m leme b i hibi i g he ac i a i Hel c l he al e a i e a h a
f he i i ial age f he cla ical a d lec i beca e bi di g f Fac B C3b i
ah a i hibi ed
Inacti ates C1 b bi di g C1 a d C1 ca DAF 3 d mai ece
l ge ac i a e he C1 (CD55) Ha ide i e di ib i
The C1 ca ill be b d Ab, b all f he F d e i he al bl d cell ,
e d helial cell , fib bla , a d
e ma ic ac i i eeded f he ca cade ld e i helial cell
l ge be d ced. Ca able f di cia i g b h cla ical
C1 & C1 a e im a f he ca cade a d al e a i e a h a C3
ha e . c e a e
Bi d b h C3b a d C4b imila
I ac i a e MASP-2 i he lec i a h a
CR1 b d e e ma e l m dif
hem
D e e e i i ial bi di g f C2
a d Fac B b ca a idl
a cia e b h

e e ce f DAF h cell ec
hem f m b stander l sis ( ed i Regulation at assembl of membrane-attack comple (MAC)
di c imi a i f elf f m elf 1. S ei e e i e i f C5b67 MAC c m e i
beca e f eig cell d e
hi b a ce.) he memb a e
All f he e ac i c di a i i h he
Fac I
Factor I a ei e ea e ha i ac i a e C3b M im a maj eg la : S protein or
a d C4d eg la e C3 c e a e itronectin
C4BP- ab da i la ma S l ble c l ei ha i e ac ih
Ca able f c mbi i g i h ei he fl id C5b-7 c m le e e hi f m
ha e b d C4b; he ef e, C4b bi di g he cell memb a e
ca bi d C2 a d i made a ailable The c m le e MAC i f med d e
f deg ada i b Fac I. he S ei
If C4BP a ache cell-b d C4b, i ca P e e a ack f ea b cell
di cia e i f m C4b2a c m le e , Bi di g f
ca i g he ce a i f he cla ical C8 a d C9 ill ceed , b
ah a . l me i a i f C9 d e cc ;
he ef e, he c m le i able i e
3. I hibi -b d C4b i clea ed b fac I i elf i he cell memb a e d ce
4. I al e a i e a h a , CR1, MCP, or factor H e e l i
bi di g f C3b a d fac B 2. Homologous restriction factor (HRF) membrane
Factor H c cial i eg la i g C3 c e a e inhibitor of reacti e l sis (MIRL CD59) bi d C5b678,
Ac b bi di g C3b, e e i g he e e i g a embl f l -C9 a d bl cki g f ma i f
bi di g f Fac B. MAC
Ac a a c fac ha all Fac I
b eak d C3b.
I a ea ha l h e m lec le ih
igh l b d Fac H ac i e high-affi i
bi di g i e f Fac I
CD59 he memb a e i hibi f eac i e l i
I hibi -b d C3b i clea ed b fac I
(MIRL)
AFTER assembl of con ertase acti it Bl ck f ma i f MAC
C3 c e a e a e di cia ed b C4bBP, CR1, fac H, Pe e i he cell memb a e f all
a d deca -accele a i g fac (DAF) ci c la i g bl d cell
Table 7-2 Plasma Complement Regulators

Molecular Weight Concentration
Serum Protein Function
(KD) (mg/mL)
C1-INH 105 240 Di cia e C1 a d C1 f m C1
Factor I 88 35 Clea e C3b a d C4b
Factor H 150 300-450 C fac ihI i ac i a e C3b; e e bi di g f B C3b
C4-binding protein 520 250 Ac a a c fac ihI i ac i a e C4b
S protein
84 500 Pe e a achme f he C5b67 c m le cell memb a e
( itronectin)

COMPLEMENT RECEPTORS
Table 7-3 Receptors on Cell Membranes for Complement Components

Receptor Ligand Cell T pe Function
RBC , e hil , m c e , mac hage ,
C fac f Fac I;
CR1 (CD35) C3b, iC3b, C4b e i hil , B a d T cell , f llic la de d i ic
Media e a f imm e c m le e
cell
CR2 (CD21) C3dg. C3d, iC3b B cell , f llic la de d i ic cell , e i helial cell B-cell c - ece f a ige i h CD19
Adhe i a d i c ea ed ac i i f hag c ic
CR3 (CD11b/CD18) iC3b. C3d, C3b M c e , mac hage , e hil , NK cell
cell
M c e , mac hage , e hil , NK cell , Adhe i a d i c ea ed ac i i f hag c ic
CR4 (CD11c/CD18) iC3b, C3b
ac i a ed T a d B cell , de d i ic cell cell
RBC , e hil , la ele , m c e ,
Di cia e C2b Bb f m bi di g i e , h
DAF (CD55) C3b, C4b e d helial cell , fib bla . T a d B cell ,
e e i g f ma i f C3 c e a e
e i helial cell
RBC , e hil , la ele , m c e ,
MIRL (CD59) C8 Pe e i e i f C9 i cell memb a e
e d helial cell , e i helial cell
Ne hil , m c e , mac hage , la ele , C fac f Fac I
MCP (CD46) C3b, C4b
T a d B cell , e d helial cell Clea age f C3b a d C4b
RBC ed bl d cell ; NK a al kille
CR1 i al a im a ece f d he la ele
Hel i media i g a f imm e c m le e c a ed i h C3b
The e C3b-c a ed imm e c m le e ld a h gh he li e a d he lee
C3b f m he cell i em ed i he li e a d lee
The cell i hich C3b i em ed ld e he ci c la i
CR2 i al a im a ece f ce ai i e , a ic la l he E ei -Ba i (EBV)
Vi al h ece f EBV
CR3 i im a i media i g hag c i
Pe h lack CR3 i he hag c e ld ha e blem i chem a i , face adhe i , a d e e agg ega i .
CR4 ha i e he ame f c i a CR3.
1. C1q e -li ked agammagl b li emia, e e e c mbi e

COMPLEMENT AND DISEASE STATES
imm deficie c (SCID)
Complement can be harmful if: 2. Clr URT di ea e, SLE-like d me, Ch ic Kid e
1. Ac i a ed emicall a la ge cale a i g am- ega i e di ea e
e icemia 3. C2 deficienc a he cle i , ec e e a d a h
O e ac i a i fC i fec i (m c mm deficie c )
I me ca e f G (-) i fec i , hi ca lead C2 & C3 deficie c e bac e ial i fec i
e i a d a imm e di ea e
2. I i ac i a ed b i e ec i (e.g. m ca dial i fa c i ) 4. C3 deficienc most serious & most harmful b
3. L i f RBC ha c mm , ec e e i fec i , imm e c m le
Complement Deficiencies di ea e
U all ca ed b ge e ic 5. C3b inacti ator deficienc ec e ge ic
He edi a deficie cie f c m leme ld lead i fec i , ica ia
di ea e affec i g he imm e em 6. C5 SLE
Deficie cie f c m leme ld al lead 7. C5 d sfunction Lei e ' Di ea e, G (-) ki a d b el
a imm e di ea e i fec i
Maj i f deficie cie f c m leme c m e Lei e di ea e de ma i i , ec e dia hea,
ld ha e a cia ed di ea e , e cept for C9. fail e hi e
A mal ece i e

Al k a er throderma F C3 a d C4 a d he c m leme c m e
desquamati um Nephelometr ba ed mea eme
8. C5-C8 deficienc Ne e a i fec i , me i g c ccal f am ligh ca e ed
me i gi i , di emi a ed g heal di ea e The e ld be a ib die ecific
9. C7 deficienc Nei e ia i fec i , SLE, Ra a d' f C3 f ma i f imm e
he me , Scle de ma like d me, a c li i c m le mea ed h gh
10. DAF deficienc PNH CHINH deficie c : he edi a e hel me
a gi edema Rel he eci i a i f a ige
11. Factor D deficienc P ge ic i fec i (c mm ; ( he c m leme c m e bei g
beca e if a ie ha C2 deficie c , Fac D ill al be mea ed) a d a ib d .
deficie ) The m e a ige a ib d
c m le e ha a e e e , he
Table 7-4 Deficiencies of Complement Components m e a beam f ligh ill ca e a
i a e h gh he l i .
Deficient Component Associated Disease Turbidimetr
L -like d me Rel he eci i a i f a ige
C1 ( , , )
Rec e i fec i ( he c m leme c m e bei g
L -like d me mea ed) a d a ib d .
C2 Rec e i fec i RID (radial immunodiffusion)
A he cle i Me h d ha ill be ed i he lab
Se e e ec e i fec i f C3 de e mi a i
C3
Gl me l e h i i U e aga e gel i hich
C4 L -like d me Immunologic ecific a ib d i i c a ed.
assa s Se m e e a he a ige a d
C5 - C8 Ne e a i fec i i laced i ell ha a e c i he
C9 N k di ea e a cia i gel.
Diff i f he a ige f m he
C1-INH He edi a a gi edema
ell cc i a ci c la a e
DAF Pa mal c al hem gl bi ia ELISA f C1 i hibi (C1-INH i hibi )
MIRL Pa mal c al hem gl bi ia C m e f a da di ed g : C1 , C4,
C3, C5, Fac B, Fac H, a d Fac I
Fac H Fac I Rec e ge ic i fec i
N e f he a a f i di id al
P e m c ccal di ea e c m e a e able di i g i h he he
MBL Se i he m lec le a e f c i all ac i e
Ne e a i fec i
RID a d e hel me a e b h e i i e
P e di Ne e a i fec i e
MASP-2 P e m c ccal di ea e
C1-INH C1 i hibi ; DAF deca -accele a i g fac ; MASP-2
ma e-a cia ed e i e ea e; MBL ma e-bi di g lec i ; MIRL
memb a e i hibi f eac i e l i
N di ec di ea e a cia i i C9 deficie c beca e he
MAC ca ill be effec i e
Deficie c i MBL i al c mm
P e m ia, e i , e m c ccal di ea e i
i fa , ca ce , SLE Radial Immunodiffusion
The eci i i i g i mea ed
The la ge he i g, he highe he am f C3
LABORATORY DIAGNOSIS
Hemol tic Titration (CH50) assa - m c mm
Mea eme fc m e a a ige i e m
C de c ee i g e de ec de ec
de e mi e i le el (if deficie c i e e ) Classical
c m leme ac i i i e m
Mea eme f he f c i al ac i i path a
A deficie cie i he c m leme ,
U all d ei di a lab a ie ; d e i efe e ce assa s
e eciall i he cla ical a h a , ld
eciali ed lab a ie
lead ab mal e l .

Ab mal e l = m likel Rabbi RBC a e ed a he i dica

ha e a deficie c i e f he beca e he ide a ideal face f
c m leme c m e f he al e a i e a h a ac i a i
cla ical a h a ELISA
Mea e am f e m e i ed l e Ca de ec C3bBbP C3bP c m le e i
50% f a a da di ed c ce a i f e mall a i ie .
e i i ed RBC Mic i e ell a e icall c a ed i h
E e ed i CH50 i bac e ial l accha ide igge ac i a i
Reci cal f he highe f he al e a i e a h a .
dil i h i g 50% Other tests:
l i ( imila ie) C m leme fi a i e
Mea ed i all De e mi e he am de ec i
ec h me icall f C -fi i g Ab
Beca e all ei f m C1 C9 a e A lica i : Diag i f diffe e
ece a f hi cc , ab e ce f a i fec i di ea e i bac e ial,
ec m e ill e l i a ab mal i al, a a i ic, f gal i fec i
CH50, e e iall ed ci g hi mbe E ec ed e l : (+) hem l i
e . Mea ed am f
Di ad a age : C m lica ed e f m, c m leme added i
lack e i i i he e em i fi ed b
he C -fi i g Ab
Interpretation of Laborator Results
Dec ea ed le el a e d e :
Dec ea ed d ci C deficie c
C m i beca e f C ac i a i , a a
ababa a g e e , a-c e
I i c m i ma ha e beca e f
im e ecime c llec i ha dli g
S ecime C llec i a d Ha dli g c cial
Bef e e l a e elea ed, m ake e
Se m am le i dil ed e iall
ha he ecime c llec i a d ha dli g a e d e
C ai he c m leme
el
Add e i i ed hee RBC c a ed i h
U e a lai ( ed ) be, SST ( i h e m
Ab
e aa )
I he e e ce f imm e c m le e ,
If he e i a dela : if he ecime i ce ed
c m leme ill be ac i a ed, a d ca
i hi 1-2 h , f ee e immedia el i d
mea e he am f e m e i ed
ice
l e 50% f he added ed cell he
A id e ea ed ef ige a i ( ef f ee e
diffe e be
a a gga a ef)
Ma deg ade c m leme
L tic acti it
CH50 and AH50
ca al be mea ed b adial hem l i
If a c m leme deficie c i ec ed, i i
i aga e la e
ible a d he ible ca dida e
AH50 imila CH50 b mag e i m chl ide c m e i h a CH50 a d a AH50 a a
a d e h le e gl c l e aace ic acid a e added. If CH50 is normal a d AH50 is lo , he al e a i e
Calci m i em ed. a h a i im lica ed ha e a blem.
Alternati e B ffe MgCl2 + e h le e gl c l e aace ic Al e a i e a h a c m e eed
path a acid be i e iga ed.
assa s B ffe chela e calci m, hich bl ck If CH50 is lo a d AH50 is normal, c m leme
cla ical a h a ac i a i . i he cla ical a h a a e im lica ed ha e a
T ima il a e he al e a i e blem.
ah a

C m e i e he cla ical
a h a h ld be i e iga ed
If both are lo , he e i m likel a blem i
he e mi al a h a (f ma i f he MAC)
Tha a h a i ha ed b b h he
cla ical a d al e a i e a h a
I e i ecime c llec i a d
ha dli g a e al c ide ed.
Al ible, if he e i fficie
ac i a i f c m leme h gh a e
a h a , ha he ac i a i c ld
c me e gh c m e l e he
f ci f he he a h a .
★ C m leme ac i a i i a el limi ed
j e ah a .
Sc ee i g e l ; if e l a e ab mal,
ceed a m e ecific e f C f c i
mea eme
T ical Sc ee i g Te f C' ab mali ie i l e :
C3, C4 a d hem l ic c e
Te i g f C3 C4a C5a Ba m i i g i flamma
ce e
Impaired Function or Path a s

Deficienc Classical Lectin Alternati e
C1 , C1 , C1 N N
C4, C2 N
MBL, MASP-2 N N
B, D, P N N
C3, C5, C6, C7, C8, C9
C1-INH
Fac H&I
Im e l ha dled e a
For the qui : focus on the path a s!

MT6326 | Immunology and Serology Lecture
1st Shifting (A.Y. 2020 - 2021)
Mr. Benjie M. Clemente, RMT, MLS (ASCPi)cm, MPH
UNIT 9A: IMMUNOPATHOLOGY: HYPERSENSITIVITY REACTION UNIT 9D: TRANSPLANTATION IMMUNOLOGY
I. What is Hypersensitivity I. Pre-Test

A. The Four Types of Hypersensitivity II. Transplantation
1. Type I-Immediate (Anaphylactic) Hypersensitivity a. Types of Grafts
2. Type II-Cytotoxic Hypersensitivity b. Immunology of Allogeneic Transplantation
3. Type III-Immune Complex c. Role of CD4+ and CD8+
4. Type IV-Cell Mediated Reactions d. Types of Allograft Rejection
e. Tissue and Organ Transplantation
f. Immune Privilege in Transplantation
UNIT 9B: IMMUNOPATHOLOGY: AUTOIMMUNE DISEASE g. Immunosuppression
III. Post Test
I. Autoimmunity
a. Concepts of Tolerance UNIT 9E: IMMUNODEFICIENCY DISEASE
b. Immune Privilege
c. Mechanisms of Autoimmune Disorders I. Introduction
II. Autoimmune Disorders II. Deficiencies Of B-cell System
a. Systemic Lupus Erythematosus III. Deficiencies Of Cellular Immunity
b. Rheumatoid Arthritis IV. Combined Deficiencies Of Cellular And Humoral Immunity
c. Hashimoto’s Thyroiditis V. Defects Of Neutrophil Function
d. Grave’s Disease VI. Complement Deficiencies
e. Type 1 Diabetes Mellitus VII. Laboratory Evaluation Of Immune Dysfunction
f. Multiple Sclerosis
g. Myasthenia Gravis
h. Other Autoimmune Diseases UNIT 10: IMMUNOMODULATION
UNIT 9C: TUMOR IMMUNOLOGY I. Immunomodulation

a. Immunomodulators
b. Non-specific immunomodulation by IV immunoglobulin
I. Pre-test c. Monoclonal antibodies for specific immunomodulation
II. Review of Tumor Biology
a. Characteristics of a Cancer Cell
III. Tumor Antigens
a. Tumor Specific Antigens (TSA)
b. Tumor Associated Antigens (TAA)
IV. Clinically Relevant Tumor Markers
a. Tumor Markers
b. Clinical Uses of Tumor Markers
c. Serum Tumor Markers
V. Laboratory Detection of Tumors
a. Tumor Morphology
b. Immunohistochemistry
c. Molecular Methods
VI. Interaction Between the Immune System and Tumors
VII. Immunoediting and Tumor Escape
VIII. Immunotherapy
a. Active Immunotherapy
b. Passive Immunotherapy
c. Adoptive Immunotherapy
References: PPT, Clinical Immunology and Serology: A Laboratory Perspective , Lecturer 3OMT | CASTILLO, C. | CASTILLO, E. | HERNAEZ | KASILAG | LAGMAN | ROSALES | TORRES |1
1st Shifting (A.Y. 2020 - 2021)
UNIT 9A: IMMUNOPATHOLOGY: HYPERSENSITIVITY REACTION TYPES OF HYPERSENSITIVITY
I. What is Hypersensitivity ● Based on Gell & Coombs system/classification

A. The Four Types of Hypersensitivity
1. Type I-Immediate (Anaphylactic) Hypersensitivity ● Hypersensitivity is divided into four types (I-IV), making it easier to
2. Type II-Cytotoxic Hypersensitivity understand immunopathology.
3. Type III-Immune Complex ● Types I-III involve antibody, while Type IV, delayed hypersensitivity, is cell
4. Type IV-Cell Mediated Reactions mediated.
Links ● Each type is quite distinct in its action and the damage that it causes.
PPT ● Many diseases, however, have elements of more than one type in their
Video (1 & 2) pathogenesis.
● Other literatures said that there are 5 types of hypersensitivity, but in our
official textbook there are only 4 types.
PRE-TEST ○ CLASSIFICATIONS:
■ Type I (Immediate type or IgE-mediated type)
1. True or False. An anaphylactic reaction involves as simple as developing a ■ Type II (Antibody-mediated type)
rash after exposure to an allergen. ■ Type III (Immune Complex-mediated type)
● Anaphylactic reactions are exaggerated reactions of the body ■ Type IV (Cell-mediated type)
usually caused by harmless antigen or allergens, but could lead to ● Types I to III are classified as immediate hypersensitivity reactions
damage of the tissue. because symptoms develop within a few minutes to a few hours after
2. True or False. Anaphylaxis can occur from eating common foods such as exposure to the antigen.
milk, eggs or shellfish. ● Type IV hypersensitivity is sometimes referred to as delayed
3. Allergy is a type of anaphylactic reaction. Which antibody is involved in this hypersensitivity because its manifestations are not seen until 24 to 48
type of reaction? hours after contact with the antigen.
a. IgG
b. IgM TYPE I - IMMEDIATE (ANAPHYLACTIC) HYPERSENSITIVITY
c. IgE
d. Ig M
4. Type IV hypersensitivity reaction is a T-cell dependent. Which ● Antigens that cause allergic reactions are called allergens.
immunoglobulin is involved in this type of reaction? Type IV does not ● Carl Wilhelm Prausnitz and Heinz Küstner
involve any immunoglobulin. ○ Provided the first clue about the cause of type I hypersensitivity.
5. If you are at risk for anaphylaxis, the best way to manage your condition is: ● They are common environmental substances that most people do not react
a. Avoid allergens that trigger symptoms to.
b. Carry auto-injectable epinephrine ● Ten percent of people suffer from some form of allergy and there is a strong
c. Know how to use epinephrine familial tendency.
d. Develop an anaphylaxis action plan ● Occurs within minutes
e. All of the above ○ Short time lag phase upon exposure to the allergen.
● Mediated by IgE (as well as mast cells and basophils)
● Examples:
HYPERSENSITIVITY ○ Food allergies
○ Hay fever
● A normal but exaggerated or uncontrolled immune response to an antigen ■ Seasonal allergic rhinitis, triggered by tree and grass
that can produce inflammation, cell destruction, or tissue injury. pollens in the air during the spring in temperate climates.
● Normal response of the body but there was an exaggeration. ○ Asthma
■ Caused by inhalation of small particles such as pollen,
dust, or fumes that reach the lower respiratory tract.
○ Systemic Anaphylaxis
1st Shifting (A.Y. 2020 - 2021)
● In a normal immune response, the activity of Th2 cells and Th1 cells are
balanced
○ Results in protective immunity that does not harm the host.
● In people with allergies, Th2 cells predominate.
○ Results in production of several cytokines, including IL-4 and IL-13.
ROLE OF IgE
● IgE binds to high-affinity receptors on mast cells or basophils called FcεRI

through the Fc portion of the IgE-heavy chain molecule.
● Patients who exhibit allergic hypersensitivity reactions produce a large ○ Sensitization phase
amount of IgE antibody in response to a small concentration of allergen. ● Langerhans and dendritic cells internalize and process allergens from the
● IgE levels depend on the interaction of both genetic and environmental environment and transport the allergen-MHC class II complex to local
factors. lymphoid tissue where synthesis of IgE occurs.
● Atopy ● Mast cells are leukocytes with large, abundant cytoplasmic granules
○ Derived from the Greek word “atopos” (meaning “out of place”) containing the preformed inflammatory mediators of allergy.
○ Inherited tendency to develop classic allergic responses to naturally ○ Principal effector cells of immediate hypersensitivity.
occurring inhaled or ingested allergens. ○ Long lived, residing for months in tissues.
ALLERGENS
● Common allergens are bee venom, pollen, drugs, mold spores, animal hair,
dander, and the feces and particles from mites.
● Other examples of common allergens include peanuts, eggs, and pollen.
○ Food allergens include cow’s milk, soy, wheat, fish, and shellfish.
● Allergens can be inhaled, ingested, or enter through the skin, mucus
membrane, digestive tract or genitourinary tract.
● Avoidance of allergen is the first line of defense against allergies.
Mast cell with IgE antibody on Fc receptor
ALLERGEN PROCESSING ● Binding of IgE to cell membranes increases the half-life of the antibody from
2 or 3 days to at least 10 days.
○ Once bound, IgE serves as an antigen receptor on mast cells and
● Key immunologic components involved are IgE antibody, mast cells,
basophils.
basophils, and eosinophils.
● Just like any other antigen, allergens are processed by macrophages and
presented to T Helper cells. IgE CROSS LINKING
● In allergic individuals a subclass of Helper T cells (TH2 cells) stimulates B
cells with specific receptors for allergen to form IgE antibodies. ● Activation phase
○ IgE is the least abundant in the circulation. ● When allergen is encountered again it is bound by specific IgE molecules on
○ Th2 cells regulate IgE. the surface of mast cells.
● IgE is primarily synthesized by B cells and plasma cells in the: ○ Leads to degranulation of mast cells.
○ Lymphoid tissue of the respiratory tract ○ Large numbers of these receptors are found on mast cells and
○ Lymphoid tissue of the gastrointestinal tract basophils.
○ Lymph nodes
1st Shifting (A.Y. 2020 - 2021)
● The allergen cross-links the IgE and this causes aggregation in the surface NEWLY SYNTHESIZED MEDIATORS
of the FcRI receptors to release the contents of its granules and to start
synthesizing new chemical mediators.
○ Initiates complex intracellular signaling events involving multiple ● When the mast cell is triggered to release the contents of its granules, it also
phosphorylation reactions, an influx of calcium, and secretion of starts to synthesize and release other mediators (secondary mediators) -
cytokines. leukotrienes, bradykinin, prostaglandins, and platelet-activating factors.
■ Increase in intracellular calcium triggers rapid ● Secondary mediators are more potent than the primary mediators and are
degranulation of the mast cells and basophils. responsible for a late-phase allergic reaction
○ Seen in some individuals 6 to 8 hours after exposure to the antigen.
○ Eosinophils play an important role in the late-phase reaction.
MAST CELL DEGRANULATION ● Eosinophils , neutrophils, Th2 cells, mast cells, basophils, and
macrophages, exit the circulation and infiltrate the allergen- filled tissue.
● Mast cell granules contain preformed mediators (primary mediators) such as ○ Release additional mediators that prolong the hyperactivity and
histamine, serotonin and eosinophil, and neutrophil chemotactic factors may lead to tissue damage.
(ECF and NCF). ● These molecules also result in dilation of small vessels (vasodilation),
○ Chemotactic factors will recruit eosinophils and neutrophils in the leakage of fluid (edema), smooth muscle contraction, increased mucus
area = upsurge in eosinophils and neutrophils. secretions, and pain.
○ Histamine is the most important and abundant chemotactic factor.
■ Primarily increases permeability of blood vessels and
usually promotes contraction of smooth muscles like
trachea (contraction of trachea = breathing difficulties).
○ The most abundant preformed mediator is histamine (10% of total
weight of the granules in mast cells).
○ Other primary mediators include heparin, eosinophil chemotactic
factor of anaphylaxis (ECF-A), and proteases.
● The release of preformed mediators is responsible for the early-phase
symptoms seen in allergic reactions.
○ Occurs within 30 to 60 minutes after exposure to the allergen.
Mast cell releasing newly synthesized mediators
SUMMARY OF TYPE I HYPERSENSITIVITY MEDIATORS
GRANULES MEDIATOR ACTIONS
Histamine Smooth muscle contraction,

vasodilation, increased vascular
permeability
Primary (Preformed) Heparin Smooth muscle contraction,
Mast cell releasing preformed mediators vasodilation, increased vascular
permeability
1st Shifting (A.Y. 2020 - 2021)
Eosinophil chemotactic Chemotactic for eosinophils

factor of anaphylaxis
(ECF-A)
Neutrophil chemotactic Chemotactic for neutrophils

factor of anaphylaxis
(NCF-A)
Proteases (e.g., Convert C3 to C3b, stimulate

tryptase, chymase) mucus production, activate
cytokines
Prostaglandin PGD2 Vasodilation, increased vascular

permeability
Leukotriene LTB4 Chemotactic for neutrophils,

eosinophils
Leukotrienes LTC4, Increased vascular permeability,

LTD4, LTE4 bronchocon- striction, mucus
Secondary (Newly ● Symptoms depend on such variables as:
secretion
Synthesized) ○ Route of antigen exposure
Platelet activating Platelet aggregation ○ Dose of allergen
factor (PAF) ○ Frequency of exposure
● Inhalation of allergen = respiratory symptoms such as asthma or rhinitis.
Cytokines IL-1, IL-3, Increase inflammatory cells in area, ○ Rhinitis is the most common form of atopy or allergy.
IL-4, IL-5, IL-6, IL-9, and increase IgE production ● Ingestion of an allergen = gastrointestinal symptoms
IL-13, IL-14, IL-16, ● injection into the bloodstream = can trigger systemic response.
TNF-α, GM-CSF ● Local inflammation of the skin (dermatitis)
○ Acute urticaria (hives)
THE EFFECTS OF ALLERGIC REACTION ■ Wheal-and-flare reaction
■ When these reactions occur deeper in the dermal tissues,
they are known as angioedema.
● The severity of allergic reactions varies with the sensitivity of the individual ○ Atopic Eczema
and the target organ or organs. ■ Can take on a variety of forms, from erythematous, oozing
● Anaphylaxis: a severe type of allergic reaction that involves two or more vesicles to thickened, scaly skin, depending on the stage
body systems (e.g. hives and difficulty breathing). of activity and age of the individual.
○ Coined by biologists Paul Portier and Charles Richet in 1902 which
means “without protection”.
○ Triggered by glycoproteins or large polypeptides. ALLERGY SHOTS
○ The severity of the reaction depends on the number of previous
exposures to the antigen. ● Allergy shots or hyposensitization therapy is the process where the patient is
■ Multiple exposures result in additional accumulation of IgE injected with a very small amount of allergen, increasing over many weeks.
on the surface of the mast cells and basophils. ○ Also known as “allergy immunotherapy”.
○ Standard practice is administration of allergens subcutaneously
over 3 to 5 years.
● The patient produces IgG (IgG4) “blocking antibodies” instead of IgE allergic
antibodies.
1st Shifting (A.Y. 2020 - 2021)
○ Shifts the immune response to Th1-type of response and induces ○ Uses radiolabeled IgE to compete with patient IgE for binding sites
the development of T regulatory cells (Tregs) that release IL-10. on a solid phase coated with anti-IgE.
○ The IgG blocking antibodies mock-up the allergens before it ○ Due to expense and difficulty of use, RIST has largely been
reaches the IgE antibodies on mast cells. replaced by noncompetitive solid-phase immunoassays or
○ It is also suggested that hyposensitization therapy inhibits Th2 cells, nephelometry assays with enhanced sensitivity.
favoring IgG synthesis over IgE production. ● Chemiluminescent Enzyme Immunoassay
○ Automated immunoassays with high level of specificity and
TREATMENT sensitivity.
○ Can be run with a single allergen or as a multi-allergen screen using
a panel of allergens in a single run.
● Persistent asthma → leukotriene receptor antagonists and mast cell ● Protein Microarray
stabilizers ○ Allows for parallel detection of IgE antibodies to more than 100
● Corticosteroids potential allergens using only 20 μL of patient serum.
○ Block recruitment of inflammatory cells and their ability to cause ■ Serum is incubated with a biochip containing miniature
tissue damage. spots to which the purified allergenic components have
● Systemic anaphylaxis → epinephrine injection been applied.
● Omalizumab (anti-IgE monoclonal antibody) ■ If allergen-specific IgE is present, it will bind to the
○ Composed of human IgG framework genes recombined with appropriate spots.
complementarity-determining region genes from mouse ■ The chip is scanned by a laser for fluorescence following
anti-human IgE. addition of a fluorescent-labeled anti-IgE.
○ Prevents circulating IgE from binding to mast cells and basophils ○ Highly sensitive and specific
and sensitizing them by binding to the Cε3 domain of human IgE, ● Immunocap
which is the binding site of FcεRI receptors.
TYPE II - CYTOTOXIC HYPERSENSITIVITY

LABORATORY EVALUATIONS
● Also known as antibody-mediated cytotoxic hypersensitivity

● Radioallergosorbent testing (RAST) ● Insoluble antigens
○ Measures amount of allergen-specific IgE ● Antibodies involved are IgG or IgM in cell surface
○ Measures total IgE but specific ○ Binding of the antibody to a cell can have one of three major
■ Shrimp effects, depending on the situation:
■ Pollen ■ Cell destruction
■ Chicken ■ Inhibit function of the cell.
○ Involves incubating patient serum with a paper disk to which ● Occur when antibody blocks the binding of a
various allergens were covalently linked. physiological ligand to its receptor, resulting in
■ After incubation, serum is washed to remove unbound dysfunction of the cell.
antibodies. ■ Increase the function of the cell above normal.
■ Bound IgE is detected by adding a radiolabeled anti-IgE. ● Activates NK and complement
■ Serum will be washed again, then the amount of ● Cell surface antigens
radioactivity detected will be measured by a gamma ○ Target cell
counter. ○ Self antigen
■ Radioactivity is directly proportional to amount of allergen ○ Heteroantigens
specific IgE. ○ Infection
● Competitive Radioimmunosorbent testing (RIST) ● Complement system is usually involved.
○ Measures total IgE ○ Complement attaches to the Fc of the IgG or IgM.
■ Regardless of specificity ○ End result is cytotoxicity, cytolysis, or cellular destruction.
1st Shifting (A.Y. 2020 - 2021)
○ This is due to the binding of antigen. ■ Rh, Kell, and Duffy antigens may also be involved in
immediate transfusion reactions.
● Hemolytic disease of the newborn (Rh disease)
● Autoimmune hemolytic anemia
○ Warm Autoimmune Hemolytic Anemia
■ Referred to as idiopathic autoimmune hemolytic anemia
■ Associated with IM, CMV, chronic active hepatitis, chronic
lymphocytic leukemia and lymphomas.
○ Drugs that can induce antibody production which causes hemolytic
anemia:
■ Penicillins and cephalosporins
■ Quinidine and phenacetin
■ Methyldopa
○ Paroxysmal Cold Hemoglobinuria
MECHANISMS ■ Occurs after infection with measles, mumps, chickenpox
or IM.
● Autoimmune thrombocytopenia
● Antibody-dependent, complement mediated cytotoxic reactions
● Myasthenia gravis
○ Involves the activation of the classical pathway of the Complement.
○ Receptors of acetylcholine are blocked, leading to muscle
○ Lead to the formation of MAC and later cell lysis.
weakness.
● Antibody-dependent, cell-mediated cytotoxicity antibody
● Pemphigus
○ Coated cells are lysed by effector cells, such as natural killer (NK)
● Pemphigoid
cells and macrophages.
● Goodpasture’s syndrome
■ Mediated through binding of IgG antibody to its
○ Production of antibodies that reacts with basement membrane
corresponding antigen on the target cell and to Fc
protein.
receptors on macrophages or natural killer cells.
■ Usually affects glomeruli in the kidney and pulmonary
○ Coating of the cell surface by antibodies promotes opsonization,
alveolar membranes.
and subsequent litho phagocytosis.
● Grave’s disease
■ Opsonization occurs either through binding of IgG
● Insulin-dependent diabetes (Juvenile diabetes)
antibody to Fc receptors on macrophages and neutrophils
or binding of cell surface C3b to complement receptors on
phagocytic cells.
● Antireceptor antibodies
○ Autoimmune hypersensitivity against solid tissue, Hyperacute graft
rejection
○ Cell damage will result from mechanisms of the antibodies and
antibody-dependent through binding of the IgG to the
corresponding antigen on the target cell.
TARGET ANTIGENS OF TYPE II REACTIONS REMEMBER
● Transfusion reactions Normal individuals may have autoantibodies in their serum, but it is not a diagnosis
○ ABO, Rh, Kell, Kidd and Duffy. of the disease unless these autoantibodies block receptors and lead to different
○ Antigens most involved in delayed reactions include those in the conditions.
Rh, Kell, Duffy, and Kidd blood groups.
1st Shifting (A.Y. 2020 - 2021)
RH-HDN ○ Antigen is soluble

● Soluble immune complexes are carried into the circulation and become
lodged in the basement membrane.
● Severe HDN → Erythroblastosis fetalis ○ Skin, lungs and joints
○ Most common antigen involved is D antigen. ○ Normally such complexes are cleared by phagocytic cells;
● Depending on the degree of antibody production in the mother, the fetus however, if the immune system is overwhelmed, these complexes
may be aborted, stillborn, or born with evidence of hemolytic disease as deposit in the tissues.
indicated by jaundice. ● This differs from the Type II since antigen is not part of the target cell
○ Similar to type II reactions in that IgG or IgM is involved and
destruction is complement-mediated.
● Caused by the deposition of immune complexes in blood vessel walls and
tissues due to the precipitation of soluble complexes out of the plasma.
○ The complement system is activated, macrophages and leukocytes
are attracted and immune-mediated damage occurs.
○ E.g. Farmer’s lung and the Arthus reaction
■ The Arthus reaction involves the injection of the antigen
into the skin intramuscularly, which will cause the antibody
to circulate and act on that antigen.
● Can be seen in individuals receiving vaccinations
and booster shots.
● Demonstrated by Maurice Arthus.
○ Typically occurs in the glomerular basement membrane, vascular
endothelium, joint linings, and pulmonary alveolar membranes.
(a) Rh-positive (b) Anti-Rh antibodies are (c) During succeeding ● Immune complex-induced inflammation may affect many sites.
erythrocytes from fetus produced by woman’s pregnancy, antibodies ● Unlike Type I anaphylaxis, the reaction takes hours for the inflammation to
enter blood of immune system that pass placental barrier reach its peak.
Rh-negative woman remain in the woman’s and enter fetal blood ● If the antigen persists the inflammation may become chronic.
during the birth process. bloodstream. causing the destruction ● Complement is nonselective.
of fetal erythrocytes. ○ Once it is activated, it will destroy all the cells nearby.
● Other examples:
○ Serum sickness
LABORATORY EVALUATIONS ○ Systemic lupus erythematosus (SLE)
○ Acute glomerulonephritis
● Direct Antiglobulin Test (DAT)
○ A mixture of antibodies to IgG and complement components such
as C3b and C3d, is used for initial testing.
○ Positive test should be repeated using monospecific anti-IgG,
anti-C3b, and anti-C3d
● Indirect Antiglobulin Test (IAT)
● Platelet Agglutination Assay
● Direct Fluorescent Examination
TYPE III - IMMUNE COMPLEX
● Involves IgG or IgM that remain soluble in the circulation.
1st Shifting (A.Y. 2020 - 2021)
MECHANISMS OF TYPE III HYPERSENSITIVITY
● The complement components, C3a and C5a also act as chemotaxins and
attract polymorphonuclear granulocytes (PMN) and macrophages to the site.
HOW DOES TYPE III HYPERSENSITIVITY OCCUR?
● Immune complexes activate the classical complement pathway with the

formation of complement components such s C3a, C4a, and C5a - the
anaphylatoxins.
● The complexes deposit on the vessel wall lead to vasculitis and the PMN
tries to destroy them by releasing enzymes, damaging the wall.
● Platelet aggregation causes microthrombi (small clots) which interfere with
the local blood supply.
● The process may resolve or result in chronic inflammation.
● Anaphylatoxins cause basophils and platelets to degranulate, releasing

mediators such as granulocyte chemotactic factors and histamine.
● This in turn causes vasodilation and vasopermeability or vessel leakage
(edema).
EXAMPLES OF TYPE III REACTIONS
● Autoimmune disease
● Hypersensitivity pneumonia
1st Shifting (A.Y. 2020 - 2021)
● Infection LABORATORY EVALUATIONS
● Drug reactions
● Indirect Immunofluorescence
DISEASE ASSOCIATED WITH IMMUNE COMPLEXES ● EIA
TYPE EXAMPLES ● FLuorescent Microsphere Multiplex Immunoassay
● Latex Agglutination
Rheumatoid arthritis, systemic lupus erythematosus, ● Nephelometry
Autoimmune disease Sjogren’s syndrome, mixed connective tissue disease, ● Measuring complement levels
systemic sclerosis, glomerulonephritis
Neoplastic disease Solid and lymphoid tumors TYPE IV - CELL MEDIATED HYPERSENSITIVITY
Bacterial infective endocarditis, streptococcal infection,

Infectious disease ● First described by Robert Koch
viral hepatitis, infectious mononucleosis
● Mostly involved is the skin (integumentary system)
● Part of normal cell immune response
SERUM SICKNESS ○ Sensitized T cells, rather than antibodies, play the major role in its
manifestations.
● A clinical course of type III ● No antibodies are involved
● Results from passive immunization of humans with animal serum. ● 24-72 hours
● After injection of drug molecules may combine with self proteins to form ● Lymphocytes (T cells) do not recognize the antigens of microorganisms or
antigen. other living cells, but are immunologically active through various types of
● The host reacts and produces antibodies. direct cell to cell contact.
● At first, there is little antibody → antigen excess ● Once there is an exposure to an antigen, CD4+ T cells will recruit cytokines
○ 7-10 days → ill rash, fever, vasculitis, and joint pain in the area.
○ Generalized symptoms appear 7 to 21 days after injection of the ○ Cytokines will release inflammatory mediators leading to
animal serum inflammation and tissue damage.
■ Headache, fever, nausea, vomiting, joint pain, rashes, and ● May occur within 48-72 hours or longer
lymphadenopathy ● Involves CD4+ T cells
● As more antibodies are produced, the conditions clear. ○ Primarily T-helper cells (Th 1)
○ Self limiting disease ○ 1 to 2 weeks of initial sensitization phase after first contact with
○ Recovery could take weeks after the antigen has been eliminated antigen.
from the body. ■ Langerhans cells in the skin and macrophages in the
tissues capture antigen, migrate to nearby lymph nodes,
and present it to naive T-helper cells which differentiate
into Th1 cells.
■ At the site, activated Th1 cells release IL-3, GM-CSF, and
MCP-1/CCL2.
■ Recruited monocytes differentiate into macrophages and
are activated by IFN-γ and TNF-β.
● Antigen that can trigger type IV hypersensitivity:
○ Intracellular pathogens
■ Bacteria (eg.Mycobacterium tuberculosis, Mycobacterium
leprae), fungi (eg. Pneumocystis carinii), parasites
(Leishmania spp.), viruses (eg. Herpes simplex virus)
○ Contact antigens
1st Shifting (A.Y. 2020 - 2021)
■ Plants (eg. poison ivy, poison oak), metals (eg. nickel ■ Cosmetics
salts), and components of hair dyes and cosmetics. ■ Medications (topical anesthetics, antiseptics, and
● Examples: antibiotics)
○ Allergy or infection ■ Latex
○ Contact dermatitis ○ Produces a skin eruption characterized by erythema, swelling, and
○ Tuberculin reaction the formation of papules that appears from 6 hours to several days
after the exposure.
TYPE IV HYPERSENSITIVITY REACTIONS ARE MEDIATED BY ■ Papules may become vesicular with blistering, peeling,
ANTIGEN-SPECIFIC EFFECTOR T CELLS and weeping.
● Patch test
SYNDROME ANTIGEN CONSEQUENCE ○ Gold standard in testing for contact dermatitis.
○ Done when the patient is free of symptoms or at least has a clear
● Proteins: ● Local skin swelling:
test site.
○ Insect venom ○ Erythema
Delayed-type ○ A nonabsorbent adhesive patch containing the suspected contact
○ Mycobacterial ○ Induration
hypersensitivity allergen is applied on the patient’s back and the skin is checked for
proteins (tuberculin, ○ Cellular infiltrate
a reaction over the next 48 hours.
lepromin) ○ Dermatitis
○ Positive Test - Redness with papules or tiny blisters
● Haptens: ● Local epidermal reaction: ■ Individuals with deficient cell-mediated immunity will
○ Pentacecacatechol ○ Erythema display anergy -- absence of positive reactions for all of
(poison ivy) ○ Cellular infiltrate the common antigens used in the skin test.
Contact ○ Dinitrofluorobenzene ○ Vesicles ○ Final evaluation is conducted at 96 to 120 hours.
hypersensitivity (DNFB) ○ Intraepidermal ● Involves antigen-sensitized T cells or particles that remain phagocytized in a
● Small metal ions: abscesses macrophage and are encountered by previously activated T cells for a
○ Nickel second or subsequent time.
○ Chromate
Gluten-sensitive ● Gliadin ● Villous atrophy in small EXAMPLES OF TYPE IV REACTIONS

enteropathy (celiac bowel
disease) ● Malabsorption ● Granulomatous reactions
○ Leprosy (skin granulomas)
○ Tuberculosis (lung granulomas)
TYPE IV DELAYED-TYPE HYPERSENSITIVITY (DTH) ○ Developed due to chronic persistence of antigen.
○ Consist of epithelioid-shaped and multinucleated fused
● Contact dermatitis - small molecules or low molecular weight compounds macrophages with an infiltrate of lymphocytes or other WBCs.
react with proteins in the skin to form antigens which provoke a ○ Cells in the granuloma can release large amounts of lytic enzymes
cell-mediated immune response. that can destroy surrounding tissue and promote fibrin deposition.
○ Poison ivy, poison oak, and poison sumac ● Delayed hypersensitivity tests
■ Urushiol ○ Used to test for reactivity to candida, tuberculin, histoplasmin,
■ Most common causes of contact dermatitis coccidioidin, and other microbial antigens
○ Other common compounds that produce allergic skin ○ A positive reaction, 10 mm or more diameter, appears in 24-72
manifestations include: hours in sensitized individuals and indicates exposure and that the
■ Nickel immune system is working, not necessarily active infection.
■ Rubber ○ Erythema (red) and indurated (thickened due to lymphocytes and
■ Formaldehyde macrophages)
■ Hair sprays and dyes
■ Fabric finishes
1st Shifting (A.Y. 2020 - 2021)
1ST EXPOSURE
● Poison ivy produces contact dermatitis.

● Urushiol binds to proteins in EC and becomes sensitizing antigen.
● The itchy, painful dermatitis of poison ivy appears 48 hours after

○ Dermatitis spreads to adjoining areas.
● TDH that bear matching antigen receptors come in contact with the antigen
and proliferate clones, which sensitize the individuals.
CLASSIFICATION OF HYPERSENSITIVITY REACTIONS
PARAMETER TYPE I TYPE II TYPE III TYPE IV
Reaction Anaphylactic Cytotoxic Immune T cell

Complex dependent
Antibody IgE IgG, possibly Ag-Ab None

other Ig complexes
(IgG, IgM)
Complement No Yes Yes No

2ND EXPOSURE
Involved
● 2nd exposure activates TD cells which proliferates and release lymphokines Cells Involved Mast cells, Effector cells Macrophages, Antigen -
○ It will stimulate macrophage to attack targeted epithelial cells basophils, (macrophages, mast cells specific T cells
granules PMN
(histamine) leukocytes)
Cytokines Yes No Yes Yes (T cell

Involved cytokines)
Comparative Antibody Antibody Immune T cell
1st Shifting (A.Y. 2020 - 2021)
Description Mediated, dependent; complex mediated, mast cells and antibody and complement cytokines that
immediate complement or mediated delayed type basophils complement, proteins. recruit
cell mediated (immune opsonization Neutrophils are macrophages
complex , or ADCC recruited and and induce
disease) ● Cell function release inflammation
inhibited by lysosomal or activate
Mechanism of Allergic and Target cell Immune Inflammation,
antibody enzymes that cytotoxic T
Tissue Injury anaphylactic lysis; cell complex cellular
binding cause tissue cells to cause
reactions mediated deposition, infiltration
● Cell function damage. direct cell
cytotoxicity inflammation
stimulated damage.
Examples ● Anaphylaxis ● Transfusion ● Arthus ● Allergy or by antibody
● Hay fever reactions reaction infection binding
● Allergic ● Autoimmune ● Serum ● Contact
rhinitis Hemolytic sickness dermatitis
TYPE OF PATHOLOGIC IMMUNE MECHANISMS OF
● Asthma Anemia ● SLE ● Tuberculin
HYPERSENSITIVITY MECHANISMS TISSUE INJURY &
● Food allergy ● HDN ● Rheumatoid and anergy
DISEASE
● Urticaria ● Drug arthritis skin tests
reactions ● Drug ● Hypersensiti Immediate Th2 cells, IgE antibody, mast ● Mast cell derived
● Myasthenia reactions vity Hypersensitivity cells, eosinophils mediators (vasoactive
gravis pneumonitis (Type I) amines, lipid
● Goodpasture mediators, cytokines)
’s syndrome ● Cytokine-mediated
● Grave’s inflammation
disease (eosinophils,
● Thrombocyt neutrophils)
openia
Antibody-mediated IgM, IgG antibodies against cell ● Complement and Fc
diseases (Type II) surface or extracellular matrix receptor-mediated
COMPARISON OF HYPERSENSITIVITY REACTIONS antigens recruitment and
activation of leukocytes
TYPE I TYPE II TYPE III TYPE IV
(neutrophils,
Immune macrophages)
IgE IgG or IgM IgG or IgM T cells ● Opsonization and
Mediators
phagocytosis of cells
Synonym Anaphylactic Antibody Complex Cell mediated ● Abnormalities in
mediated mediated or delayed cellular function (eg.
cytotoxic type hormone receptor
Timing Immediate Immediate Immediate Delayed signalling)
Antigen Heterologous Cell surface; Soluble; Autologous or Immune complex - Immune complexes of ● Complement and Fc
autologous or autologous or heterologous mediated diseases circulating antigens and IgM or receptor-mediated
heterologous heterologous (Type III) IgG antibodies deposited in recruitment and
vascular basement membrane activation of leukocytes
Immune Release of ● Cell Ag-Ab Antigen
Mechanism mediators from destruction complexes sensitized Th1
Ige sensitized caused by activate cells release
1st Shifting (A.Y. 2020 - 2021)
T cell - mediated ● CD4+ T cells (delayed type ● Macrophage activation,

diseases (Type IV) hypersensitivity) cytokine mediated
● CD8+ CTLs (T cell mediated inflammation
cytolysis) ● Direct target cell lysis,
cytokine mediated
inflammation.
TYPE V HYPERSENSITIVITY
● Instead of destruction, mimicry happens.

○ Mimicry of function
● Example:
○ Grave’s disease - hyperthyroidism
■ Antibody mimics TSH and binds to TSH receptors, leading
to hyperthyroidism
POST-TEST
1. The type of reaction to skin test such as tuberculin is a type of what

hypersensitivity reaction? Type IV hypersensitivity
2. Which of the following type of hypersensitivity reaction is involved in
immune complex diseases? Type III hypersensitivity
3. True or False. Anaphylaxis always requires medical treatment.
4. 4. What mechanism is involved in the hemolytic disease of the newborn?
a. cell-mediated cytotoxicity antibody
b. complement-mediated cytotoxic reactions
c. Antireceptor antibodies
5. This type of hypersensitivity reaction does not involve cytokine.
1st Shifting (A.Y. 2020 - 2021)
○ Self-tolerance- ability of the immune system to accept self-antigens
UNIT 9B: IMMUNOPATHOLOGY: AUTOIMMUNE DISEASE and not initiate a response against them.
I. Autoimmunity ■ Can be caused by several mechanisms, e.g. Clonal
a. Concepts of Tolerance deletion, clonal anergy, suppression.
b. Immune Privilege ○ Tolerance to self antigens must be specific for the inducing epitope.
c. Mechanisms of Autoimmune Disorders
II. Autoimmune Disorders
a. Systemic Lupus Erythematosus CENTRAL TOLERANCE
b. Rheumatoid Arthritis
c. Hashimoto’s Thyroiditis
d. Grave’s Disease ● Destruction of self-reactive lymphocytes in the primary lymphoid organs.
e. Type 1 Diabetes Mellitus ● Early lymphocytes that are destroyed or undergo apoptosis.
f. Multiple Sclerosis ● Remember the bone marrow and the thymus because these are your
g. Myasthenia Gravis
h. Other Autoimmune Diseases primary lymphoid organs and this is where the B and T cells mature.
Sources:
PPT PERIPHERAL TOLERANCE
Video Part 1
Video Part 2
● Tolerance induced in mature lymphocytes from the outside of the primary
lymphoid organs.
AUTOIMMUNITY
CENTRAL TOLERANCE
● Autoimmunity – a condition in which the body responds to one or more
self-antigens (auto-antigens) ● Occurs in central or primary lymphoid organs, the thymus and bone marrow.
○ A condition by which there is a loss of self-tolerance. ● Negative selection
○ Self-tolerance is the normal characteristic/state of the immune ○ A process where T cells that express T cell receptors with a strong
system wherein the body can recognize or discern whether the affinity for these self-antigens are deleted by apoptosis.
antigen is self or non-self. ○ Occurs with both the immature, double-positive CD4+/CD8+ cells
● Horror autotoxicus – coined by Paul Ehrlich in the cortex and with the more mature, single-positive CD4+ or
○ Mechanism of Autoimmune Diseases CD8+ cells in the medulla.
○ “Horror” talks about how autoimmune disorders may inflict severe
outcomes to the patient. MECHANISMS
● Autoimmune Disease
○ Disorders in which immune responses are targeted toward
self-antigens and result in damage to organs and tissues in the 1. Clonal Deletion
body. ● Happens when early CD4+ T cells, which contain receptors for
○ These harmful effects may be caused by T-cell mediated immune endogenous molecules, are deleted after contact with self-antigens
responses or autoantibodies that are directed against host in the thymus.
antigens. ● Early B cells with self-reactive receptors are eliminated after an
interaction with self-antigens in the bone marrow.
CONCEPTS OF TOLERANCE
● Tolerance
○ Refers to the state of the immune system by which it is
unresponsive to an antigen.
1st Shifting (A.Y. 2020 - 2021)
■ Explains the interaction of the BCR or TCR with
its auto antigen which determines
survival/apoptosis.
○ BCR-Specific for non self antigen
■ BCR has been edited to not react with the self
antigen.
○ BCR-Specific for self antigen
■ There is affinity towards the self antigens which
will undergo apoptosis.
PERIPHERAL TOLERANCE
● Needed if there are B- or T-cells that managed to escape central tolerance.

● Clonally ignorant lymphocytes generally do not pose a threat to the host,
2. Clonal Anergy
except there are factors which are very strong and make them autoreactive.
● Unresponsive
○ If they are exposed to high concentrations of auto antigens there is
● The loss of T- and B-cell functions after the exposure to antigens in
a tendency for them to be activated.
the absence of co-stimulatory signals or following exposure to cells
○ When large amounts of intracellular self antigens are released, it will
with deficient MHC class II molecules.
make them auto reactive.
● B cell is an example of an APC which has a capacity to present
● Lymphocytes that recognize self-antigens in the secondary lymphoid organs
antigen towards the T-cells through the use of MHC class II
are rendered incapable of reacting with those antigens.
molecules, this requires 2 signals.
● Can result from anergy caused by the absence of a costimulatory signal
from an antigen-presenting cell (APC) or binding of inhibitory receptors such
as CTLA-4.
● May also result from inhibition by Tregs or death by apoptosis.
MECHANISMS
1. Anergy
● B-cell anergy
○ Anergic B cells cannot compete with the non-anergic
B-cells entering the B-cell follicles in the lymph
node/spleen → Apoptosis.
● T-cell anergy
○ Absence of co-stimulation the T-cell-APC interaction will
anergize the T-cell.
3. Receptor Editing
● Important mechanism of Central Tolerance for B-cell in which the
immature B-cell with BCR specific for auto-antigen is replaced with
a BCR specific for a non-self antigen.
○ Receptor avidity
1st Shifting (A.Y. 2020 - 2021)
ORAL TOLERANCE
● Immune system is unresponsive to ingested food antigens.

○ Our immune system has created and induced mechanisms that will
be able to process food antigens in the GALT (Gut Associated
Lymphoid Tissue) in order for it to also mediate T cells which can
induce suppression or regulation.
● Mediated by T cells
● Dependent on ingested antigen (dosage)
● A small dose of ingested antigen will induce regulatory T cells, whereas a
high dose will induce T-cell anergy or deletion.
IMMUNE PRIVILEGE
2. Fas-mediated activation causing cell death
● Fas mediated apoptosis ● Immune privileged sites
○ The removal of mature autoreactive B- and T-cells ○ Body sites that are usually unresponsive to pathogens, tumor cells,
● Fas (expressed by activated cells including T- and B-cells) binds to or tissue transplants.
FasL/Fas ligand present on several activated cell types. ○ Ex: cornea, testis, brain, placenta, and ovary
○ Once bound, Fas initiates apoptosis in the cell with Fas by 1. Lack of lymphatic drainage
activating the death domain. 2. Presence of blood barriers
○ Ex. Self-reactive B cells with Fas are susceptible to 3. Presence of immunosuppressive cytokines
Fas-mediated apoptosis if there is an interaction with Th ● E.g. IL-10,
expressing FasL. 4. Expression of FasL
○ If the FasL and Fas is bound together in the T or B-cell, it
will induce certain cascades inside the activated T or MECHANISMS OF AUTOIMMUNE DISORDERS
B-cell. e.g Death domain.
3. Induction of Treg
● Treg/Regulatory T cells/ Suppressor T cells ● Inability to maintain central and peripheral tolerance leads to the activation
○ They have the ability to down regulate the T-cell functions. of autoreactivity of immune system.
○ Purpose of T cells ● Initiation of autoimmune disorders:
■ “We do not want that CD4+ t helper cell to ○ Genetic
continuously activate because continuous ○ Environmental
activation of T cell will further activate several
cascades of the immune system, such as causing GENETIC PREDISPOSITION
reduction of interleukins or cytokines that can
also activate other mechanisms like phagocytosis
● No individual gene is sufficient to induce autoimmune disorders BUT the
etc”.
products of SEVERAL GENES are likely to induce one.
● Suppressive functions:
● Overexpression or underexpression of genes needed in:
○ Treg cells respond to signals via CTLA-4
○ Apoptosis, cellular survival, cytokine expression, BCR or TCR
○ Activation of LAG-3 which binds to MHC class II molecule
signaling, co-stimulatory molecule interactions, and immune
○ Secretion of IL-10 and TGF-B
clearance of apoptotic cells and immune complexes = autoimmune
phenotype.
1st Shifting (A.Y. 2020 - 2021)
● There is an association between the presence of certain human leukocyte HLA-DR3 Weak
antigen (HLA) types and the risk of developing a particular autoimmune Myasthenia gravis
HLA-B8 (class I) Intermediate
disorder.
○ The strongest link found is between the HLA-B27 allele and the Goodpasture’s Syndrome HLA-DR2 Strong
development of ankylosing spondylitis, an autoinflammatory
disease that affects the spine. ● If certain HLA products are mutated or if there are products that are
● Differences in MHC genes are thought to influence influence the affecting the HLAs, some of it will have disease correlation with autoimmune
development of autoimmune disease because the specific structure of the disorders.
MHC molecule can determine whether or not a self-antigen can attach to
the peptide-binding cleft of the molecule and subsequently be processed
and presented to T cells. ENVIRONMENTAL SUSCEPTIBILITY
● Polymorphisms in non-MHC genes can also be associated with
development of autoimmune disease. RELEASE OF SEQUESTERED ANTIGENS
○ PTPN22 gene- T- and B-cell receptor signaling
○ IL2RA gene- T-cell activation and maintenance of Tregs
○ CTLA4 gene- inhibitory effect on T-cell activation ● Sequestered/protected antigens may be found in privileged sites.
○ BLK gene- B-cell activation and development ● “Hidden’’ (cryptic) antigenic determinants that were unavailable when fetal
○ AIRE (autoimmune regulator) gene- development of T-cell tolerance clonal deletion was occurring can become available following
in the thymus. injury/infection.
● Single-gene mutations that can be inherited in a Mendelian fashion have ● Immunologic ignorance.
been associated with rare autoimmune disorders. ○ Production of autoantibodies to the lens of the eye following an
ocular injury.
○ Autoantibodies to sperm after a vasectomy.
HLA STRENGTH OF ○ Autoantibodies to DNA following damage to skin cells by
AUTOIMMUNE DISEASE
ASSOCIATION ASSOCIATION overexposure to UV rays from the sun.
MHC CLASS I
MOLECULAR MIMICRY
Ankylosing spondylitis
HLA-B27 Strong
Reiter’s Syndrome ● Refers to the fact that many bacterial or viral agents contain antigens that
closely resemble the structure or amino acid sequence of self-antigens.
Grave’s Disease HLA-B8 Weak
● Exposure to foreign antigens may trigger immune responses that
Psoriasis vulgaris HLA-Cw6 Intermediate cross-react with similar self-antigens.
● Autoreactive B cells can be activated, synthesizing antibodies if T-cell
MHC CLASS II recognizes a foreign antigen with an epitope that can cross-react with
Rheumatoid Arthritis HLA-DR4 Strong self-antigen.
● Examples:
Sjögren’s Syndrome HLA-DR3 Weak ○ M protein of S. pyogenes, which cross-react with sarcolemmal
HLA-DR2 Intermediate heart muscle (cardiac myosin) = seen in Rheumatic fever.
SLE ○ A peptide derived from Coxsackievirus cross reacts with a peptide
HLA-DR3 Weak
from glutamic acid decarboxylase (an antigen in Beta-islet cells).
Celiac Disease HLA-DR3 Strong This is recognized by T cells which is seen DM type 1.
HLA-DR3 Intermediate
DM Type 1 POLYCLONAL ACTIVATION
HLA-DR4 Strong
Multiple Sclerosis HLA-DR2 Intermediate

● Pathogen Associated Molecular Pattern (PAMP)
1st Shifting (A.Y. 2020 - 2021)
● Microbial antigens (ex. LPS/LTA) may nonspecifically activate B cells or T Platelet membrane protein;
cells, some of which may render these cells to become autoreactive = ITP B cells/autoantibody
Integrin
autoimmune disease.
Salivary duct antigens; SS-A,
Sjögren’s Syndrome B cells/autoantibody
SS-B
DRUG AND HORMONAL CAUSES
Centromeric proteins of
● Quinidine, sulfathiazole are adsorbed onto an endogenous molecule/cell Scleroderma fibroblasts; Nucleolar antigens; Unknown
(e.g. platelets) = formation of antigenic hapten-carrier complex. Scl-70
○ Antibody to the drug is formed and reacts with the drug on the
Pemphigus vulgaris Desmolglein 3 B cells; autoantibody
platelet membrane. Complement is activated, resulting in platelet
lysis. Renal and lung basement
Goodpasture’s syndrome B cells; autoantibody
● SLE-associated drugs → chlorpromazine, hydralazine and procainamide membrane collagen type IV
○ They have been observed to produce antinuclear antibodies (ANE)
in SLE. Thyroglobulin, Microsomal
CD4+ T cells; B
● Drug-induced HA → penicillin Hashimoto’s thyroiditis antigens and thyroid
cells/autoantibody
● SLE risk of women : men (10:1). peroxidase
○ Estrogen effects among females with SLE. MBP, Myelin oligodendrocyte
● Women are 2.7 times more likely to acquire an autoimmune disease than Multiple sclerosis CD4+ T cells; B cells
protein
men.
○ Women develop autoimmunity at an earlier age and have higher CD4+ T cells; CTLs; B
DM Type 1 Pancreatic B-islet antigen
risk for acquiring more than one autoimmune disease as compared cells/autoantibody
with men.
IgG; Citrullinated and CD4+ T cells; CTLs; B
○ Females have been found to have higher absolute CD4+ T-cell Rheumatoid arthritis
carbamylated proteins cells/autoantibody
counts and higher levels of circulating antibodies than men.
○ The stimulatory effects of female hormones may place women at CD4+ T cells (Th1 and
Psoriasis Unknown
greater risk for developing autoimmune disease. Th17)
AUTOIMMUNE DISORDERS SPECTRUM OF AUTOIMMUNE DISEASES
SPECIFICITY DISEASE TARGET TISSUE

AUTOIMMUNE
AUTOANTIGEN EFFECTORS Organ-specific Hashimoto’s thyroiditis Thyroid
DISEASES
|
AIHA Blood Group Antigen B cells/autoantibody Grave’s Disease Thyroid
|
Myasthenia gravis Acetylcholine receptor B cells/autoantibody | Pernicious anemia cells Gastric parietal
|
Grave’s Disease TSH receptor B cells/autoantibody | Addiso’s Disease Adrenal glands
| Type I diabetes mellitus Pancreas
SLE dsDNA, histones, RNP B cells/autoantibody
|
Gastric parietal cells; intrinsic | Myasthenia gravis Nerve-muscle synapses
Pernicious anemia B cells/autoantibody |
factor
Multiple sclerosis Myelin sheath of nerves
|
Antineutrophil | Autoimmune hemolytic anemia RBCs
Cytoplasmic antigen - Myeloperoxidase; Proteinase 3 B cells/autoantibody |
associated vasculitis | Idiopathic thrombocytopenic Platelets
1st Shifting (A.Y. 2020 - 2021)
| purpura (anemia, leukopenia, thrombocytopenia or lymphopenia) and (+)

| anti-nuclear antibodies.
Goodpasture’s syndrome Kidney, lungs ○ The disease is marked by alternating relapses or flares and periods
|
| of remission.
Rheumatoid arthritis Joints, lungs, skin
| ○ Nephritis is a major cause of illness and death.
| Scleroderma Skin, gut, lungs, kidney ○ Diffuse proliferative glomerulonephritis- most dangerous type of
| lesion characterized by cell proliferation in the glomeruli that can
↓ Skin, joints, kidney, brain, heart, lead to end-stage renal disease.
Systemic Lupus Erythematosus
Systemic lungs ○ In drug-induced lupus, symptoms usually disappear once the drug
is discontinued.
■ Most common drugs implicated are: procainamide,
SYSTEMIC LUPUS ERYTHEMATOSUS hydralazine, chlorpromazine, isoniazid, quinidine,
anticonvulsants and oral contraceptives.
● A chronic systemic inflammatory disease
● Peak stage of onset is usually between 20 and 40 years.
● Exposure to sunlight is a well-known trigger of the photosensitive skin
rashes seen in many lupus patients.
● B cells and the antibodies they produce are believed to play a central role in
the pathogenic mechanisms that are responsible for this complex disease.
● The presence of autoantibodies can precede the onset of disease by 9 to 10 “Malar Rash”
years.
● Immune response is directed against a broad range of target antigens
● There is a strong association with human leukocyte antigens (HLA) DR and
DQ
○ Remember: HLA antigens play a role in presentation of foreign or
self-antigens to T and B cells
● Depressed suppressor T cell function allows the production of antibodies
against self-antigens
○ Risk: Female > males | African Americans, Asians, Hispanic
descent > Caucasians
● Treatment: a high dose of aspirin or other anti-inflammatory drug (for mild
symptoms)
○ For skin manifestations, antimaliarials such as hydroxychloroquine
or chloroquine and topical steroids are prescribed.
○ For acute fulminant lupus and lupus nephritis, systemic
corticosteroids are used because they suppress the immune
response and lower antibody titers.
● The most common cause of death in lupus patients is infection followed by
heart disease.
● Clinical Signs:
○ Extremely diverse, and nonspecific symptoms such as: fatigue,
weight loss, malaise, fever, anorexia, arthritis (joint involvement-
most frequently reported manifestation), skin lesions,
photosensitivity, butterfly rash (responsible for the name lupus-
“wolf-like”, renal disease, pericarditis, ventricular enlargement,
seizures, oral ulcers, immunologic disorders, hematologic disorders
1st Shifting (A.Y. 2020 - 2021)
● Diagnosis of SLE – SLICC Criteria (American College of Rheumatology, nuclear antigen
2012): (RNA component)
Proteins SLE, mixed

Anti-RNP complexed with Speckled connective tissue
DIAGNOSIS OF SLE - SLICC CRITERIA (ACR, 2012)
nuclear RNA diseases
CLINICAL FEATURES IMMUNOLOGIC FEATURES
Proteins
SLE, Sjögren’s
Acute cutaneous lupus (maculopapular lupus, rash, Anti-SS-A(Ro) complexed to Finely Speckled
High ANA concentration Syndrome, others
malar rash, photosensitive lupus rash, etc.) RNA
Chronic cutaneous lupus (discoid rash, mucosal High anti-dsDNA antibody Phosphoprotein
SLE, Sjögren’s
lupus, etc.) concentration Anti-SS-B(La) complexed to Finely Speckled
Syndrome, others
RNA polymerase
Oral or nasal ulcers Presence of anti-Sm
RNA polymerase, Homogenous staining of SLE, systemic
Nonscarring alopecia Positive APA Anti-nucleolar
nucleolar protein nucleolus sclerosis
Low complement (C3, C4,
Synovitis in > 2 joints Systemic
CH50) DNA
Anti-Scl-70 Atypical Speckled sclerosis,
topoisomerase I
Serositis Direct CoombsTest Scleroderma
Renal (urine protein or RBC casts) Histidyl-tRNA Fine cytoplasmic

Anti-Jo-1 Polymyositis
Must have a total of 4 features synthetase speckling
Neurologic (seizures, psychosis, others)
with > 1 clinical feature and 1
Hemolytic anemia immunologic feature LABORATORY DIAGNOSIS
or
Leukopenia or lymphopenia (without an identifiable
Biopsy-proven LN with
cause) ● Initial evaluation: CBC, platelet count, and urinalysis.
anti-dsDNA antibodies or ANA
● First laboratory findings in lupus patients are leukopenia and possible
Thrombocytopenia (without an identifiable cause)
anemia, and thrombocytopenia
● ESR may be elevated even though the CRP levels tend to be low or normal.
COMMON ANTINUCLEAR ANTIBODIES ● C3 is the most commonly measured complement protein.
● Striking feature: (+) anti-nuclear antibodies
AUTOANTIBOD CHARACTERISTI IMMUNOFLUORESCENT DISEASE ○ BUT NOT diagnostic for SLE and should be further identified for the
Y C OF ANTIGEN PATTERN ASSOCIATION specific antibody [identify the type].
Anti-dsDNA dsDNA Homogenous SLE ● (+) LE cells – neutrophils with ingested LE bodies in a rosette form
● Deficiency in complement
Related to purines Not detected on routine SLE, many other ● Hyperglobulinemia
Anti-ssDNA
and pyrimidines screen diseases
Drug-induced
Different classes
Anti-histone Homogenous SLE, other
of histones
diseases
DNA-histone SLE, Drug -

Anti-DNP Homogenous
complex induced SLE
Anti-Sm Extractable Speckled Diagnostic for SLE
1st Shifting (A.Y. 2020 - 2021)
○ Multiplex bead assays
LABORATORY DIAGNOSIS: SEROLOGICAL
● FANA testing (fluorescent anti-nuclear antibodies) from ANA

○ Highly sensitive, detects a wide range of antibodies, inexpensive
and easy to perform.
○ Principle: Indirect fluorescent antibody procedure for the detection
and semi-quantitation of human antinuclear autoantibodies.
■ Utilizes primary testing/reactions of immune tests.
■ Uses fluorescent tags or enzymes. ● These patterns are not conclusive but may give a correlation not just with
○ Mouse Kidney/Human epithelial (HEp-2) cells (substrate) are used FANA but in the clinical findings of the patient.
for this test (standard substrate for clinical laboratories worldwide). ○ Homogenous
○ Observation of a specific pattern of fluorescence on the HEp-2 ■ Also known as “diffuse” pattern.
cells indicates the presence of autoantibodies in the patient's ■ Characterized by uniform staining of the entire nucleus.
serum. ■ Nucleus in the interphase cells/stage.
○ Specimen: serum (in gold/red-top tube) ■ Condense chromosomal region in the metaphase cells.
○ Antigens are in their original form and location within the cells used ■ Strong correlation with native DNA, dsDNA and DNP
in the test. ■ associated with RA, SLE, Sjögren’s Syndrome, MCTD.
● Recall Primary Tests: ○ Peripheral
○ The use of immunofluorescence (IF) microscopy for the detection of ■ Also known as ring/rim membranous.
antibodies in patient serum was one of the first techniques ■ Seemingly diffuse staining, but intense staining at the
developed in immunopathology. periphery/perimeter at each interphase cell.
○ A substrate is mounted on a glass slide and antibodies labeled with ■ There is an outer circle that surrounds the nucleus of
a fluorescent tag. interphase cells.
○ Fluorescent tags are used to identify the presence of either antigen ■ Associated with native DNA, dsDNA and DNP antibodies.
in the substrate (direct IF) or of antibody on the substrate (indirect ■ Related with active SLE and Sjögren’s Syndrome.
IF) using a fluorescence microscope. ○ Speckled
● Disadvantages of IF: ■ Large, coarse patterns
○ Time consuming ■ Seen in interphase cells.
○ Labor intensive ■ Staining is not present in the nucleus and chromatin
○ Requires skilled operator region of the dividing cells which causes the coarse
○ Subjective component that may cause significant variation in staining appearance of cells.
results. ■ associated with anti-Sm and anti-RNP.
● Replaced by automated methods: ■ Correlated with SLE, Sjögren’s Syndrome, and MCTD.
○ EIA ○ Nucleolar
1st Shifting (A.Y. 2020 - 2021)
■ Less coarser and smaller compared to speckled.
■ Prominent staining at the nucleoli of interphase cells.
■ Staining of nucleoli varies on the number of nuclei present
in each cell.
■ Related with anti-RNP and anti-RNA.
■ associated with Scleroderma, Sjögren’s Syndrome and
MCTD.
○ Discrete/Centromere
■ Numerous discrete speckles in the nuclei of interphase
cells and chromatin of dividing cells.
■ Correlated with anti-centromere, anti-RNA, and anti-ENA.
■ associated with CREST Syndrome (Calcinosis, Reynauds,
Esophageal dysmotility, Sclerodactyly, Telangiectasia).
Figure 15-7. Extractable nuclear antibody immunodiffusion pattern. A mixture of

extractable nuclear antigens (ENA), including RNP, Sm, and other soluble nuclear
antigens, is placed in a central well in an agarose gel. Sm antibody and RNP antibody
are run as positive controls and patient samples are placed between the controls.
The pattern of precipitin lines formed indicates the antibodies present in patient
serum. The arc of serological identity formed between Sm and patient A indicates
that serum A contains anti-Sm antibodies. The arc of partial identity formed between
serum A and RNP occurs because RNP is always found complexed to Sm antigen.
RNP antibodies are not present. Serum B contains neither Sm nor RNP antibody.
● Patient A in figure 15-7 may develop photosensitivity, butterfly rash, malaise,
● ds-DNA Testing using Crithidia luciliae (hemoflagellate substrate) fatigue, complement deficiency, presence of LE cells.
○ (+) Bright staining kinetoplast containing circular ds-DNA with ○ Suggestive of SLE.
patient serum and an antibody conjugate.
■ This method is based on the principle that the kinetoplast Major ENA against which ANA form and their Disease Association
of this trypanosome contains circular dsDNA.
■ This can also be positive if the kinetoplast is stained along EXTRACTABLE
COMMENTS ON COGNATE ANTIBODIES
with the nucleus. NUCLEAR ANTIGEN
○ (-) no staining within the cell or was stained but at the basal body.
● Highly specific for SLE.
○ High specificity for dsDNA but lesser sensitivity in case low titer of
● Present in ~30% of pSLE cases (low sensitivity).
ANA (dsDNA) is being used.
● Associated with development of less severe forms of
nephritis and with CNS disease and serositis in SLE.
● Anti-ENA antibodies are detected to varying degrees in SLE patients.
Sm (Smith) ● Target antigens found in protein components of U1-,
U2-, U4-, U5-small nuclear RNP particles; additional
proteins in the U1snRNP particle are recognized by
anti-RNP antibodies, hence the frequent co-occurence
of anti-Sm and anti-U1RNP antibodies SLE.
● Common in Sjögren’s Syndrome and subacute

Ro (SSA)
cutaneous lupus.
1st Shifting (A.Y. 2020 - 2021)
● Also found in other diseases (eg. SLE, systemic

sclerosis and polymyositis and/or dermatomyositis).
● Implicated in the pathogenesis of neonatal lupus
erythematosus.
● Two subtypes known by their molecular weight and
with different intracellular distributions - Ro52
(cytoplasmic) and Ro60 (nuclear/nucleolus); antibodies
do not necessarily form against both.
● Ro52 is more common in systemic sclerosis and
myositis.
● Ro60 transiently co-localized with La/SSB on some
small cytoplasmic RNA molecules (hY-RNAs), hence the
frequent co-occurence of anti-Ro and anti-La
antibodies.
● May occur in the absence of anti-La antibodies. ● Passive immunodiffusion using the Ouchterlony technique which shows:
● May not be detected on HEp2 IIF cell lines. ○ Reaction of identity shown by fusion of precipitins between two
● Less common than anti-Ro antibodies and rarely found sera containing antibodies to U1 RNP
La (SSB) in their absence. ○ Reaction of partial identity shown by spurring of the precipitins
● Seen mainly in SLE and Sjögren’s Syndrome. between sera containing antibodies U1 RNP and Sm, respectively.
This indicates that sera react with different antigens on the same
● Characteristic of MTCD molecular complex, and that one antigen also occurs
U1 RNP ● Seen also in other diseases (eg. SLE, systemic independently. Both Sm and U1 RNP antigenic sites, for example,
sclerosis). occur on the same U1 RNP particle, while Sm is also expressed on
other nuclear RNP particles
● Associated with polymyositis, typically with interstitial
○ Reaction of non-identity shown by crossing of the precipitins
pulmonary fibrosis and hyperkeratotic “mechanics”
Jo-1 (histidyl-tRNA between the sera containing antibodies to La and those containing
hands.
synthetase) anti-Sm and anti-Jo1.
● Presence may predict poorer response to treatment.
○ Ouchterlony technique: method used to determine the
● May also be found in DM, SLE, MTCD.
immunologic specificity of a positive FANA test, particularly when a
● Highly specific for systemic sclerosis if detected using speckled pattern is observed.
immunoblotting, immunodiffusion, or
Scl-70 immunoprecipitation, but only moderate sensitivity.
(Topoisomerase-1) ● Associated with development of pulmonary fibrosis.
● Occasionally found in other disease (eg. SLE) especially
if detected by ELISA.
● Associated with polymyositis - scleroderma overlap

PM-Scl
syndrome.
● [A] Urine from a patient with glomerulonephritis (left).
1st Shifting (A.Y. 2020 - 2021)
○ Sediment demonstrated in the same urine after centrifugation (right) ○ Radiographic evidence of erosions in the joints of the hands, the
● Urinary cast: wrists, or both.
○ [B] Hyaline
○ [C] Red cell
RHEUMATOID ARTHRITIS
● RA is a chronic, systemic inflammatory disease that is characterized by

granulation tissue (pannus) formation and subcutaneous nodules in joints.
○ Edematous joints
● It is characterized as a chronic, symmetric, and erosive arthritis of the
peripheral joints that can also affect multiple organs such as the heart and
the lungs. ○ Nonspecific symptoms: malaise, fatigue, fever, weight loss, and
○ Local bone erosion is a feature that is a characteristic of the transient joint pain that begin in small joints of the hands and feet.
pathology of RA. ■ Joint pain can lead to muscle spasms and limitation of
● It strikes individuals between the ages of 25 and 55. motion.
● Progress of disease varies because there may be spontaneous remissions
or an increasingly active disease in some individuals that rapidly progresses EXTRA ARTICULAR MANIFESTATIONS OF RHEUMATOID ARTHRITIS
to joint deformity and disability.
● Strongest environmental risk factor for RA is cigarette smoking.
● Occurs outside the joints.
● IgG–IgM complexes → activate complement → lesions
● Patients are most likely to have had a history of smoking, early disease
● Appears to be an association of RA with certain MHC class II genes
onset, and test positive for anti-CCP or RF.
○ The strongest association appears with certain DR4 alleles
● Includes the formation of subcutaneous nodules, pericarditis,
○ Strongest associations have been between a subset of patients
lymphadenopathy, splenomegaly, interstitial lung disease, or vasculitis.
with RA and specific HLA-DRB1 alleles or PTPN22 gene
● Some patients have small masses of tissue called nodules, which are found
polymorphisms.
in the myocardium, pericardium, heart valves, pleura, lungs, spleen and
■ Patients are positive for rheumatoid factor or antibodies to
larynx.
CCP.
● 10% of patients develop Sjogren’s syndrome , an autoimmune disorder
● Triggering pathogens: Mycoplasma, rubella, CMV, EBV, and parvovirus.
characterized by the presence of dry eyes and dry mouth in addition to
● The synovium is densely packed with dendritic cells, macrophages, T and B
connective tissue disease.
cells, NK cells, and plasma cells.
● Felty’s syndrome- a combination of chronic, nodular RA coupled with
○ The synovium is tested for the presence of mucin and WBC
neutropenia and splenomegaly.
counting is performed.
● Most common cause of death in RA is cardiovascular disease because of
● Anti-cyclic citrullinated peptide antibody (anti-CCP/ ACPA)
acceleration of arteriosclerosis by proinflammatory cytokines released
○ Second major type of antibody associated with RA.
during the disease process.
● Clinical Signs:
○ Swelling of the soft tissue around three or more joints.
■ Initial symptoms: joints, tendons and bursae
○ Swelling of the proximal interphalangeal, metacarpophalangeal, or
wrist joints.
○ Symmetric arthritis
■ Joints are affected in symmetric fashion.
○ Subcutaneous nodules
○ A positive test for rheumatoid factor (RF)
1st Shifting (A.Y. 2020 - 2021)
● Elevated/plateaued inflammatory markers: ESR or CRP

● Detection of serum RF and anti-CCP antibodies is important in
differentiating RA from other polyarticular diseases.
○ RF is the antibody that is most often tested to aid in making the
initial diagnosis since it is one of the classification criteria for RA.
● Synovial Fluid Analysis
○ Synovial fluid white blood cell (WBC) counts = 5000 to 50,000
WBC/μL (compared to <2000 WBC/μL for a noninflammatory
condition such as osteoarthritis) is correlated with RA.
○ Increased protein, poor mucin clot development, decreased
complement, (+) RF (increases macrophage activity and enhancing
antigen presentation to T cells by APCs)
● Joint Imaging
● A negative result does not rule out the presence of RA since 70-90% of
patients with RA tests positive for RF.
● Positive results are not specific for RA since they can be found in patients
with other connective tissue disorders.
IMMUNOLOGIC FINDINGS
● RF
○ Group of immunoglobulins IgG or IgM (typically an IgM) that
interacts specifically with the Fc portion of an IgG (target molecule)
● Sheep Cell Agglutination Test
○ (+) agglutination = (+) RF factor
○ Uses IgG as an agglutinin
● RF Latex Slide Test
● Rose Waaler Hemagglutination Test
● Nephelometric assays test for two other antibody classes of RF, IgG or IgA
TREATMENT FOR RA
● Non-steroidal anti-inflammatory drugs:

○ Salicylates and ibuprofen
○ Disease-modifying antirheumatic drugs:
■ Methotrexate: most notable; prescribe at the time of
diagnosis. Inhibits adenosine metabolism and T-cell
activation.
■ Hydroxychloroquine
■ Sulfasalazine
■ Leflunomide
■ Penicillamine
○ Corticosteroids
1st Shifting (A.Y. 2020 - 2021)
● Patients develop a combination of goiter (or enlarged thyroid, it is irregular
and rubbery), HYPOthyroidism (symptoms: dry skin, decreased sweating,
puffy face with edematous eyelids, pallor with yellow tinge, weight gain,
fatigue, dry and brittle hair), and thyroid autoantibodies.
○ Thyroid autoantibodies: antithyroglobulin, antithyroid peroxidase
(microsomal antigen), and second colloid antigen (CA-2)
○ Immune destruction of the thyroid gland occurs.
● The thyroid shows hyperplasia with an increased number of lymphocytes.
○ Hyperplasia will cause goiter.
● Cellular types present: activated T and B cells (with T cells predominating),
macrophages, and plasma cells.
● Certain drugs can trigger autoimmune thyroiditis: denileukin diftitox,
interferon-alpha, IL 2, lithium, tyrosine kinase inhibitors
● Mild dry mouth (xerostomia) or dry eyes (keratoconjunctivitis sicca) related
to Sjögren syndrome.
● Pathology to the thyroid gland is mediated primarily by CD8+ cytotoxic cells
which bind to the thyroid cells and destroy them by releasing enzymes that
cause apoptosis or necrosis.
● Immune response results in the development of germinal centers that
almost completely replace the normal glandular architecture of the thyroid
and progressively destroy the thyroid gland.
● Serum thyroid-stimulating hormone (TSH) level is elevated if thyroiditis

causes hypothyroidism.
● Antithyroperoxidase levels increased in 90%
● Antithyroglobulin antibodies increased in 40%
○ However, some patients with autoimmune thyroiditis have no
detectable antithyroid antibodies.
● Sensitive ELISA and chemiluminescent immunoassays
*Patient 1, 3, and 5 are showing positive mat agglutination indicating presence of RF. ● Antibodies to TPO are the best indicator of the disease
● Anti-cyclic citrullinated peptides (anti-CCP) assay TREATMENT

○ Second-generation anti-CCP EIA assays
● Anti-CCP is now the lead marker for detection of RA, because it is much
● Daily oral thyroid hormone replacement therapy, with levothyroxine (T4) as
more specific than RF.
the preferred drug.
● TSH levels should be monitored throughout the treatment and are used in
HASHIMOTO’S THYROIDITIS adjusting the dose of the drug so that normal TSH levels are maintained.
● Also known as chronic autoimmune thyroiditis. GRAVES’ DISEASE

○ Chronic lymphocytic thyroiditis
● Often seen in middle-aged women.
● It is characterized by HYPERthyroidism.
○ State of excessive thyroid function
1st Shifting (A.Y. 2020 - 2021)
● The most common cause of hyperthyroidism. ○ Binding assays (automated solid-phase ELISA & chemiluminescent
CLINICAL SIGNS immunoassays): a labeled TRAb reagent competes with the patient
antibody for TSH receptor bound to a solid phase.
○ BIoassays: difficult to perform because it requires tissue culture.
● Thyrotoxicosis, with a diffusely enlarged (hyperplasia) goiter that is soft
instead of rubbery.
● Symptoms TYPE 1 DIABETES MELLITUS
○ Nervousness, insomnia, depression, weight loss, heat intolerance,
sweating, rapid heartbeat, palpitations, breathlessness, fatigue, ● A chronic autoimmune disease that occurs in a genetically susceptible
cardiac dysrhythmias, and restlessness individual as a result of environmental factors.
● Result in elevated free and total T3 and T4; and decreased serum thyroid ● It is characterized by insufficient insulin production caused by selective
stimulating hormone (TSH) destruction of the beta cells of the pancreas.
○ Exophthalmos - hypertrophy of the eye muscles and increased ● Autoantibodies and CTLs are reactive against the pancreatic beta cells =
connective tissue in the orbit cause the eyeball to bulge out so that atrophy and fibrosis.
the patient has a large-eyed staring expression. ○ Beta cells are located in the pancreas in clusters called the islets of
■ There is conjunctival and periorbital edema which causes Langerhans.
the “bulging eyes” look. ● Progressive inflammation of the islets of Langerhans in the pancreas leads
to fibrosis and destruction of most beta cells.
● Diabetics carry HLA-DR2 or DR4 gene = increased risk for DM type 1
● It may also occur in the HLA-DQ region, especially in the coding of the DQ
chain.
● It is apparent that autoantibody production precedes the development of
T1D by months or several years.
● Thyroid-stimulating hormone receptor antibodies (TRAbs) ● Environmental influences include the possibility of viral infections and early
○ Major antibodies involved in Graves disease’ pathogenesis. exposure to cow’s milk.
○ When TRAbs bind to TSH receptors, they mimic the action of TSH ○ Linked viruses: rubella virus, cytomegalovirus, and Coxsackie B4
resulting in uncontrolled receptor stimulation with excessive release virus with diabetes, but most research is inconclusive.
of thyroid hormones. ○ Viruses can trigger autoantibody production by molecular mimicry.
TREATMENT TREATMENT
● US: first line of treatment involves radioactive iodine administered for 1-2 ● Daily injectable insulin has been the mainstay therapy for T1D.
years and results in a 30-50% long-term remission rate. ● Transplantation of pancreatic beta islet cells has been used for T1D patients
● Europe and Japan: patient is first placed on antithyroid medications with who have poor glucose control but this requires continual
beta blockers as adjuvant therapy then it is continued with drug treatment, immunosuppressive therapy in order to prevent rejection and the number of
radioactive iodine therapy, or surgery to remove part of the thyroid. suitable donors is limited.
● Surgery is recommended for patients resistant to drug treatment, but can
damage the laryngeal nerves and cause permanent hoarseness. LABORATORY DIAGNOSIS
LABORATORY DIAGNOSIS ● When T1D is suspected, tests for antibodies to GAD and IA-2A can be done
to confirm the diagnosis.
● Low/ undetectable levels of TSH and increased levels of FT4 ● Combined screening for IA-2A, ICA, and GAD antibodies appears to have
● TRAbs are highly indicative and one component of the diagnostic criteria of the most sensitivity and best positive predictive value for T1D in high risk
Graves disease. populations.
1st Shifting (A.Y. 2020 - 2021)
MULTIPLE SCLEROSIS MYASTHENIA GRAVIS
● An inflammatory autoimmune disorder of the central nervous system. ● Neuromuscular disease in which the nerve muscles do not function
● It is characterized by the formation of lesions called plaques in the white normally.
matter of the brain and spinal cord, resulting in the progressive destruction ● (+) antibodies to Acetylcholine receptors at the motor end plate = Blocking
of the myelin sheath of axons. the nerve impulses hence, damaging the neurons
● Considered a chronic progressive inflammatory disease with demyelination ○ Sensitivity of 80–90% for the diagnosis of myasthenia gravis.
of the nerves ● Other immunologic findings: serum antibodies to muscle-specific tyrosine
● Most closely associated with inheritance of particular HLA molecule coding kinase (MuSK)*.
for the beta chain of the DR subregion, namely DRB1*1501. ● Patients present with ptosis (drooping of eyelids), diplopia (double vision),
● Environmental factors: reduced exposure to sunlight, vitamin D deficiency, difficulty in chewing or swallowing, respiratory difficulties, limb weakness,
and cigarette smoking inability to retract the corners of the mouth often resulting in a snarling
● Associated viral infections: Epstein-Barr virus and Human Herpes 6 appearance, or some combination of these problems.
● Increased IgG in the CSF ● Characterized by weakness and fatigability of skeletal muscles.
● Early onset MG (EOMG) occurs before the age of 40 and affects
LABORATORY DIAGNOSIS predominantly females
○ Has strong association with the HLA haplotype, A1, B8 and DR3.
● Late onset MG (LOMG) occurs after 40 and is seen more often in males.
● IgG index = used to differentiates true IgG increase due to production rather ○ HLA Antigens B7 and DR2
THAN the increase in permeability of the BBB
○ IgG index = (IgG CSF/ Albumin CSF) / (IgG serum/ Albumin serum)
■ Ref range: 0.0 – 0.77 TREATMENT
○ CSF Electrophoresis = (+) Oligoclonal bands in the CSF
■ NON SPECIFIC, also seen in SLE, viral meningitis, ● Anticholinesterase agents to prevent destruction of neurotransmitter,
neurosyphilis acetylcholine, are used as main therapy
● Thymectomy should be performed on patients with thymoma.
CLINICAL SIGNS ● If these treatments aren’t effective, immunosuppression is recommended
● Treatment generally begins with high doses of corticosteroid drugs followed
by other immunosuppressive drugs (azathioprine or mycophenolate mofetil)
● Damage to tissue of CNS can cause visual disturbances, weakness/ to maintain response.
diminished dexterity in one or more limbs, locomotor incoordination,
dizziness, facial palsy, and sensory abnormalities (tingling/ “pins and
needles” that run down the spine or extremities and flashes of light seen on LABORATORY DIAGNOSIS
eye movement)
● Begins in young and middle-aged adults between ages 20 and 50. ● Radioimmunoprecipitation assay (RIPA): most commonly used procedure for
● Most patients with MS eventually develop progressive deterioration of the antibody to the ACHR, which is based on precipitation of the patient’s
CNS and functional disability. antibody with ACHRs isolated from human muscle.
● Immunofluorescence cell-based assays: patient serum is incubated with
TREATMENT HEK293 cells expressing all four ACHR subunits
○ Highly sensitive assay
○ Can detect antibodies directed toward ACHR clusters in patients
● Aimed at easing recovery from acute attacks and reducing the risk of future that were previously classified as seronegative by RIPA.
relapses. ● Fluorescence immunoprecipitation assays: uses ACHR subunits or MuSK
● Acute exacerbations are treated with corticosteroids to reduce inflammation. antigens labeled with green fluorescent protein to detect patient antibodies
● Therapy with natalizumab: greatly reduces severity of MS and has sensitivity that is similar to RIPA.
1st Shifting (A.Y. 2020 - 2021)
Autoimmune
thrombocytopenic Platelets Antiplatelet antibody
purpura
Inflammatory infiltrate of T and B cells;

Crohn’s disease Intestines
mechanism unknown
Disseminated
CNS Sensitized T cell
encephalomyelitis
Parietal cell antibody, intrinsic factor

Pernicious anemia Stomach
antibody
Poststreptococcal Streptococcal antibodies that

Kidney
glomerulonephritis cross-react with kidney tissue
Streptococcal antibodies that

Rheumatic fever Heart
cross-react with heart tissue
Connective Antinuclear antibodies; anti-Scl - 70 ,

Scleroderma
tissue anticentromere antibody
Antinuclear antibodies, RA factor

Sjögren’s Syndrome Eyes, mouth anti-salivary duct antibodies,
anti-lacrimal gland antibodies
Multisystem
granulomas,
Sarcoidosis Activation of T lymphocytes
pulmonary
manifestations
● Paroxysmal Cold Hemoglobinuria

○ Extrinsic defect due to immune function.
○ IgG reacting on the p antigen at cold conditions.
■ Initiates the early complement proteins.
■ C3 - C9 needs to be exposed to 37o C to be activated.
● Warm Autoimmune Hemolytic Anemia
○ Warm immunoglobulin such as IgG.
OTHER AUTOIMMUNE DISEASES ● Cold Agglutinin Disease
○ Due to IgM
○ Highly correlated with “Ii” antigen.
ORGAN OR
DISEASE IMMUNOLOGIC MANIFESTATIONS
TISSUE
Addison’s disease Adrenal glands Antibody to adrenal glands
Autoimmune hemolytic
RBCS Antibody to RBCs
anemia
1st Shifting (A.Y. 2020 - 2021)
7. (True or False) Malignant tumors are always encapsulated and rarely spread
UNIT 9C: TUMOR IMMUNOLOGY to adjacent spaces.
I. Pre-test 8. Antigens that can only be found in tumor cells are called: ________________
II. Review of Tumor Biology
a. Characteristics of a Cancer Cell
III. Tumor Antigens REVIEW OF TUMOR BIOLOGY
a. Tumor Specific Antigens (TSA)
b. Tumor Associated Antigens (TAA) ● Tumor immunology is the study of the relationship between the immune
IV. Clinically Relevant Tumor Markers
a. Tumor Markers system and cancer cells
b. Clinical Uses of Tumor Markers ● Salient points:
c. Serum Tumor Markers ○ Tumors arise due to dysregulated growth and impaired apoptotic
V. Laboratory Detection of Tumors mechanisms. These tumors can either be benign or malignant
a. Tumor Morphology
b. Immunohistochemistry ○ Cancer cells have an aberrant DNA. Normally, if cells have an
c. Molecular Methods aberrant DNA or it fails to replicate the correct DNA sequence that
VI. Interaction Between the Immune System and Tumors cell should die. However, some cells escape this mechanism due to
VII. Immunoediting and Tumor Escape the interaction of proto oncogenes and other regulatory
VIII. Immunotherapy
a. Active Immunotherapy mechanisms. It would result in replication with the aberrant DNA.
b. Passive Immunotherapy ○ Malignant tumors are rarely encapsulated and are able to invade
c. Adoptive Immunotherapy the adjacent tissues and other organs
■ Commonly exhibit metastasis
Links
PPT ○ Benign tumors don’t invade
Video ■ Benign tumors are composed of slowly growing cells that
are well differentiated and organized
■ These tumors are surrounded by a capsule, which secures
PRE-TEST them in place and prevents them from circulating to other
parts of the body
1. This tumor marker is used for monitoring hepatocellular carcinoma: ○ Malignant tumors are generally classified into carcinomas,
a. AFP leukemias/lymphomas and sarcomas.
b. hCG ■ Carcinoma- epithelial
c. CA-125 ■ Leukemia- bone marrow
d. CA-19-9 ■ Lymphoma- lymphoid tissue
2. This tumor marker can be used to screen for prostate cancer ■ Sarcoma- mesenchymal
a. AFP ○ Malignant tumors usually arise from a single clone of cells carrying
b. CEA flawed genes/DNA that usually arise from carcinogens
c. PSA ○ The presence of proto-oncogenes and tumor suppressor genes
d. CA-125 highly influence carcinogenesis.
3. (True or False) Tumor markers alone can diagnose the presence of cancer ■ The interplay between proto-oncogenes and tumor
4. (True or False) Tumor cells are polyclonal in nature suppressor genes lead to homeostasis
5. (True or False) Carcinomas are malignant tumors that are mesenchymal in ○ Generally arises from a lack of balance in growth and apoptosis
origin
6. Which of the following is not an oncofetal antigen? CHARACTERISTICS OF A CANCER CELL
a. AFP
b. CEA
● Sustained signaling of proliferation
c. PSA
● Resistance to cell death
d. CA-125
● Ability to induce angiogenesis
● Immortality in terms of cell division
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● Invasion and Metastasis ● The only normal cells in which they have been detected are testicular germ
● Ability to avoid suppressors of cell growth cells and placental trophoblastic cells to a lesser extent
● Reprogramming of energy metabolism to support malignant proliferation ● They become TAAs when the transformation process causes them to be
● Ability to evade the immune system expressed on tumors originating from other cell types
● Genomic instability and mutations ○ Example:
● Inflammatory responses that promote tumor growth ■ Melanoma Antigen Gene (MAGE) that are expressed by
melanoma tumors
TUMOR ANTIGENS
DIFFERENTIATION ANTIGENS
● Arsenal in the laboratory
● Used to screen the presence of a tumor or monitor treatment ● Expressed on immature cells of a particular lineage
● Tumor antigens can either be ○ Example:
○ Tumor Specific Antigens (TSA) ■ CD10 antigen which is normally found on pre-B
○ Tumor Associated Antigens (TAA) lymphocytes but not on mature B-lymphocytes
● Identifying the lineage is very important in treating leukemia
TUMOR SPECIFIC ANTIGENS ● Includes oncofetal or embryonic antigens that are normally expressed on
developing cells of the fetus but not on adult cells
● It is thought that genes encoding for these antigens are silent during the
● Unique to a tumor or shared by a limited number of patients with the same development of the embryo and malignant transformation causes them to
type of tumors be re-expressed
● Coded by viral oncogenes or by host proto-oncogenes or tumor suppressor
genes that have undergone mutations
○ Example: ONCOFETAL ANTIGENS
■ Philadelphia chromosome in CML (BCR-ABL gene)
● Some TSAs originate from point mutations in key genes involved in cell ● Carcinoembryonic Antigen (CEA)
proliferation ● Alpha-fetoprotein (AFP)
○ Examples include p53 gene and the gene encoding for Caspase 8 ● Prostatic Specific Antigen (PSA)
● These antigens can be found in the nucleus, cytoplasm, or plasma
membrane of the associated tumor cell OVEREXPRESSED ANTIGENS
● TSAs can also be produced by mutations induced by carcinogenic
chemicals and radiation
● Antigens that arise from genetic mutations that occur during transformation
which results in deregulated expression of these proteins
TUMOR ASSOCIATED ANTIGENS ○ Example:
■ Her2 protein (Human Epithelial Growth Factor Receptor 2)
● These are expressed in tumor cells and normal cells ● Important marker in the treatment of breast
● Tumor cells abnormally express these proteins or carbohydrate antigens in cancer
terms of their concentration, location, or stage of differentiation ● Not limited to breast cancer
● They are increased when tumor is present ● Glycolipid and glycoprotein antigens may be overexpressed in certain
● The normal cell still express this antigen but not that many tumors.
○ Examples:
■ Cancer Antigen 125 (CA-125) and Cancer Antigen 19-9
SHARED TSAs
(CA-19-9)
● Epithelial in origin
● These are expressed in many tumors but not in most normal tissues
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CLINICALLY RELEVANT TUMOR MARKERS cells (WBCs) WBC neoplasms
● Tumor Markers - Biological substances that are found in increased amounts Proteins Thyroglobulin (TG) Well-differentiated
in the blood, body fluids or tissues of patients with a specific type of cancer. Immunoglobulins (Ig) and Ig papillary or follicular
● These substances can be produced by the tumor itself or by the patient’s light chains (Bence Jones thyroid carcinoma
body in response to the tumor or related benign conditions proteins) Multiple myeloma and
● The concentration of a tumor marker in the serum depends on the degree of lymphoid malignancies
tumor proliferation, the size of the tumor mass, the proteolytic activities of
the tumor, or release of the marker from dying tumor cells Oncofetal antigens Alpha-fetoprotein (AFP) Germ cell carcinomas
● Tumor markers can be proteins, carbohydrates, oncofetal antigens, Carcinoembryonic antigen Hepatocellular carcinoma
hormones, metabolites, receptors, or enzymes (CEA) Colorectal, breast, or lung
cancer
TUMOR MARKERS
Carbohydrate CA 125 Ovarian cancer
antigens CA 15-3 Breast cancer
● Used for screening, diagnosis, or monitoring of treatment CA 19-9 Pancreatic and
● The concentration of a tumor marker in the serum depends on the degree of gastrointestinal cancers
tumor proliferation, tumor mass, the proteolytic activity of the tumor or
release of the marker from the dying tumor cell. Enzymes and Prostate-specific antigens Prostate cancer
● An elevated level of a tumor marker suggests that a significant amount of a isoenzymes (PSA) Bone and liver cancer
particular type of tumor is present. Alkaline phosphatase (ALKP) Neural tissue neoplasms
● Problem: there are elevation even if the patient has no cancer Neuron-specific enolase
IDEAL TUMOR MARKER
Hormones Human chorionic Germ cell carcinoma
gonadotropin (hCG) Trophoblastic tumors
● Should be produced by the tumor itself or by the patient’s body in response Calcitonin Medullary thyroid cancer
to the tumor (unique) Gastrin Pancreatic gastrinoma
● Be secreted into a biological fluid where it can be inexpensively and easily
quantified
● Have a circulating half-life long enough to permit its concentration to rise CLINICAL USES OF TUMOR MARKERS
with increasing tumor load
● Increase to clinically significant levels above the reference level while the
● Four major applications
disease is still treatable
○ Screening
● Have a high sensitivity
○ Diagnosis
● Have a high specificity
○ Prognosis
● Unfortunately very few of the tumor markers in clinical use are ideal because
○ Monitoring
they are not tumor specific
SCREENING
CATEGORIES OF CLINICALLY RELEVANT TUMOR MARKERS
Tumor Marker Class Examples Disease Associations ● Early detection of cancer significantly improves the survival rate
● Tumor markers can be used to screen asymptomatic patients
Cell surface markers Estrogen or progesterone Prognosis for hormone ● Pros:
receptors therapy in breast cancer ○ Screening asymptomatic patients can lead to earlier detection
CD markers on white blood Clonality and lineage of ○ Patients can also be reassured through a negative result
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● Cons: ● A significant decrease in the concentration of a tumor marker after surgery,
○ Tends to be expensive. chemotherapy, or other treatment indicates that the therapy has been
○ The possibility of a false negative result can occur. effective in shrinking the tumor
● The effectiveness for screening is dependent on the sensitivity of the test ● An increasing level of the marker after a return to normal indicates that the
and the prevalence of the disease in the population tumor has recurred and that more aggressive treatment may be needed
● Prostatic Specific Antigen
○ Was once highly touted because it is a good marker for prostate
cancer
○ However it is also increased when prostate enlarge (does not
necessarily mean there is cancer)
○ Not used alone
○ Should be accompanied by digital rectal exam
DIAGNOSIS
● Help physicians distinguish diseases with similar symptoms.

● Better used together with other tests, imaging and clinical data
○ Follow-up staining of the biopsy for tumor markers could help
determine the neoplasm’s tissue origin
● This figure above shows tumor marker levels from a hypothetical cancer
○ It is done in order to improve the sensitivity and specificity of the
patient who has been treated with surgery and two chemotherapy drugs
testing
○ As expected, the level of the tumor marker in the patient’s serum
● A tumor marker alone cannot diagnose a disease
declined after the initial tumor mass was removed by surgery
○ However, after a few months, the concentration of the tumor
PROGNOSIS marker began to increase, indicating that the tumor had recurred
● A high level of a particular tumor marker usually indicates that the tumor is
aggressive
● Tumor markers can also be used to determine the treatment modality that
best suits the patient
● Can also be indicators for effectivity of a drug
○ Example:
■ Her2 positive breast cancer patients can benefit from
trastuzumab
■ CML- imatinib
MONITORING RESPONSE TO TREATMENT
● Probably the most important use of a tumor marker at present

● If the tumor marker decreased after treatment then that can be an indicator
of response.
● This can be done because the level of a serum tumor marker often
correlates with the amount of tumor in the patient
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COMMON TUMOR MARKERS
NONCANCEROUS
MARKER CANCER(S) USES NORMAL SOURCES CONDITIONS WITH COMMENTS
ELEVATIONS
AFP Nonseminomatous Screening Fetal liver and yolk Pregnancy, non-neoplastic Screening conducted in high - risk populations for
testicular cancer germ cell Diagnosis and sac, adult liver liver disease liver cancer such as those with liver cirrhosis and
Liver staging chronic hepatitis.
Prognosis In germ cell tumors, both AFP and hCG are
Monitoring elevated.
β2-Microglobulin B lymphocyte malignancies Prognosis Part of class I MHC Inflammatory and high cell Higher levels imply poor prognosis in multiple
Monitoring molecule turnover conditions myeloma.
Calcitonin and Familial medullary thyroid Diagnosis Thyroid In hypercalcemia, Can be elevated in other forms of cancer.
Ca++ carcinoma Monitoring increased calcitonin is
expected. Serum Ca++ may
be low when calcitonin is
elevated in medullary
carcinoma.
CD Markers WBC Diagnosis All WBCs WBC increase such as Different CD markers are associated with specific
Monitoring infection WBC malignancies.
CEA Colorectal Prognosis Tissues of Renal failure, Values increased with age and in smokers.
Breast Monitoring endodermal origin non-neoplastic liver and
Lung intestinal disease, age
CA 125 Ovarian adenocarcinoma Screening Ovaries and various Endometriosis, pelvic Increases can occur during menstruation.
Diagnosis other tissues inflammatory disease, Screening is only recommended for women with a
Prognosis uterine fibroids, and family history of ovarian cancer.
Monitoring pregnancy
CA 15-3 Breast cancer Prognosis Mammary tissue Benign breast disease, CA 15-3 is a monoclonal antibody directed against
Can also be increased in Monitoring benign liver disease an epitope of epsilon.
pancreatic, lung, colorectal,
ovarian, and liver cancers
CA 19-9 Pancreatic Diagnosis Sialylated Lewisa Benign hepatobiliary and Can be elevated in some non-pancreatic
Prognosis blood group antigen pancreatic conditions malignancies. Subjects who are Lewisa and b
Monitoring negative persons cannot synthesize CA 19-9
ER/PR Breast adenocarcinoma Prognosis Breast N/A EP/PR+ breast cancers benefit from estrogen or
progesterone reduction therapy.
hCG Nonseminomatous Diagnosis Placenta Pregnancy hCG has a high homology with LH. Malignancies
testicular cancer germ cell Prognosis can produce free α and β chains as well as intact α
trophoblastic (hydatidiform Monitoring and β dimer. Immunoassays that detect only intact
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mole, choriocarcinoma) hCG should not be used for tumor marker

detection. In germ cell tumors, both AFP and hCG
are elevated.
HER2 (neu) or neu Breast Prognosis Growth factor gene in N/A Cancers associated with overexpression of HER2
all cells (neu) or neu have a good response to monoclonal
antibody therapy (trastuzumab).
Monoclonal free Ig Plasma cell, B lymphocytes Diagnosis Normal Igs are Monoclonal gammopathy Bence Jones proteins are free Ig light chains in
light chains Monitoring polyclonal. Few free of undetermined urine detected by urine immunofixation
Prognosis light chains exist. significance (MGUS), electrophoresis.
amyloidosis, nonsecretory
myeloma
Monoclonal Igs Plasma cell, B lymphocytes Diagnosis Normal Igs are Monoclonal gammopathy Monoclonal IgG/IgA → multiple myeloma
Monitoring polyclonal of undetermined Monoclonal IgM → Waldenström’s
Prognosis significance macroglobulinemia
PSA Prostate Screening No tissues other than UTI or prostatitis, benign Levels directly proportional to prostate size. Many
Diagnosis prostate prostatic hypertrophy elevations are benign or not clinically significant.
Monitoring Screening is routinely conducted in men aged 50
Prognosis and older, but is controversial.
Decreased percent of free PSA and PSA velocity
greater than 0.75 ng/mL/year are more strongly
associated with prostate cancer. Collect specimen
before ejaculation, digital rectal examination, or
prostate manipulation.
PTH and CA++ Parathyroid Carcinoma Diagnosis Parathyroid glands In hypocalcemia, increased PTH has a short half-life, so levels are done
Prognosis PTH is expected. Serum intraoperatively to ensure complete parathyroid
Monitoring Ca++ may be high when tumor removal.
PTH is elevated in
parathyroid carcinoma.
TG Thyroid Monitoring Thyroid TG reflects thyroid mass, Assays must simultaneously test for thyroglobulin
injury, and TSH levels. antibodies because these can cause falsely
Thyroid markers (T4, TSH) decreased results. Often tested after TSH
are generally normal in stimulation (or less often, by with-holding thyroid
thyroid cancer. medication) to see if TG production by residual
tumor cells occurs.
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● CA 125 testing, together with transvaginal ultrasound, is recommended for

SERUM TUMOR MARKERS women with a family history of ovarian cance.
CARCINOEMBRYONIC ANTIGEN (CEA)
ALPHA-FETOPROTEIN (AFP)
● This is a glycoprotein with a molecular weight of 180,000 to 200,000,
● Oncofetal Antigen depending on the exact structure of its carbohydrate side chains
● Abundant in fetal serum ● First oncofetal antigen discovered
● Frequently elevated in patients with Hepatocellular Carcinoma (HCC) and ○ In 1965, Gold and Freedman described its presence in tissues
Nonseminomatous germ cell testicular cancer (NSGC) from the fetal colon and colon adenocarcinoma
● Used to monitor, stage and prognose patients with HCC ● Increased concentration is associated with colorectal cancer
● Its use for screening purposes is still debatable but used in areas with high ● Increasing levels of CEA is highly sensitive for liver metastasis and can
prevalence of HCC detect recurrent colorectal cancer by an average of 5 months before clinical
● Testing for the L3 isoform is said to have a stronger correlation to HCC symptoms appear
● AFP’s sensitivity increases when tests for DCP, ALT and platelet count are ● Should be used in conjunction with clinical examination, imaging and
● done. histologic confirmation
● High levels of AFP tend to have a poor prognosis for patients with HCC ● Not recommended for colon cancer screening because of low sensitivity
● Used for NSGC and specificity
○ Sensitivity for NSGC increases when done with hCG and LDH ○ CEA is not increased in all patients with colorectal cancer and
○ High levels = poor prognosis elevated CEA levels can be present as a result of other conditions,
● Also used to monitor fetal abnormalities including colitis, diverticulitis, irritable bowel syndrome, and
○ High levels – neural tube defects nonmalignant liver disease.
○ Low levels – Down Syndrome ● Cigarette smoking can increase CEA levels
● Increased CEA levels are also seen in cancers of the lung, breast, pancreas
and other parts of the gastrointestinal tract
CANCER ANTIGEN 125 (CA-125)
HUMAN CHORIONIC GONADOTROPIN (hCG)

● This is a large, heavily glycosylated, mucin like protein that is a marker for
ovarian cancer.
● Popularly used as a tumor marker for ovarian cancer ● Known as the “pregnancy hormone”
● Not unique to ovarian tumors as it is also present in the normal ovary as well ○ because it is synthesized by trophoblasts, cells that contribute to
as other tissues such as endocervix, endometrium, fallopian tubes, pleura, development of the placenta and promote implantation of the
colonic epithelium, pancreas, lung, kidney, prostate, breast, stomach and embryo.
gallbladder ● hCG is a 45,000 MW glycoprotein that is composed of an α subunit, which
● Used for screening, diagnosis, prognosis and monitoring of ovarian cancer is shared by
● NV: 35 kU/L ○ Luteinizing hormone (LH)
● Generally not recommended for screening the general population for ovarian ○ Follicle-stimulating hormone (FSH),
neoplasms because it lacks sensitivity and specificity. ○ Thyroid-stimulating hormone (TSH),
● Non-specific ○ β subunit that is unique to hCG.1
○ Increases also in benign gynecological conditions such as ● Elevated in the first few weeks of pregnancy
endometriosis and other malignancies ● Associated also with germ cell tumors of the ovary and testes and
○ Also increases during pregnancy and menstruation choriocarcinoma
● Best used together with imaging studies and physical examination ● In the laboratory the beta subunit is the one detected as the alpha subunit is
● Rising CA-125 levels can predict tumor recurrence homologous with LH, FSH and TSH
● High levels (greater than 65 kU/L) has poor prognosis ● Increasing levels of hCG in a sequential manner is indicative of testicular
cancer
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○ Because hCG levels can also increase in men as the result of ● PSA plus histological observations of prostate biopsy can be used to predict
malfunction of the testes the stage of prostate cancer and guide physicians to the best treatment for
● Elevations of hCG can also occur as a result of gonadal suppression caused the patient
by chemotherapy and do not necessarily indicate tumor recurrence ● A rapid rise in PSA or the amount of time it takes to double are indicators of
a more aggressive disease
PROSTATE SPECIFIC ANTIGEN (PSA) ● A persistently high level of PSA after radical prostatectomy indicates
residual disease is present
● Once the tumor is removed the levels of PSA will decrease to undetectable
● It is a 28,000 MW glycoprotein that is produced specifically by epithelial levels
cells in the prostate gland.
● PSA was first discovered in semen, where its function is to regulate the
viscosity of the seminal fluid to facilitate mobility of the sperm cells. LABORATORY DETECTION OF TUMORS
● Widely used marker for prostate cancer
● Largely used for monitoring ● Three types of laboratory methods are routinely used for cancer screening
● Produced specifically by the prostate gland and diagnosis:
● Used in screening for prostate cancer but the practice became controversial ○ Gross and microscopic morphology of tumors
as patients with high levels somewhat underwent unnecessary treatment ■ Most of the time, it identifies the tumor even without the
● Also elevated in benign prostatic hyperplasia (BPH) help of other tumor markers
● Transient increases in PSA also occur after ejaculation, prostate ■ Histopathology
manipulation and digital rectal examination ○ Detection of tumor markers by immunohistochemistry or
● It aids in the diagnosis of prostate cancer automated immunoassays
● Testing now includes PSA-alpha 1-antichymotrypsin complex aside from ○ Molecular diagnostics
testing for free PSA alone which increases the specificity to prostate cancer ■ Confirm the result seen in microscopic morphology
● The proportion of free PSA is higher in benign conditions and the proportion ● The combination of these things makes the diagnosis more accurate
of complexed PSA is higher in malignant conditions
● PSA degrades quickly at temperatures above 4 degrees centigrade. TUMOR MORPHOLOGY
● Testing should be performed within 3 hours of sample collection or to store
the sample at -70 degrees centigrade if a longer interval is needed
● Calculation of the PSA velocity (PSAV) ● Tissue processing of the tumor (histopathology)
○ Calculated as the difference in the PSA concentration divided by ● H&E staining – gold standard in tissue diagnosis
the number of years spanning the interval between sequential tests ● Tumor marker antibodies, special stains and nucleic acid probes can
(reported as ng/mL/year) enhance visible features
○ The rationale for this approach is that the PSA will increase more
rapidly if a growing tumor is present. IMMUNOHISTOCHEMISTRY
○ PSAV greater than 0.75 ng/mL/year was shown to be strongly
associated with the presence of prostate cancer
● Helpful in identifying tumors that looks similar
● PSA density (PSAD)
● Uses labeled antibodies to detect tumor antigens in formalin-fixed tissues or
○ Rationale: An increase in serum PSA is more likely to be caused by
frozen tissue sections.
the occurrence of cancer in a man with a small prostate gland
● Before testing the formalin-fixed tissues should be treated with heat to make
versus a large prostate gland • Calculated as the ratio of the total
antigen epitopes accessible
PSA to the prostate gland volume.
● An unlabeled primary antibody specific for the antigen to be detected is
○ Downside: The need to perform transrectal ultrasonography can be
applied to the tissue section on a slide
costly
● Following an incubation and wash, a labeled secondary antibody directed
● Has an important role in the management of prostate cancer
against the Fc portion of the primary antibody is applied
● The label can be an enzyme such as peroxidase, alkaline phosphatase or
glucose oxidase
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● The indirect staining method is used because larger immune complexes are ○ The high-dose hook effect can result in a falsely decreased
formed, providing more sensitive amplification of the signal than is achieved measurement in the area of antigen excess
through direct staining ○ Solution: Dilute the specimen
● Fluorescent dyes can also be used (FITC, rhodamine or Texas red)
● Antigen-antibody reaction would produce color
● This offers a more dynamic range in visualizing the tissue
● Use of positive and negative control tissues is essential for accurate results
○ Negative controls are necessary to ensure that the staining
observed is because of antibody binding and not the background
(i.e., nonspecific reactivity)
○ Positive controls confirm that the antibody reagents are working
properly
● Immunohistochemistry is valuable in certain tumors that have almost similar
histomorphologic features
● Immunohistochemistry : Her2-neu for breast cancer
● Optimum area of the antigen should be achieved

○ High amounts of antigen would lead to zonal reactions
● Heterophile antibodies –capable of reacting with similar antigens from two
or more unrelated species
○ These antibodies usually have low avidity but can react with a
broad range of antigens
● Left: usually the brown color is peroxidase
○ Since animals are usually used to create the antibodies for the
reagent anti- animal antibodies present in the patient’s sample can
IMMUNOASSAYS FOR CIRCULATING TUMOR MARKERS interfere with the test
○ Can cause false elevation or false decrease
● Serum tumor markers are most commonly measured by immunoassays
because they are highly sensitive, lend themselves to automation, and are
relatively easy to use.
● Despite their advantages, immunoassays can be affected by several factors
● Factors to be considered:
○ Antibody reagents from different manufacturers vary greatly in
terms of what they detect, particularly if monoclonal antibodies are
used.
○ Thus the same method should be used in monitoring the tumor
marker levels
○ Although antibodies are employed for their specificity, it is not
absolute.
○ Antibodies will cross-react with similar structures
○ Antigen excess can affect the results of these tests (postzone ● To confirm the presence of interfering antibodies, the sample can be diluted
phenomenon) and the linearity of the results can be analyzed
● When the measurements exceed the linear range of reportable results this ● Specimens with interfering antibodies tend to exhibit nonlinear behavior.
phenomenon is called the high-dose hook effect
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MOLECULAR METHODS MICROARRAYS
● Genetic Biomarkers ● In this method, single-stranded DNA or RNA from the tumor is tagged with a
○ Essential for hematologic malignancies (e.g. Philadelphia fluorescent label and incubated with known nucleic acid sequences that
Chromosome) have been spotted onto different areas of a membrane.
○ Detection of gene rearrangements in certain lymphoid neoplasms ● The sample will hybridize to any complementary sequences on the tiny
to determine the lineage spots, allowing for simultaneous testing of the specimen for multiple genes.
○ MSH gene – Familial Colorectal Cancer ○ Aberrant sequences are unique to a particular tumor
○ Estrogen and Progesterone Receptors and Her2 – Breast Cancer. ● Microarrays can also be used to compare the levels of gene expression in
Useful to guide treatment cancer cells with those of normal cells by using two different colors of
○ Methods: FISH, Nucleic Acid Amplification Techniques, Microarray fluorescence to tag nucleic acid from each cell type
and DNA sequencing ● Microarray technology has been developed to test for panels of markers,
○ The aberrant DNA would produce an aberrant mRNA which will rather than individual mutations
produce an aberrant protein
■ With the current technology that we have today, aberrant NEXT GENERATION SEQUENCING
receptors may be characterized
■ Polymerase Chain Reaction: maps the aberrant DNA to
visualize the sequence that is faulty ● Thousands of genes within the tumor can be sequenced simultaneously in
○ Genetic biomarkers can also be used for prospective and post just a few hours to identify genetic variations
diagnostic evaluation of malignancies. ● Can also be used to detect metastases by analyzing DNA from tumor cells
■ Prospective markers can provide valuable information circulating in the peripheral blood
regarding the risk for an asymptomatic person to develop
a particular type of cancer, the growth rate of the cancer, PROTEOMICS
or the development of metastatic disease.
■ Post Diagnostic genetic markers are used to guide
● Analysis of the entire protein complement of a cell population
clinicians in making appropriate treatment decisions for
● Method: Tandem Mass Spectrometry
known cancer patients
● Surface-enhanced laser desorption/ionization mass spectrometry
CYTOGENETICS ● Antibody arrays
● The most common format uses beads that are coated with specific capture
● Karyotyping – To detect aneuploidy, deletions and rearrangements in the antibodies to bind the target proteins and streptavidin- or
chromosomes fluorescent-labeled detection antibodies that can be detected by flow
○ Karyotype analysis has been used for many years to detect the cytometry
chromosomal abnormalities associated with many cancers ● Proteomic methods may allow laboratories to identify unique patterns of
● FISH- can better visualize the rearrangements at a molecular level using proteins and their metabolites that are characteristic of particular types of
probes cancer. This process is called biomarker profiling.
○ Can be used to detect the Philadelphia Chromosome and the
Her2neu gene INTERACTIONS BETWEEN THE IMMUNE SYSTEM AND TUMORS
○ FISH is most often used to detect chromosome rearrangements
and gene amplification.
● One may ask the question “How does our immune system deal with these
tumor cells?”
● The initial theory that tried to explain this is immunosurveillance that runs in
the premise that our immune system is constantly monitoring our body for
References: PPT, Clinical Immunology and Serology: A Laboratory Perspective , Lecturer 3OMT | CASTILLO, C. | CASTILLO, E. | HERNAEZ | KASILAG | LAGMAN | ROSALES | TORRES |
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the presence of cancerous and precancerous cells and eliminates them ● Has a limited role in controlling the growth of tumors
before they become clinically evident ● Macrophages activated in vitro by IFNγ have been shown to possess
○ The cells that cannot transform should be killed tumoricidal capabilities
● The immunosurveillance theory was supported by observations that people ● If activated by Interferon Gamma, macrophages exhibit antitumor abilities
who are under immunosuppressive treatment had a higher risk of having ● They appear to kill cancer cells the same way they kill other microorganisms
cancer ● Macrophages produce Tumor Necrosis Factor-Alpha, a cytokine that is
● Also cancer is more prevalent in people 60 years old and above which thought to cause necrosis of tumors by inducing local inflammation and
further supports this theory. thrombosis in the blood vessels within the cancerous mass
● People who are immunosuppressed are prone to have cancer ● Generally, the significance of macrophages in the anti-tumor response
○ HIV+ remains not fully understood
○ Elderly
● Main cells involved: ADAPTIVE IMMUNITY: CYTOTOXIC T-LYMPHOCYTES (CTL)
○ Natural Killer Cells
○ Macrophages
○ Cytotoxic T-lymphocytes (CD8+) ● The primary mechanism of adaptive immunity against tumors is mediated by
○ T-helper lymphocytes (to a certain extent) cytotoxic T lymphocytes (CTLs)
● Antibodies and cytokines play a big role in the immune response to tumor ● Begins with an antigen presenting cell (APC, which is usually a dendritic cell)
● Tumor bearing individuals can also produce antibodies against tumor process tumor antigens in conjunction with class I MHC molecules
antigens. ● The APC presents the tumor-peptide antigen complexes to specific T-cell
○ These antibodies can kill tumor cells by inducing receptors (TCR) on the CTLs and provide co-stimulatory signals that
complement-mediated lysis or ADCC. promote the maturation of the CTLs
○ ADCC occurs when the antibodies coat the tumor cells and bind to ● The mature CTLs use their antigen specific TCRs to bind class I MHC
Fc receptors on the surface of the macrophages, NK cells or associated tumor antigens on the surface of the tumor cell.
neutrophils, stimulating them to release enzymes that can destroy ● Within minutes, their granules migrate toward the plasma membrane and
the tumor targets release cytotoxic proteins within the synapse formed between the CTL and
○ These mechanisms however are clear only in in-vitro studies the target cell
● Dendritic cells are also thought to activate CD4+ Th cells through
presentation of tumor antigens in conjunction with class II MHC molecules
NK-CELLS ○ The activated Th cells may play a role in tumor immunity by
secreting cytokines such as IL-2, which can promote CTL
● Able to kill cells without prior sensitization to tumor antigens development and enhance NK cell activity, and IFNγ, which
● They are activated to kill cells that lack class I MHC molecules which is a activates macrophages and increases class I MHC expression on
feature of transformed cells the tumor cell surface.
● Activating receptors on NK cells bind to tumor antigens or substances
released from the stressed tumor cells, initiating signals that promote CYTOTOXIC T-CELLS
degranulation and the release of perforin and granzymes which ultimately kill
the cell via apoptosis. ● Among the proteins released by the CTL is perforin which creates pores in
● NK cells may also participate in antibody dependent cell cytotoxicity (ADCC) the membrane of the tumor cell, and granzymes which enter the pores and
● in the presence of tumor antibodies cause apoptosis of the tumor target.
● NK cells are thought of to be most effective against malignant cells ● NKT cells – A cell that expresses surface antigens of both CTL and NK cells
circulating in the bloodstream during the early stages of tumor development are able to destroy tumor cells in a mechanism that is similar to CTLs but
● The activity of NK cells can be increased by incubation with IL-2 have a unique type of TCR that recognizes glycolipid antigens instead of
peptide antigens
MACROPHAGES
● Engulf aberrant cells
1st Shifting (A.Y. 2020 - 2021)
● Under selective pressure from immunologic forces of attack by cells in the
tumor microenvironment, some of the tumor cells may develop into genetic
T-HELPER CELLS variants that are resistant to immune defenses.
● These cells move past the equilibrium phase and enter the escape phase.
● Secretion of cytokines such as IL-2 which can promote CTL development

and enhance NK cell activity, and IFN-gamma which activates macrophages ESCAPE
and increases class I MHC expression on the tumor cell surface
● In this phase the balance between immunologic control and tumor
IMMUNOEDITING AND TUMOR ESCAPE development is tipped in favor of the neoplasm and tumor growth responses
even in the presence of anti tumor responses.
○ Interventions such as chemotherapy, surgery may be needed
● Despite the mechanisms of the immune system to attack tumor cells they ● Some of the escape mechanisms employed by tumors are a result of
still do manage to somehow escape these mechanisms changes in the edited tumor themselves which lead to reduced
● The theory of immunoediting attempts to explain such a phenomenon. immunogenicity.
● Immunoediting has three (3) phases: ● Some tumors, for example, downregulate the expression of MHC molecules
○ Elimination on their cell surface
○ Equilibrium ● Other modifications may involve defects in the components of the antigen-
○ Escape processing machinery associated with class I MHC molecules.
● Tumor antigens may also be masked by glycoproteins and glycolipids on the
ELIMINATION cell surface making them inaccessible to the immune system
● Other mechanisms:
○ Impaired surface binding of perforin
● Essentially the same as the immunosurveillance concept
○ Defective apoptosis-inducing molecules
● If the immunologic mechanisms involved in immunosurveillance are highly
○ Suppression of anti-tumor responses: Indirect recruitment of
effective, they will likely result in complete elimination of the tumor
T-regulatory cells, myeloid derived suppressor cells or
● If the immune surveillance is not adequate, the cancer/tumor cell will reach
macrophages that produce cytokines such as TGF-beta and IL-10
the next phase
which can inhibit protective immune responses
● The immunoediting hypothesis suggests that these cells will then enter the
● Through inflammation
equilibrium phase.
○ Chronic inflammation can change the cellular microenvironment in
ways that can promote tumor growth
EQUILIBRIUM
● The cancer cell are thought to enter a state of dynamic equilibrium with the
immune system which keeps the tumor cell under control so that they are
not clinically evident
● During this period, tumor cells may remain dormant or evolve slowly over
time.
● The dynamic interactions between the tumor and the immune system are
thought to shape the phenotype of the tumor and its ultimate outcome,
hence the term immunoediting.
● During this phase mutations can occur in the genetically unstable
transformed cells.
○ When the body is overwhelmed and can’t kill the cell, it would
contain the cell
■ Prone to mutate
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PASSIVE IMMUNOTHERAPY
● Expensive
● Involves the administration of soluble components of the immune system to
boost the immune response
● Two approaches to passive immunotherapy in cancer patients involve:
○ Administration of cytokines
○ Monoclonal antibodies
■ MAP
■ Tocilizumab- Covid19 patient
● Cytokines – small proteins that play an important role in regulating the
immune response by serving as chemical messengers.
● Two main applications
○ Used as hematopoietic growth factors
○ Therapeutic Agents
CYTOKINES
IMMUNOTHERAPY
● Hematopoietic growth factor (HGF)/ Colony Stimulating Factors
● In a nutshell, immunotherapy is basically harnessing the ability of the ○ Chemotherapy often suppresses the bone marrow thus decreasing
immune system to kill tumor cells WBC production which are vital for the immune response
● Classified into three (3) types: ○ HGF can be used to prevent this toxicity and to induce the bone
○ Active marrow to produce the much needed WBCs
○ Passive ○ Examples
○ Adoptive ■ GranulocyteColonyStimulatingFactor(G-CSF)
■ Granulocyte-MacrophageColonyStimulatingFactor(GM-CS
F)
■ Erythropoietin
ACTIVE IMMUNOTHERAPY
■ Interleukin-11
● Interferons (IFN)
● Patients are treated in a manner that stimulates them to mount an immune ○ IFN-alpha – most commonly used IFN for cancer therapy
response against their tumors ○ It is thought that IFN-a promotes anti-tumor effects by increasing
● Stimulation of the immune system tumor immunogenicity, enhancement of dendritic cell response,
● Examples: enhances Th1 responses and cell-mediated cytotoxicity, promoting
○ BCG for the treatment of urothelial (bladder) cancer tumor apoptosis and inhibiting angiogenesis
■ Bacille Calmette-Guerin: a vaccine that protects us from ● Interleukins (IL)
extrapulmonary tuberculosis ○ IL-2 is the most extensively studied IL
■ Stimulation of the immune system would help kill urothelial ○ It induces T-cell proliferation and enhancement of CTL and NK-cell
(bladder) cancer function
○ HPV vaccine for cervical cancer ○ Problem: Short half-life and some serious side effects
○ HBV vaccine for prevention of hepatocellular cancer ○ Used only in selected cases (e.g. some cases of melanoma)
■ Hepatitis B destroy hepatocytes
● The intensive repair process tends to create a
mutation that would lead to cancer
1st Shifting (A.Y. 2020 - 2021)
MONOCLONAL ANTIBODIES ● Lymphocytes from tumors are harvested and grown in culture and are
administered to the patient. These lymphocytes are thought to have a better
ability to respond to the tumor since they have been exposed to the tumor
● Monoclonal antibodies take a more specific approach to immunotherapy antigens
● These antibodies are derived from a single clone of cells, providing for an ● At present we can now select these lymphocytes, the only ones that can
abundant source of highly specific antibodies directed toward one particular react to the tumor antigen, and selectively culture that clone.
epitope of an antigen ● Downside:
● Generally directed against seven (7) major categories of antigens: ○ HLA typing- body may reject lymphocytes
○ CD antigens ○ Tends to be expensive.
○ Glycoproteins ○ Not all countries have the technology to do such.
○ Glycolipids
○ Carbohydrates
○ Vascular Targets
○ Stromal and Extracellular Antigens
○ Growth Factors
● Some monoclonal antibodies are directed against antigens found on the
surface of the tumor cells.
● These antibodies are believed to destroy the tumor through the same
mechanisms that are used to attack infectious organisms, namely
opsonization, complement-mediated cytotoxicity and ADCC.
● A second group of monoclonal antibodies target surface cell receptors
involved in intracellular pathways that lead to the growth and immortality of
cancer cells
● These antibodies block these known pathways of sustained growth leading
to “immortality”
● A third group of monoclonal antibodies targets antigens involved in
angiogenesis
● These antibodies are directed against vascular endothelial growth factor
(VEGF) ● FIGURE 17–8
● A fourth group boosts the immune response to the tumor by blocking ○ Adoptive immunotherapy with tumor-infiltrating lymphocytes (TILs).
inhibitory pathways that inactivate T-lymphocytes The patient’s tumor is surgically removed and cut into fragments,
● One strategy to increase the effectiveness of monoclonal antibodies involves which are cultured in vitro with IL-2.
linking them to potent cytotoxic drugs that can be taken up by the tumor ○ The cultures are screened for lymphocytes with potent anti-tumor
cells. These products are known as antibody-drug conjugates or activity.
immunotoxins. ○ Positive cultures are expanded further in the presence of IL-2 and
● Limitations to monoclonal antibody treatment: Hypersensitivity reactions are infused into the cancer patient.
○ Before infusion, the patient has been treated with high-dose
ADOPTIVE IMMUNOTHERAPY chemotherapy or radiation to deplete immunosuppressive cells.
● It was discovered that adoptive immunotherapy could be applied to the TABLE 17.8 CANCER IMMUNOTHERAPY USING MONOCLONAL ANTIBODIES
treatment of human cancer TARGET OF MECHANISM OF
● Cells from the immune system are provided to patients. EXAMPLES
THERAPY ACTION
○ Some treatments may combine different types of immunotherapy
● Involves transferring of cells of the immune system to the patient Surface antigens on Opsonization ● Rituximab, a MAb* directed
tumor cells Complement - against the CD20 antigen on B
44
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mediated cells; used to treat B cell 1. (True or False) T-helper lymphocytes have the biggest role in the immune
cytotoxicity neoplasms. response against tumor cells
ADCC ● Alemtuzumab, a MAb directed 2. These cells can kill tumor cells without prior sensitization of the target cell:
against mature lymphocyte ____________________
antigen, CD52; used to treat 3. Shaping of the phenotype of the tumor cell over time to eventually evade
chronic lymphocytic leukemia and the immune system is called: ___________________
T cell lymphomas 4. Enumerate the phases of immunoediting:
a. Elimination
Cell surface Block signalling ● Panitumumab, a MAb directed b. Equilibrium
receptors pathways involved against epidermal growth factor c. Escape
in cell proliferation receptor (EFGR), used to treat 5. The theory that can explain how the immune system responds to tumor
and survival colorectal cancer. cells: ____________________________
● Trastuzumab, a MAb directed 6. Infusing immune cells to the cancer patient is called:
against HER2, used to treat ____________________________________________
breast and gastroesophageal 7. These antibodies capable of reacting with similar antigens from two or more
tumors with overexpressed HER2. unrelated species:___________________________
8. (True or False). Majority of tumor markers have high sensitivity and
Antigens involved in Inhibit formation of ● Bevacizumab, a MAb directed
specificity
angiogenesis blood vessels against vascular endothelial
necessary for growth factor (VEGF); for
delivery of oxygen treatment of glioblastoma, colon,
and nutrients to the lung, and renal cancers.
tumor
Molecules that lock Enhance anti - ● Ipilimumab, a MAb directed

T-cell activation and tumor - specific T against CTLA-4; for treatment of
proliferation by cell responses by metastatic melanoma.
binding to molecules preventing T cell ● Nivolumab and Lambrolizumab,
on inhibition MAbs directed against
antigen-presenting programmed death 1 (PD-1); used
cells to treat melanoma, color cancer,
and other tumors.
Antibody-drug Deliver potent toxic ● Brentuximab vedotin, an

conjugates molecules directly immunotoxin directed against the
(immunotoxins) to tumor cells CD30 antigen; used to treat
directed against Hodgkin lymphoma and systemic
TSAs anaplastic large cell lymphoma.
● Trastuzumab-DM1, an
immunotoxin directed against the
HER2 antigen; for treatment of
HER2-positive metastatic breast
cancer.
POST-TEST
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UNIT 9D: TRANSPLANTATION IMMUNOLOGY

TYPES OF GRAFTS
I. Pre-Test
II. Transplantation 1. Autograft
a. Types of Grafts
b. Immunology of Allogeneic Transplantation ● Transfer of tissue from one area of the body to another of the same
c. Role of CD4+ and CD8+ individual.
d. Types of Allograft Rejection ● Examples:
e. Tissue and Organ Transplantation ○ Integumentary system - skin
f. Immune Privilege in Transplantation
g. Immunosuppression ○ Blood - autologous donation
III. Post Test 2. Isograft
Sources: ● Aka syngeneic graft, or syngraft (from lecture)
PPT; VIDEO ● Transfer of cells or tissues between individuals of the same species
who are genetically identical, i.e. identical twins.
3. Allograft
PRE-TEST ● Aka homograft
● Transfer of cells of tissue between two genetically disparate
1. T/F. The recipient of graft may also serve as his/her donor. individuals of the same species.
2. The type of transplantation where the donor is from another species. Xenograft ● Most transplants fall under this category.
3. A type of allograft rejection associated with vascular and parenchymal injury with 4. Xenograft
infiltration of lymphocytes. ● Transfer of tissue between two individuals of different species.
a. Hyperacute rejection
b. Acute rejection
c. Chronic rejection
d. All of the above
4. T/F. In kidney transplantation, the parents of the patient usually are the best donor
candidate. (nearest possible donors is/are your sibling/s)
5. A type of transplantation rejection which involves preformed antibodies within the
recipient. Hyperacute Rejection
TRANSPLANTATION
● Potentially lifesaving treatment for end-stage organ failure, cancers,

autoimmune diseases, immune deficiencies, and a variety of other diseases.
● Trying to remove what is already dead or not functioning and then replace it
with a functioning one.
● However, the HLA system is the major barrier for a successful
transplantation.
○ It is hard to find a compatible donor with the similar MHCs thus, the
nearest possible donor (best candidate) would be your sibling/s.
● The HLA disparity between donor and recipient that occurs with allografts
and xenografts will result in a vigorous cellular and humoral immune
response to foreign MHC antigens- this response is the primary stimulus
of graft rejection.
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IMMUNOLOGY OF TRANSPLANT REJECTION

GRAFT ACCEPTANCE AND REJECTION
COMPONENTS OF IMMUNE SYSTEM INVOLVED IN GRAFT REJECTION

1. Graft Acceptance
● Graft acceptance is highly dependent on MHC molecules
● Within 3-7 days after transplant, there will be revascularization and 1. Antigen Presenting Cells
afterwards the blood vessels will return and the tissue or organ will 2. B cells
become part of the system 3. T cells
2. Graft Rejection 4. NK cells
● Immunosuppressants are given so that there can be time for
resolution; gives time for the transplanted organ to be part of the
body
a. First-set rejection
● first time a graft is encountered and rejected
● Upon 7th-10th day cellular infiltration may occur where
macrophage can infiltrate and lead to thrombosis and
necrosis
b. Second-set rejection
● The organ is encountered the second time around
● Revascularization will not occur
IMMUNOLOGY OF ALLOGENEIC TRANSPLANTATION
● Recognition of transplanted cells that are self or foreign is determined by

MHC molecules.
● There should be recognition of the transplanted cells that are self or foreign
which is determined by the MHC molecule.
● Alloantigens elicit both cell-mediated and humoral immune responses.
1st Shifting (A.Y. 2020 - 2021)
similarities in the structure of the allo-HLA protein itself or to structural
similarities of allo-HLA protein + peptide.
● Virus-specific T cells may be an important source of alloreactive cells.
● Characterized by a high frequency of responding T cells compared with the
responder frequency in a typical T-cell response to a foreign antigen.
● Mixed Lymphocyte Reaction (MLR)
○ In vitro correlate of direct allorecognition
○ Lymphocytes from an individual needing a transplant are
incubated with lymphocytes from a potential donor that
have been inactivated so they cannot proliferate.
● A high level of radioactivity indicates that the recipient’s T cells have divided
in response to different HLA-D antigens on a potential donor’s cells and that
such a donor would be more likely to stimulate graft rejection.
RECOGNITION OF ALLOANTIGENS
DIRECT RECOGNITION
● Donor APCs directly present to the alloreactive T cells

● It involves the CD8 and CD4
○ MHC molecules presented by the APCs of the donor cells may be
recognized by the CD8 (Cytotoxic cell) and CD4 (Th cell)
● Recipient T cells bind and respond directly to foreign (allo) HLA proteins on
graft cells.
● Although an individual T lymphocyte can recognize self-HLA + peptide,
foreign HLA proteins may mimic a self-HLA + peptide complex because of
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INDIRECT RECOGNITION
● Donor’s MHC molecules is process by the APCs of the recipient.

● Allogeneic MHC is now considered as an antigen then it will be uptaken by
the recipient’s APCs.
● Allogeneic MHC
○ Exogenous antigen that is taken up by macrophage or dendritic
cells thus, it will be processed by the MHC Class II molecule and
afterwards presented to the T helper cells
● Indirect recognition only happens or involves the T helper cells because it is
processed by the MHC Class II molecules.
● Second pathway by which the immune system recognizes foreign HLA
proteins.
● Involves the uptake , processing, and presentation of foreign HLA proteins
by recipient APCs to recipient T cells.
ROLE OF CD4+ AND CD8+
● It is analogous to the normal mechanism of recognition of foreign antigens.
● May play a predominant role in induction of alloantibody and chronic
rejection. ● CD4+ differentiate into cytokine producing effector cells.
○ Damage graft by reactions similar to DTH.
● CD8+ cells activated by direct pathway kill nucleated cells in the graft.
● CD8+ cells activated by the indirect pathway are self MHC-restricted.
TYPES OF ALLOGRAFT REJECTION
1. Hyperacute - Fastest; within 24 hours

2. Acute - Within a week to months
3. Chronic - Spans into years
49
1st Shifting (A.Y. 2020 - 2021)
● Occurs within minutes to hours after the vascular supply to the transplanted
organ is established.
● Mediated by a preformed antibody that reacts with donor vascular
endothelium.
● ABO, HLA and certain endothelial antigens may elicit hyperacute rejection.
○ Antibodies may be present as a result of blood
transfusion, prior transplantation, or exposure of a
pregnant woman to fetal antigens of paternal origin.
● Binding of preformed antibodies to the alloantigens activates the
complement cascade and clotting mechanisms and leads to thrombus
formation.
○ Results to ischemia and necrosis of the transplanted
tissue.
● Seldom encountered in clinical transplantation
● Absence of donor HLA-specific antibodies is confirmed before transplant by
performing crossmatch test.
HYPERACUTE REJECTION
● Accelerated Rejection
○ Antibody-mediated rejection may take place over several
1. Preformed Ab days.
● Ab that are already presented in the circulation. ○ Occur in individuals who possess low levels of
● Transfusion of incompatible blood types. donor-specific antibody in the pretransplant period.
2. Complement activation ○ Involves intravascular thrombosis and necrosis of donor
● Interaction between the preformed Ab and antigen will activate the tissue.
complement which will result in lysis.
3. Neutrophil margination
ACUTE REJECTION
4. Inflammation
5. Thrombosis formation
● Follows the usual recognition of foreign substance and then produce
antibodies.
● It takes weeks to months because there will be processing unlike in
hyperacute where Ab is already present.
● The larger the tissue, the faster the rejection.
○ Immunosuppressants are usually given.
● Mediated by a cellular alloresponse (ACR) or by donor-specific antibody
(aka antibody-mediated response; AMR)
1. T-cell, macrophage and Ab mediated
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2. Myocyte and endothelial damage
3. Inflammation
● Results from a process of graft arteriosclerosis characterized by progressive

fibrosis and scarring with narrowing of the vessel lumen caused by
proliferation of smooth muscle cells.
● Most significant cause of graft loss after the first year post-transplant
because it is not readily amenable to treatment.
● Characterized by parenchymal and vascular injury. ● Predisposing factors that affect the development of chronic rejection:
● Interstitial cellular infiltrates contain a predominance of CD8+ T cells as well ○ Prolonged cold ischemia
as CD4 T cells and macrophages ○ Reperfusion injury
● CD8 cells: likely mediate cytotoxic reactions to foreign MHC-expressing ○ AR episodes
cells. ○ Toxicity from immunosuppressive drugs
● CD4 cells: likely produce cytokines and induce delayed-type ● Has an immunologic component, presumably a delayed-type
hypersensitivity (DTH) reactions. hypersensitivity reaction to foreign HLA proteins.
● Antibody may be involved in acute graft rejection by binding to vessel walls ● CYtokine and growth factors- secreted by endothelial cells.smooth muscle
and activating complement. cells, and macrophages activated by IFN gamma- stimulate smooth muscle
● The antibody induces transmural necrosis and inflammation as opposed to cell accumulation in the graft vasculature.
the thrombosis typical of hyperacute rejection. ● Alloantibody production contributes to the development of chronic rejection.
● Diagnostic criteria:
○ Characteristic histological findings TISSUE AND ORGAN TRANSPLANTATION
○ Deposition of the complement protein C4d in the peritubular
capillaries.
○ Detection of donor-specific HLA antibodies. Including:
1. Blood Transfusion
● Most common tissue transplanted
CHRONIC REJECTION 2. Bone marrow
3. Organs
1. Macrophage – T cell mediated 4. Tissues
2. Concentric medial hyperplasia
● Blood vessel lining is thickened BLOOD TRANSFUSION
3. Chronic DTH reaction
● Preformed Ab vs. Antigens present on the red cell surface

● Most preferred blood is that of the similar blood type
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GRAFT VS. HOST DISEASE
● Graft rejects the host

BONE MARROW TRANSPLANTATION
● Usually, the patient is already severely immunocompromised.
● The recipient can not fight the graft.
● Considered as one of the hardest transplantations as the bone marrow is the ● Cells produced by the bone marrow transplant would still identify that of the
source of blood. donor’s; Donor’s antigens will be recognized as self antigens.
● Used for Leukemia, Anemia and immunodeficiency, especially severe ○ If the donor bm produces a lymphocyte and circulates in the
combined immunodeficiency (SCID). recipient, it will recognize all cells as antigens and it will be
● About 109 cells per kilogram of host body weight, is injected intravenously activated.
into the recipients. ● If the individual’s immune system is competent enough, the recipient will
● Recipients of a bone marrow transplant are immunologically suppressed easily kill the lymphocyte.
before grafting. ● If the patient is severely immunocompromised, it won’t be able to fight off
the lymphocyte.
● Irradiation tries to kill the immune cells produced by the bm so that it won’t
be activated and avoid the graft vs host disease.
ORGAN TRANSPLANTATION
● Heart
● Lungs
● Kidney
● Liver
● Skin
IMMUNE PRIVILEGE IN TRANSPLANTATION
● Refers to the observation that tissue grafts placed in certain anatomical

sites, including the brain and eye, can survive for extended periods of time.
● Areas in the body that are not detected by the immune system thus,
transplantation is not easily recognized.
1st Shifting (A.Y. 2020 - 2021)
● Theory before is that these sites are protected by barriers that protect them IMMUNOSUPPRESSIVE AGENTS
from the immune system but later on found out that these areas have certain
mechanisms that prevent them from induction of immune response.
● Example: ● May be used in induction and maintenance of immune suppression and
○ Eyes treatment of rejection.
■ Lacks lymphatic vessels ● Combinations of different agents are frequently used to prevent graft
■ Low levels of MHC molecules infection.
■ High expression of CD59 and DAF - serves as inhibitors of ● Immunosuppressive state (and graft survival) induced by these agents
MAC comes at a price of increased susceptibility to infection, malignancies, and
○ Placenta other associated toxic side effects.
○ Testicles
○ Central nervous system 3 MAIN IMMUNOSUPPRESSIVE DRUGS
1. Cyclosporins
● Act by inhibiting T-cell activation, thus preventing T-cells from
attacking the transplanted organ.
2. Azathioprine
● Mitotic inhibitor
3. Corticosteroids
● Such as prednisolone suppress the inflammation associated with
transplant rejection.
● Potent anti-inflammatory and immunosuppressive agents used for
immunosuppressive maintenance.
● At higher doses, they are used to treat AR episodes.
● Act by blocking production and secretion of cytokines,
inflammatory mediators, chemoattractants and adhesion
molecules.
● These activities decrease macrophage function and alter
leukocyte-trafficking patterns.
● Long-term use is associated with hypertension and diabetes
mellitus.
● Some immunosuppressants are also used to treat a variety of autoimmune
diseases:
○ Azathioprine in treatment of rheumatoid arthritis
○ Cyclosporin is used in heart, liver, kidney, pancreas, bone marrow
and heart/lung transplantation
IMMUNOSUPPRESSION ○ Glatiramer acetate is used in treatment of relapsing-remitting
multiple sclerosis.
● Immunosuppression can be brought about by 3 different ways: ○ Mycophenolate is used to prevent the kidney problems associated
○ Surgical ablation with lupus erythematosus.
○ Lymphoid irradiation ○ Sirolimus used for the treatment of psoriasis.
○ Immunosuppressive drugs
CLASSES OF IMMUNOSUPPRESSIVE AGENTS
● Antimetabolites
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○ interfere with the maturation of lymphocytes and kill proliferating
cells.
○ Azathioprine
■ First agent employed
● Calcineurin inhibitors
○ Cyclosporine and FK-506 (tacrolimus) are compounds that block
signal transduction in T lymphocytes resulting in impaired synthesis
of cytokines (IL-2, IL-3, IL-4 and interferon gamma).
○ Inhibition of cytokine synthesis blocks the growth and
differentiation of T cells, impairing anti graft response.
● Monoclonal antibodies
○ Bind to cell surface molecules on lymphocytes are used at the time
of organ transplant and to treat severe rejection episodes after
transplantation.
○ Basiliximab and daclizumab
■ Both bind the CD25 (IL-2 receptor) and thus interfere with
the IL-2 mediated T-cell activation.
● Polyclonal antibodies
○ Thymoglobulin
■ An antithymocyte antibody prepared in rabbits
○ ATGAM
■ Polyclonal antiserum prepared from the immunization of
horses.
○ Both are potent immunosuppressive agents that deplete
lymphocytes from the circulation.
POST TEST
1. Which of the following transplantation scenario is least likely to have a

hyperacute rejection?
a. Mother of five children transfused with a kidney
b. An Rh negative individual transfused with Rh positive blood for the
first time
c. A man who had multiple transfusions but of same blood type
d. None of the above
2. T/F. The safest form of graft transplantation is autograft
3. The most common transplanted tissue
4. A form of allograft rejection that involves preformed antibodies
5. In the indirect recognition of alloantigens, which of the following T cells are
involved?
a. T helper cells
b. T cytotoxic cells
c. Both T helper and T cytotoxic cells
d. NK cells
1st Shifting (A.Y. 2020 - 2021)
UNIT 9E: IMMUNODEFICIENCY DISEASE TRANSIENT OF HYPOGAMMAGLOBULINEMIA OF INFANCY
I. Introduction
II. Deficiencies Of B-cell System ● At birth, IgG is about the same as adult level due to the maternal transfer but
III. Deficiencies Of Cellular Immunity slow decrease due to catabolism over 2-3 months
IV. Combined Deficiencies Of Cellular And Humoral Immunity ● For the first few months of age, own antibodies gradually rise in response to
V. Defects Of Neutrophil Function environmental stimuli
VI. Complement Deficiencies
VII. Laboratory Evaluation Of Immune Dysfunction ● Late increase in the levels of Immunoglobulins
○ IgM and IgA
Links ■ Not affected
PPT ■ IgM reaches the normal adult level at 1 year of age
Video
○ IgG
■ 2SD (standard deviation) levels below normal
■ Lasts 9-15 months of age
INTRODUCTION
● Signs and symptoms:
○ Pyogenic sinopulmonary and skin infection
● Components of the immune system play unique but overlapping roles in the
● This condition does not appear to be X-linked, although it is more common
host-defense process
in males.
● Interact extensively through many regulatory and effector loops
● Immunodeficiency Disorders
○ Decreases ability to defend against infectious organisms BRUTON’S AGAMMAGLOBULINEMIA
○ Increases susceptibility to develop certain types of malignancies
○ Clinical symptoms range from very mild/subclinical to severe ● Agammaglobulinemia - genetic defect in B cell maturation or mutation
○ Recurrent infections or failure to thrive may also happen leading to the defective interactions between B and T cells
○ Can be inherited or acquired secondary to other conditions such as ● X-linked
certain infections, malignancies, autoimmune disorders, and ● Deficiency/lack of all classes of immunoglobulins
immunosuppressive therapy ○ Lack circulating mature CD19+ B cells
○ Ineffective immune response ■ Pre-B cells in bone marrow but no peripheral cells in
○ Due to a missing or deficient component/s of the immune system lymphoid tissues
○ Secondary immunodeficiencies ■ The differentiation stops at pre-B cell stage due to the
■ Acquired immunodeficiency syndrome (AIDS), which is deficiency in Bruton’s tyrosine kinase
caused by the human immunodeficiency virus (HIV) ● Bruton’s tyrosine kinase (BTK) - enzyme responsible for the VH gene
○ Primary immunodeficiency (PIDs) rearrangement
■ Inherited dysfunctions of the immune system ● Treatment: IM/IV Ig
● Defect in one arm of the immune system may affect other aspects of
immune function
SELECTIVE IGA DEFICIENCY
● Deficiency of one component of the system is accompanied by hyperactivity
of other components
● Most common congenital immunodeficiency
● Most patients with IgA deficiency are asymptomatic
DEFICIENCIES OF B-CELL SYSTEM (AGAMMAGLOBULINEMIA)
● Impaired differentiation of lymphocytes to become IgA-producing peripheral
cells
1. Transient Hypogammaglobulinemia of Infancy
2. Bruton’s Agammaglobulinemia ○ 30-40% of patients develop anti-IgA antibodies
3. Selective IgA Deficiency ● Signs and symptoms:
4. Common Variable Immunodeficiency ○ Infections in respiratory and gastrointestinal tract
5. Isolated IgG Subclass Deficiency ○ Increased tendency to develop autoimmune diseases such as SLE,
Rheumatoid arthritis, and other immunodeficiency diseases
1st Shifting (A.Y. 2020 - 2021)
○ Allergic disorders and malignancy are also most common X-linked All antibody Pre-B cell Infancy
agammaglobulinemia isotypes reduced differentiation
COMMON VARIABLE IMMUNODEFICIENCY (CVI)
Reduced B cell; excess T Usually 20-30
Common variable antibody; many suppression years of age
● A heterogeneous group of disorders immunodeficiency different
● Most common primary immune deficiency with a severe clinical syndrome combinations
● The disorder can be congenital or acquired, or familial or sporadic, and it
occurs with equal frequency in men and women Reduced IgG1, Defect of isotype Variable with the
Isolated IgG subclass
● Deficiency in both IgA and IgG IgG2, IgG3, or differentiation class and degree
deficiency
○ Selective IgG deficiency may occur IgG4 of deficiency
Immunodeficiency Reduced IgG, B-cell switching Infancy
○ Recurrent bacterial infections (sinusitis, pneumonia)
with IgA, IgE, with
● 3 cellular defects:
hyperimmunoglobulin elevated IgM
○ T cells or their products appear to suppress differentiation of B
M
cells
○ T cells fail to help in B cell terminal differentiation
○ Primary defect in B cell line DEFICIENCIES OF THE CELLULAR IMMUNITY
● CVI is diagnosed by demonstrating a low serum IgG level in patients with
recurrent bacterial infections. ● T cells: cell-mediated immunity
● Treatment: IM/IV Ig 1. DiGeorge Anomaly
2. Purine Nucleoside Phosphorylase Deficiency
ISOLATED IgG SUBCLASS DEFICIENCY

DIGEORGE ANOMALY
● 1 or more of the IgG subclasses is below mean age-appropriate level (>2SD)

● Abnormal development of 3rd and 4th pharyngeal pouches
○ IgG4: most common
○ Affects thymic development in the embryo
○ IgG1: least
■ Quantitative defects in thymocytes
○ IgG1, IgG3: vs protein Ags (eg., toxins)
● Severe persistent decrease in mature T cells
○ IgG2, IgG4: vs carbohydrate Ags (eg., S. pneumoniae, H.
● Most patients with DiGeorge syndrome show a deletion in chromosome 22
influenzae)
region q11 (22q11.2 deletion)
DEFICIENCIES OF B-CELL SYSTEM (AGAMMAGLOBULINEMIAS) ○ Severe, recurrent viral and fungal infections
● Treatment:
○ Fetal thymus transplantation
CHARACTERISTICS OF SELECTED DEFECTS OF THE B-CELL SYSTEM
○ Bone marrow transplantation
LEVEL OF ○ Thymic hormone administration
CONDITION DEFICIENCY PRESENTATION
DEFECT
PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY (PNP)
Transient All antibodies, Slow development 2-6 months;
hypogammaglobuline especially IgG of helper function resolves by 2
mia of infancy in some patients years ● Affects enzyme involved in purine metabolism
● T cell count progressively decreases due to accumulation of
IgA; some with IgA-B cell Often deoxyguanosine triphosphate which is a toxic purine metabolite
IgA deficiency reduced IgG2 differentiation asymptomatic ● Rare autosomal recessive trait present in infancy
also
1st Shifting (A.Y. 2020 - 2021)
● Produces a moderate to severe defect in cell-mediated immunity with
normal or only mild impaired humoral immunity JAK3 DEFICIENCY (AUTOSOMAL RECESSIVE)
○ Recurrent or chronic pulmonary infections
○ Oral or cutaneous candidiasis ● T cell- B cell+ NK cell-
○ Diarrhea ● Affect both males and females.
○ Skin infections ● Deficiency in intracellular kinase JAK3 (required for processing interleukin
○ UTI binding signal from cell membrane to the nucleus)
○ Failure to thrive ○ No signal transmission from IL2 and IL4 in lymphocytes
● Symptoms are similar to the X-linked SCID
COMBINED DEFICIENCIES OF CELLULAR AND HUMORAL IMMUNITY

ADENOSINE DEAMINASE (ADA) DEFICIENCY
● Denoted by
○ T+-, B+-, NK+- ● T cell- B cell- NK cell-
1. Severe Combined Immunodeficiency ● Impaired proliferation of T and B cells due to accumulation of toxic
2. Wiskott-Aldrich Syndrome metabolites of purines
3. Acute Telangiectasia ○ Decrease lymphocyte
SEVERE COMBINED IMMUNODEFICIENCY (SCID) OMMEN’S SYNDROME
● Most serious of the congenital immune deficiencies ● T- B- NK+

● Group of related diseases that all affect T and B cell function ● Defect in RAG1/RAG2 (recombinase activating gene)
○ X-linked ○ These genes are for the DNA rearrangement necessary for the
○ JAK3 deficiency production of functional T and B cell receptors
○ ADA (adenosine deaminase) deficiency ● Lymphocytopenia is due to failure of T and B cells to produce functional
○ Ommen’s syndrome TCR and Immunoglobulin
● Generally present early in infancy with infection by nearly any type of
organism WISKOTT-ALDRICH SYNDROME
● Oral candidal yeast infections, pneumonia, and diarrhea are the most
common manifestations.
● Rare X-linked recessive syndrome
X-LINKED SCID ● Triad of symptoms
○ Immunodeficiency
● T- B+ NK+ / T- B+ NK- cell ○ Eczema
○ Depending on where or not there is an additional defect in JAK3 ○ Thrombocytopenia (with decreased size)
gene ● High serum alpha-fetoprotein
● Most common ● Immunodeficiency
● No Ab production or lymphocyte proliferation response follows an ○ Lymphocytes and platelet have abnormal CD43 (protein
Ag/mitogen challenge glycosylation)
● Abnormal IL2RG ■ Abnormal signal transduction and defective actin
○ Codes for common gamma chain polymerization
■ Common receptors for IL2, 4, 7, 9, 15, 21 ○ Absence of isohemagglutinins (e.g., IgM Abs to ABO)
■ Defective receptors with common gamma chains ● Usually lethal in childhood because of infection, hemorrhage, or malignancy
○ Normal signalling does not occur ● WAS gene
○ The gene responsible for the defect.
1st Shifting (A.Y. 2020 - 2021)
○ Located on the X chromosome, region p11. RAG1/2; JAK3;
common gamma
chain receptor
WAS Reduced IgM and CD43 expression Usually infancy;

ATAXIA-TELANGIECTASIA
T-cell defect mild variants occur
● Rare autosomal recessive syndrome characterized by: AT Reduced IgG2, IgA, DNA instability Infancy
○ Cerebral ataxia - involuntary muscle movement IgE, and T
○ Telangiectasia - capillary swelling resulting in red patches on skin lymphocytes
especially in the earlobes and conjunctiva
Reticular All leukocytes Stem cell defect Neonatal
● Blunt Ab response to Ags, especially polysaccharides
dysgenesis
○ Low or absent IgG2, IgA, IgE
● Decreased circulating T cells
○ Rearrangement of TCR and IgG genes does not occur DEFECTS OF NEUTROPHIL FUNCTION
○ Usually occurs in early adults from either pulmonary disease or
malignancy 1. Chronic Granulomatous Disease
● Treatment: 2. Neutrophil G6PD deficiency and myeloperoxidase deficiency
○ Bone marrow transplant/cord blood stem cells 3. Leukocyte Adhesion Deficiency
● AT gene
○ Located on chromosome 11, region q22. CHRONIC GRANULOMATOUS DISEASE (CGD)
COMBINED DEFICIENCIES OF CELLULAR AND HUMORAL IMMUNITY ● A group of disorders involving inheritance of either an X-linked or autosomal
recessive gene that affects the neutrophil microbicidal function
● Most common and best characterized of the neutrophil abnormalities
CHARACTERISTICS OF SELECTED DEFECTS OF THE T-CELL SYSTEM AND ● Inability of neutrophil to produce reactive forms of oxygen necessary for
COMBINED DEFECTS bacteria killing
CONDITION DEFICIENCY LEVEL OF PRESENTATION ○ No oxidative (respiratory) burst
DEFECT ○ Diagnosed by measuring the ability of the patient’s neutrophil to
reduce the nitroblue tetrazolium dye
DiGeorge anomaly T cells; some Embryological Neonatal, with ● Symptoms:
secondary effects development of the hypocalcemia or ○ Recurrent suppurative infections
on antibody thymus cardiac defects if ○ Pneumonia
production severe; incomplete ○ Osteomyelitis
forms may be ○ Draining adenopathy
present later with ○ Liver abscesses
infection ○ Dermatitis
○ Hypergammaglobulinemia
PNP deficiency T cells; some PNP, purine Infancy
● Treatment:
secondary effects metabolism
○ Bone marrow transplant/PBSC
on antibody
○ Granulocyte transfusion
production
○ Cytokine administration
SCID Both T and B cells ADA, purine Infancy ○ Antibiotics
metabolism; HLA
expression; NEUTROPHIL GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
1st Shifting (A.Y. 2020 - 2021)
LABORATORY EVALUATION OF IMMUNE DYSFUNCTION

● Inability to generate enough NADPH
○ Defect in hydrogen peroxide production
● Screening Tests
○ Causes G6PD deficiency
● Confirmatory Tests
● Increased susceptibility to recurrent bacterial infection in children with
● Evaluation of Immunoglobulins
severe neutrophil G6PD deficiency which is a consequence of decreased
NADPH production
● Patients are prohibited from consuming soy products since these lower SCREENING TESTS FOR IMMUNODEFICIENCIES
platelet levels and causes fever
SUSPECTED DISORDER TESTS
MYELOPEROXIDASE DEFICIENCY
All immunodeficiencies Complete blood cell count, white blood cell
Humoral immunity differential count
● Autosomal recessive genetic disorder Serum IgG, IgA, IgM levels, IgG subclass levels,
● Featuring either in quantity or function of myeloperoxidase isohemagglutinin titers (IgM), IgG antibody response
● Myeloperoxidase to protein and polysaccharide antigens
○ Enzyme expressed by neutrophils
○ Secondary granules Cell-mediated immunity Delayed hypersensitivity skin tests (i.e., candida,
○ Uses hydrogen peroxide to produce hypochloric acid diphtheria, tetanus, PPD)
● Signs and symptoms: Chest X-ray (thymus shadow)
○ Recurrent candidal infections
Phagocyte defect NBT test
LEUKOCYTE ADHESION DEFICIENCY IgE level (hyper-IgE syndrome)
Complement CH50 (classical pathway)

● Abnormal adhesion, motility, aggregation, chemotaxis, endocytosis
Serum C3 level
○ LAD-1
■ Defective CD11/CD18
● Neutrophils, monocytes, T cells
SCREENING TESTS FOR IMMUNODEFICIENCIES
■ Deficiency in CD18 which is a component of adhesion
receptors on neutrophils, monocytes, and T cells SUSPECTED DISORDER TESTS
○ LAD-II
■ Deficient CD15s or sialyl Lewis X Humoral immunity B cell counts (total and IgM, IgD, IgG, IgA-bearing)
● Neutrophils B cell proliferation in vitro
● Clinically manifest as delayed wound healing, chronic skin infections, Histology of lymphoid tissues
intestinal and respiratory tract infections, and periodontitis Cell-mediated immunity T cell counts (total and helper-suppressor subsets)
T cell functions in vitro
COMPLEMENT DEFICIENCIES Enzyme assays (ADA, PNP)
Phagocyte defect Leukocyte adhesion molecule analysis (CD11a,

● C1q, 2, 4: lupus-like syndrome CD11b, CD11c, CD18)
● C2: most common complement deficiencies Phagocytosis and bacterial killing assays
● C3: lupus-like with recurrent encapsulated organism infections Chemotaxis assay
● CD5-9: recurrent Neisserial infections Enzyme assay (myeloperoxidase,
● C1 esterase inhibitor: hereditary angioedema glucose-6-phosphate dehydrogenase, components of
NADPH oxidase)
1st Shifting (A.Y. 2020 - 2021)
Complement Other specific component assays ○ Measure response to MTB Antigen

● Cylex ImmuKnow
○ Measures total T-cell activity.
SCREENING TESTS ○ Measures T cell response to phytohemagglutinin (PHA)
■ ATP production
● Most of these tests can be performed routinely in any hospital laboratory.
● The evaluation of possible immunodeficiency starts with a patient history, EVALUATION OF IMMUNOGLOBULINS
followed by CBC and WBC differential.
● Tuberculin Skin Test
○ Defects in cell-mediated (T cell) immunity SERUM ELECTROPHORESIS (SERUM PROTEIN ELECTROPHORESIS/SPE)
● CH50 Assay
○ Determination of level of functional complement ● Immunoglobulins are separated based on size and electrical charge
○ Undetectable CH50 levels may indicate a deficiency of a specific ○ IgG, IgM, IgD, IgE: gamma region
component. ○ IgA: overlapping the beta and gamma regions
○ Low CH50 levels may be caused by complement consumption and ● Allows reproducible separation of the major plasma proteins.
do not, by themselves, indicate a complement deficiency. ● Additional evaluation of serum immunoglobulin is performed if the SPE
● Nitro-Blue Tetrazolium (NBT) Reduction Test shows a monoclonal component or if there is a significant quantitative
○ Ability of neutrophils to reduce NBT (blue) to nearly colorless abnormality of serum immunoglobulins.
through oxidative burst (production of oxygen products)
○ CGD patients -> remain blue
IMMUNOFIXATION ELECTROPHORESIS
CONFIRMATORY TESTS
● Serum proteins are electrophoresed
● Specific antibodies allow to bind on the separated proteins
FLOW CYTOMETRY ● Interpret band formation
○ Diffuse: polyclonal immunoglobulin
● Enumeration of classes and subclasses of lymphocytes through CD markers ○ Narrow, intense: monoclonal
○ CD19: B cells ● Lack of bands indicates immunodeficiency of one or more immunoglobulin
○ CD3: T cells classes.
■ CD3/CD4: Th cells
■ CD3/CD8: Tc cells BONE MARROW BIOPSY
○ CD16 or CD56: NK cells
● Eg., low CD19 -> suggests Bruton’s agammaglobulinemia ● Monoclonal gammopathy
● Objective and quite reliable in detecting defects that result in a decrease in ● Immunodeficiency state
one or more types of lymphocytes.
T-CELL FUNCTION (CLASSICAL) POST TEST
● Thymidine uptake quantification 1. Most serious of the congenital immune deficiencies.

● Increased value means cell division and activation 2. Abnormal development of 3rd and 4th pharyngeal pouches.
3. Inability of neutrophil to produce reactive forms of oxygen necessary for
bacterial killing.
T-CELL FUNCTION (AUTOMATED) 4. Impaired proliferation of T and B cells due to accumulation of toxic
metabolites of purines.
5. Defective CD11/CD18
● QuantiFERON TB assay and T-spot
60
1st Shifting (A.Y. 2020 - 2021)
■ Chemokines attract the cell at the site of infections and
UNIT 10: IMMUNOMODULATION the regulatory cytokines (eg. interleukin) helps control the
I. Immunomodulation inflammation
a. Immunomodulators ● Proinflammatory and antiviral cytokines induced by immunomodulators
b. Non-specific immunomodulation by IV immunoglobulin such as OM-85 as part of the innate response include IL-1β, IL-6, and tumor
c. Monoclonal antibodies for specific immunomodulation necrosis factor α, and IL-12, interferon (IFN)-α, IFN- β, IFN-γ, respectively.
Links ● Bacterial lysate immunomodulators also induce cytokines related to the
PPT adaptive immune system including the B cell-activating cytokines IL-10, B
Video cell activating factor (BAFF), and IL-6.
○ The activation of the adaptive T helper cell and B cell classes of
immunomodulators has been demonstrated as the immunoglobulin
PRE-TEST response cascade of rapid IgM production, followed by IgA and
IgG.
1. Drugs that either suppress or stimulate the immune system ○ Alongside IgA, which is central to the mucosal immune response,
2. Substances that stimulate the immune system by inducing activation and IgG has the advantage of being more widely distributed and
increasing the activity of any of its components. providing a longer humoral memory response.
3. Suppress the immune system ● The immunoregulatory effects of bacterial lysate immunomodulators involve
maturation of both plasmacytoid and myeloid dendritic cells, indicated by
the presence of T cell regulatory proteins CD80 and CD86.
IMMUNOMODULATION
IMMUNOMODULATORS
● Change in the body's immune system, caused by agents that activate or
suppress its function.
● Immunomodulation by bacterial lysates involves both induction of immune ● Drugs that either suppress or stimulate the immune system
system effector cells and activation of immunoregulatory cell classes.
○ This effect mirrors commensal microorganisms which both IMMUNOSTIMULANTS
stimulate immune system maturation and reduce allergic
sensitization.
● Are substances that stimulate the immune system by inducing activation
○ Bacterial lysates immunomodulators induce immune effector cells
and increasing the activity of any of its components.
hence reducing the infection and activates the immunoregulatory
● They are used in disorders which include immunodeficiency diseases,
cells thus reducing inflammation.
malignancy, viral, fungal and certain autoimmune disorders.
● Evidence from in vitro, in vivo, and human trials indicates that the
immunomodulatory effects of bacterial lysates induce effector cells in both
the innate and adaptive immune system and their respective regulatory IMMUNOSUPPRESSION/IMMUNOSUPPRESSANTS
dendritic cell and regulatory T and B cell populations.
● Much of the immunomodulatory response is dependent on the previously ● Cytotoxic agents
mentioned TLR, expressed on epithelial cells, dendritic cells, macrophages, ● Inhibition of lymphocyte signalling
monocytes, and T and B lymphocytes. ● Cytokine inhibitors
○ TLR (toll-like receptor) ● Depletion of specific immune cells
■ Class of proteins that plays a role in the innate immune ● Blockade of cell adhesion
system. ● Inhibition of complement activation
■ The type of TLR that is activated determines the
downstream activity, thus the production of cytokines is
based on immunoinflammatory responses against the NON-SPECIFIC IMMUNOMODULATION
pathogen.
● Facilitated by intravenous immunoglobulin.
1st Shifting (A.Y. 2020 - 2021)
● Immunoglobulin replacement is essential for patients with primary antibody
deficiencies and of proven value in several forms of secondary
hypogammaglobulinemia.
● Beneficial effect of IVIG ,which has been established by control trials against
the placebo or conventional treatment in several disorders.
○ Benefit has been claimed in open trials which provides inclusive
evidence for general use.
○ Mechanism of IVIG as the treatment of choice against Kawasaki
disease in children is unknown.
■ Neutralization of the unknown infectivity plays a role in the
treatment of Kawasaki disease.
● IVIG raised the platelet count in two hypogammaglobulinaemic children with
idiopathic thrombocytopenia inspired a new approach to the therapy of
autoimmune disease.
MONOCLONAL ANTIBODIES
● Used for specific immunomodulation.

● A wide array of monoclonal antibodies have been developed with the aim of
interrupting interaction between antigen-presenting cells, T cells and B
cells though not all have been either safe or efficacious.
○ A major concern using monoclonal antibody is potential for
triggering reactions after repeated usage.
■ The production of human monoclonal antibody by
transforming B cells with Epstein Barr virus or fusing
antibody producing with human cell lines has overcome
this problem.
● The use of antitumour necrosis factor antibodies (anti- TNF) as a
therapeutic agent is an excellent example of targeted immunotherapy.
○ Used in some autoimmune diseases
■ Immuno IVIG
● Several approaches are available for pharmacologic suppression of
immunity ranging from the relatively low-specificity approaches to the more
specific cell- signalling inhibitors and antibody therapies.
● Immunostimulants are used in immunodeficient people and also improve the
resistance to infection.
○ Immunomodulators are used to treat autoimmune diseases (ie.
immunostimulants and immunosuppressants)
○ The mechanism of some drugs are unknown
○ Most common: IVIG

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IMMUNOLOGY SEROLOGY LECTURE

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D RE 2022

Demons ra ed ha diph heria & Based on he ass mp ion ha

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D RE 2022

prod cing cell ha prod ces I F

FO P3 - ​The gene direc ing reg la or T-cell

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D RE 2022

430 BC Th c dides Recogni ion of imm ne s a s

1798 Ed ard Jenner Smallpo accina ion

1862 Haeckel Erns Phagoc osis

Fa he fI l g ​; li e a en a ed accine, an hra accine, chicken

1885 Therape ic accina ion; Firs li e a en a ed accine for rabies

1883-1905 Elie Me chnikoff Cell lar heor of imm ni

1891 Rober Koch Demons ra ed c aneo s (dela ed- pe) h persensi i i

1900 Pa l Ehrlich An ibod forma ion heor / side chain heor

Nicolas Ma rice Ar h s Ar h s reac ion of immedia e h persensi i i

1944 Pe er Brian Meda ar Fa he fTa la a i ;​ Allograf rejec ion

1949 Jonas Salk & Alber Sabin Polio accine

1951 Wal er Reed Yello fe er li e a en a ed accine

1953 Dick W. Van Bekk m Graf - s-Hos reac ion

B rne Clonal selec ion heor

1958-1962 Jean Da sse H man le koc e an igen (HLAs)

Pablo DT Valen ela Monoclonal hepa i is B accine

2001 FO P3 ​gene (direc s reg la or T-cell de elopmen )

2005 Ian Fra er HPV accine

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D RE 2022

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

Al h gh i i ec i e in na e, in me ca e i All imm ne cell ld be c ming f m a c mm n ance -

CELLS of he IMMUNE SYSTEM

Cell f nd in ​ e i he al bl d​: ​monoc e, ne ophil,

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

3. Le k iene B4 P ein 1 Chem a in a e elea ed d e

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

agen / m b ec e ing in e fe n 𝝲 Eo inophil Ba ophil Ma Cell

Inna e Imm ne F nc ion Adap i e Imm ne F nc ion Relea e inflamma media ha

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

Mac hage , B-cell , Va c la End helial NATURAL KILLER CELLS

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

he NK cell de ec (cell d cing e ADCC (An ibod Dependen Cell-media ed C o o ici )

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

Addi ional no e f om i Al in: P ec cell: ​l mphoid em cell

ONTOGENY OF T & B CELLS

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

F nd healing & ec i n d ced b med lla e i helial

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

- In e ac i h ​MHC c a I ​m lec le he e CD4+ cell can al ac i a e CD8+ cell

Remembe :​ T-c ic cell in e ac i h cell ha ing MHC

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

P ec cell: ​L mphoid S em Cell CD40 and MHC cla 2 im an f he

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

Once he ma e B-cell mee an an igen, i bec me

Addi ional no e f om i Al in:

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

L ca ed in ge minal cen e in e i he al l m h id gan

FOLLICULAR DENDRITIC CELLS Bi h lace f all hema ie ic em cell ( ed b ne ma )

DUNGCA, M. CASTILLO, J. FELISILDA, J. 3D REVS 2022

Th mic c ical EC - able d ce IL-7 L m h fl l l h gh in e lined i h mac hage

FO P3 - The gene direc ing reg la or T-cell

Fa he fI l g ; li e a en a ed accine, an hra accine, chicken

1944 Pe er Brian Meda ar Fa he fTa la a i ; Allograf rejec ion

2001 FO P3 gene (direc s reg la or T-cell de elopmen )

Cell f nd in e i he al bl d: monoc e, ne ophil,

Addi ional no e f om i Al in: P ec cell: l mphoid em cell

- In e ac i h MHC c a I m lec le he e CD4+ cell can al ac i a e CD8+ cell

Remembe : T-c ic cell in e ac i h cell ha ing MHC

P ec cell: L mphoid S em Cell CD40 and MHC cla 2 im an f he

Cen al c llec ing in f l m h fl id f m adjacen i e Addi ional no e f om i Al in:

EXTERNAL BARRIERS TO INFECTION (1 Line) INNATE DEFENSE SYSTEM

E e nal Defen e S em - h ical, chemical, and

C-Reac e P e (CRP) - n n- ecific

Ca dinal Sign of Inflamma ion (ac e ch nic a he

8. (Ide ) Collec i el , hi efe o he imm ne Ce l la min

Th m dependen Si ae e e i h he he f The e di a a ica he ce f he

CLASS I MHC Thi i he bi di g i e f he e ide i h 8-11

Lef : Fab egi i c ed f he i g b i f d he e C alli able F agmen (Fc)

IgG4 (4%) - accha ide a ige