HUMORAL IMUNE

RESPON

SUHERMAN
Magister kedoteran tropis
Universitas sumatera utara

Adaptive Immunity
Adaptive immune system has two arms

Adaptive
Immunity
Cell mediated
Humoral Immunity
Immunity

Provided by B lymphocytes
Can recognize protein,
polysaccharide, phospholipid
and nucleic acid antigens
Can act against soluble or
free antigens
Provides immunity to
extracellular bacteria, viruses
and toxins
Causes Type I, II & III
hypersensitivity

Provided by T lymphocytes
Can recognize only protein
antigens
Recognizes antigens
presented by APCs with
Class I or Class II MHC
molecule
Provides immunity to
intracellular bacteria,
viruses, fungi and protozoa
Causes Type IV

Humoral Immune Response

B cells
Maturation/ Ontogeny

Variable, D= Diversity, J= Joining segment of Ig gene, H= Heavy chain, L= Light

Humoral Immune Response

B cells
Nave

B cells express membrane bound immunoglobulin

(mIg)
Mature B cells express mIgM and mIgD on their surface
mIgM acts as antigen receptor called B cell receptor (BCR)
Each B cell contains 105 BCRs, all specific for a single
epitope
Each clone of B cell is specific for a single epitope
109 clones of B cells can recognize 109 epitopes

Humoral Immune Response

B cell activation
Mature

B cells circulate in the blood and lymph

and are carried to the secondary lymphoid
organs e.g. lymph nodes and spleen
Antigens are also carried by blood or lymph to
the secondary lymphoid organs
B cells usually meet their specific antigens in
these organs
An antigen binds to a B cell (or a clone of B cells)
which carries mIgM specific for that antigen and
activates it (clonal selection)
B cell activated by an antigen starts to
proliferate and increase number of cells (clonal
expansion)

Humoral Immune Response

B cell activation by TD and TI B cell antigens

TD= TH

Binding of a
Binding of a TD antigen with mIgM on
B cell surface provides stimulatory
TI antigen with
signal (1)
mIgM on B cell
Antigen is internalized & presented to
surface
TH cell
activates the B
CD40 on B cell also bind to CD40L on
cell specific for
TH cell that provides costimulatory
cell dependent,
TI=
T
cell
independent
it
signal (2)
H

These two signals and cytokines from

Thymus dependent antigens require B cells to have direct contact with T

helper cells in order to form antibodies. This is how a typical humoral
immune response is carried out in the case of most antigens. An APC
presents antigen to a T helper cell, the T helper cells can then present
antigen to the B cell and it is activated to produce antibodies.
Thymus independent antigens activate B cells by other mechanisms. They
can be bacterial cell wall components, like lipopolysaccharides. These are
called TI-1 Antigens. Or they can be highly repetitious molecules, like the
proteins that make up bacterial flagella. These are TI2-Antigens.
TI-1 antigens are polyclonal B cell activators, meaning they can activate B
cells regardless of their antigenic specificity. For example,
lipopolysaccharide is a component of gram negative bacterial cell walls. It
can interact with TLR4 on the surface of B cells. The activation of the B cell
by LPS binding TLR4 produces a diverse collection of antibodies to be
produced, many of which may interact with the gram negative bacteria.
TI-2 antigens activate B cells by linking the membrane bound
immunoglobulin expressed on the surface of the B cell. This bypasses the
need for T cells to activate the B cell to produce antibodies, (But the
cytokines released from the T cells are useful for proliferation or to signal
immunoglobulin class switching).

Humoral Immune Response

B cell activation by TD and TI antigens

Humoral Immune Response

Antibody production
Plasma cells secrete antibodies
Secreted antibodies have the same
specificity as the mIgM on the surface of B
cell from which the plasma cell is derived
Antibodies are the effector molecules of
humoral immune response that bind with
the antigen and eliminate the microbe
Initially plasma cells secrete IgM antibody
Within a few days antibody class switching
occurs and they secrete IgG (or IgA or IgE)
Memory B cells have a long life span and
provide heightened immune response if
the person encounters the same antigen in
future

12

Clonal Selection
Only one type of
antibodyand one
type of B cell
responds to the
antigenic determinant

That cell type

then produces a
large number of
clones
Dr.T.V.Rao MD

Humoral Immune Response

Antigen Elimination

Antibodies eliminate antigens

by
1. Neutralization of toxins and
viruses
2. Complement activation
followed by
a. Cytolysis
b. Opsonization and
phagocytosis
c. Immune complex
clearance

Opsonisasi (Enhanced
Attachment)
15

Ab:

IgG, IgE dan komplemen: C3b, C4b

menempelkan (attach) antigen ke fagosit
fagositosis >> efisien.

A. Opsonisasi oleh IgG, C3b, dan C4b:

1. IgG atau IgM dibentuk untuk melawan Ag
permukaan (surface Ag) organisme atau sel
yg akan difagositosis Fab dari Ab tersebut
bereaksi dgn epitop Ag Fc dari IgG
berikatan ke neutrofil & makrofag
menempelkan Ag ke fagosit fagosit aktif

16

2. IgG & IgM juga dapat mengaktifkan jalur klasik

komplemen C3b atau C4b menempelkan Ag
ke fagosit.
IgG, C3b & C4b berfungsi sbg opsonin (dpt.
menempelkan Ag ke fagosit).
Satu porsi/bagian C3b berikatan ke protein &
polisakarida di permukaan mikroba; porsi lainnya
menempel ke reseptor CR1 di fagosit, limfosit-B,
dan sel dendritik untuk meningkatkan fagositosis.

Opsonisasi (bakteri ke
fagosit)
17

18

Opsonisasi

Step-1

Step-2

19

Attachment

mengawali destruksi Ag.

Mikroorganisme ditempatkan dalam fagosom
dicerna lisosom
Jika Ag terlalu besar untuk ditelan/diingesti,
misal: sel inang yg terinfeksi virus, sel
transplant, dan sel kanker, fagosit
mengosongkan isi lisosomnya Ag
didestruksi ekstraselular.
Opsonisasi penting utk melawan
mikroorganisme yg punya struktur antifagositik
(mis: kapsul) Ab yg dibentuk utk melawan
kapsul dapat menempelkan kapsul ke fagosit.

20

Opsonisasi Fagosit ke Sel

berukuran besar

Step-1

Step-2

21

Opsonisasi (bakteri berkapsul)

22

MAC Cytolysis
IgG

atau IgM dibentuk utk. melawan epitop

di membran porsi Fab - IgG atau IgM
bereaksi dgn. epitop tsb. dan porsi Fc - Ab
mengaktifkan jalur komplemen klasik
C5b6789n (membrane attack
complex/MAC) membuat lubang dalam
membran tsb.

a. Pada bakteri, MAC membuat lubang dalam

membran terluar (outer membrane) &
membran sitoplasma dinding sel Gramnegatif lisis

Sitolisis Bakteri GramNegatif

23

24

b. Pada virus ber-envelop: MAC merusak

envelop

25

c. Pada sel diri sendiri yg dianggap asing, sel

terinfeksi virus, sel transplant, sel transfusi,
sel kanker MAC menyebabkan lisis sel direk

Step-1

Step-2
MAC melisis sel terinfeksi Virus

26

Antibody-Dependent Cellular
Cytotoxicity (ADCC) oleh sel NK
Sel

NK mempunyai reseptor untuk porsi Fc

- IgG.
Bila IgG dibentuk utk melawan epitop di
sel2 asing (mis: sel terinfeksi virus, sel
kanker) porsi Fab Ab bereaksi dengan
sel tsb. sel2 NK berikatan ke porsi Fc
Ab sel NK melepaskan protein
pembentuk pori/lubang (perforin), enzim
proteolitik (granzyme) dan chemokine.

27

Antibody-Dependent Cellular
Cytotoxicity (ADCC) oleh sel NK
melewati pori2 mengaktifkan
enzime2 yg menyebabkan apoptosis sel
terinfeksi dgn cara merusak struktur
protein sitoskeleton & degradasi kromosom
sel pecah menjadi fragmen2 dibuang
oleh fagosit.

Granzyme

Perforin

juga dapat menyebabkan lisis sel.

Sel NK yang menjalankan ADCC disebut
juga killer cell

28

Destruksi Sel Terinfeksi Virus

oleh Sel NK Melalui ADCC

29

Destruksi Sel Terinfeksi Virus

oleh Sel NK Melalui ADCC

30

Netralisasi Eksotoksin
Eksotoksin

harus berikatan ke reseptor di

sel inang sebelum merusaknya
Ab antitoksin (umunya IgG) dibuat utk
melawan protein eksotoksin.
Ab antitoksin bergabung dgn eksotoksin
sebelum berinteraksi dengan sel target
(sel inang) menetralisir toksin.

31

Netralisasi Eksotoksin

32

Netralisasi Virus
Virus

harus berikatan (adsorbsi) terlebih

dahulu ke reseptor di membran plasma sel
inang untuk menginfeksi sel tsb. & bereplikasi.
Ab yg dibuat utk melawan epitop2 pd. kapsid
atau envelop (glikoprotein) virus keduanya
berfungsi melekatkan virus ke reseptor di sel
inang mencegah adsorpsi virus.
Neutralizing Ab (Ab penetralisir) penting utk
mencegah reinfeksi virus.

33

Netralisasi Virus

34

Mencegah Adheren Bakteri ke Sel Inang

Bakteri

dapat bertahan dari sistem imun

innate dengan memproduksi pili, protein
adhesin di dinding selnya, dan/atau kapsul
pembentuk biofilm.
Antibodies are made against pili (def),
capsules (def), and adhesins (def) to
prevent bacteria from adhering to and
colonizing host cells

35

Blok Adheren Bakteri oleh Antibodi

2
1

36

Aglutinasi Mikroorganisme
Fungsi

utama antibodi yg mempunyai

banyak Fab misalnya pada IgM & IgA
adalah aglutinasi.
Ab tersebut mengabungkan
mikroorganisme2 berpadu (agglutinate)
dikeluarkan dari cairan limfe dan darah
difagositosis secara efektif oleh:

Makrofag mononuklear (RES),

Neutrofil dan sel2 fagosit lain

37

Aglutinasi Mikroorganisme

Imobilisasi Bakteri dan

Protozoa
38

Flagela

& cilia memungkinkan m.o. bergerak

menuju dan menjauhi sel inang proses
taxis.
Mukosa kandung kemih & usus secara konstan
membuang bakteri mencegah kolonisasi.
Bakteri motil bergerak sec. kemotaktik
permukaan mukosa kontak dgn. membran
mukosa menempel membentuk koloni.
Ab dapat berikatan ke organ2 tsb motilitas
berhenti penyebaran m.o. terhenti.

Humoral Immune Response

Antibody
Antibodies are antigen binding proteins
present on B cell membrane and secreted
(immunoglobulins) by plasma cells
Membrane-bound antibody confers antigenic
specificity to B cells; antigen-specific
proliferation of B-cell clone is elicited by the
interaction of membrane-bound antibody with
its specific antigen
Secreted antibodies circulate in the blood,
where they serve as the effectors of humoral
immunity by searching and neutralizing
antigens or marking them for elimination

Humoral Immune Response

Antibody Molecule

Consists of 4 peptide chains

MW= Molecular weight, kD= kilo

Dalton, CDR= Complementarity
determining region
Fc= Fragment crystallizable

2 identical heavy (H) chains (MW

50 kD)
2 identical light (L) chains (MW 25
kD)

Each L chain is bound to a H chain

by disulfide bond and form 2 H-L
combinations
H-L combinations are held together
by disulfide bond between H chains
Amino acid sequence in amino
terminal is variable ( V region) and
form the antigen binding site
(hypervariable region or CDR)
Amino acid sequence in carboxyl
terminal is relatively constant (C
region or Fc) and is responsible for

Humoral Immune Response

Antibody

There are 5 types of H chains: and and 2 types of L chains:

and
Both H and L chains have domain structure, 4- 5 domains in H and 2
domains in L chains
An antibody molecule contains only one type of H chain and one type of
L chain

Humoral Immune Response

Antibody Types and Subtypes
IgG contains H chain and is a monomer
IgG has 4 subtypes IgG1, IgG2, IgG3 and IgG4
IgD contains H chain and is a monomer
IgE contains H chain and is a monomer
IgA contains H chain and is a dimer where
each monomer is joined together by a J chain
and may contain a secretory component
IgA has two subtypes: IgA1 and IgA2
IgM contains H chain and is a pentamer
where monomers are joined together by
disulphide bonds and J chain

These types are called isotypes because they are

same in all members of the same species (cf.
allotype and idiotype)

eosinophils

Humoral Immune Response

Primary and Secondary Immune Response

Primary

immune
response
Immune response that
occurs after 1st exposure
to an antigen

Secondary

immune

response
Immune response that
occurs after 2nd or
subsequent exposure to

Immunological
Memory
45

Antibody Titer:

The amount of antibody in the

serum.
Pattern of Antibody Levels During Infection
Primary Response:
After initial exposure to antigen, no antibodies are found in
serum for several days.
A gradual increase in titer, first of IgM and then of IgG is
observed.
Most B cells become plasma cells, but some B cells become
long living memory cells.
Gradual decline of antibodies follows.
Dr.T.V.Rao MD

46

Immunological Memory
(Continued)
Secondary
Response:
Subsequent

exposure to
the same antigen displays
a faster and more intense
antibody response.
Increased antibody
response is due to the
existence of memory
cells, which rapidly
produce plasma cells
upon antigen stimulation.
Dr.T.V.Rao MD

Humoral Immune Response

Primary and Secondary Immune Response
Attribute

Primary response

Secondary
response

Antigen type

Both T dependent
and T independent

Only T dependent

Responding cells

Nave B or T cells

Memory B or T cells

Lag period

Longer (4- 7 days)

Shorter (1- 3 days)

Peak response

Occurs in 7- 10 days

Occurs in 3- 5 days

Magnitude

Low

High (100- 1000x)

Antibody isotype

IgM predominates

IgG predominates

Antibody affinity

Lower

Higher

Humoral Immune Response

Primary and Secondary Immune Response

Primary immune
response
IgM is produced first
then class switch to
IgG

Secondary immune
response
IgM and IgG are produced
simultaneously from the
beginning with
predominant IgG

Induction of Adaptive Immunity

Induction of Adaptive Immunity

TERIMA
KASIH

Cooperation between
Innate and Adaptive Immunity

Adaptive

immunity is not independent of

innate immunity
The phagocytic cells crucial to nonspecific
immune responses are intimately involved
in activating the specific immune response
Various soluble factors produced by a
specific immune response have been shown
to augment the activity of these phagocytic
cells
Through the carefully regulated interplay of
adaptive and innate immunity, the two
systems work together to eliminate a

Cooperation between
Innate and Adaptive Immunity
Component

Innate Immune System

Adaptive Immune System

Macrophages

Phagocytosis and killing of

microorganisms

Presentation of antigens of
phagocytosed organisms to T
lymphocytes, ADCC

Dendritic cells

Phagocytosis and killing of

microorganisms

Presentation of antigens of
phagocytosed
microorganisms to T
lymphocytes

Complements

Activation by
Alternative or Lectin
pathway

Activation by Classical
pathway

Neutrophils

Phagocytosis of microbes

Killing of microbes by ADCC

Eosinophils

Phagocytosis of microbes
(?)

Killing of parasites by ADCC

NK cells

Killing virus infected &

cancer cells

Killing of microbes by ADCC

REAKSI
HIPERSENSITIVITAS
ADALAH RESPOM IMUN YAN BERLEBIHAN DAN
TIDAK DIINGINKAN KARENA DAPAT MENIMBULKAN
KERUSAKAN JARINGAN TUBUH. OLEH GELL DAN
COOMBS DIBAGI MENJADI 4 REAKSI
TIP
E

MANIFESTASI
REAKSI HEPERSENSITIF
CEPAT
ANTIBODI TERHADAP SEL

MEKANISME
IgE dan lg lain

II
III KOMPLEKS ANTIBODI -

IgG atau IgM

IV

Sel yang disensitisasi

ANTIGEN
HIPERSENSITIVITAS LAMBAT

Biasanya IgG

REAKSI TIPE I
DISEBUT JUGA REAKSI CEPAT, REAKSI ANAFILAKSIS ATAU
REAKSI AL ALERGI DIKENAL SEBAGAI REAKSI YANG SEGERA
TIMBUL SESUDAH ALERGEN MASUK KE DALAM TUBUH.
ISTILAH ALERGI YANG PERTAMA KALI DIGUNAKAN VON
PIRGUET PADA TAHUN 1906 DIARTIKAN SEBAGAI REAKSI
PEJAMU YANG BERUBAH DENGAN BAHAN YANG SAMA
UNTUK KEDUA KALI ATAU LEBIH

REAKSI TIPE II
DISEBUT JUGA REAKSI SITOTOKSIK TERJADI OLEH KARENA
DIBENTUK ANTIBODI JENIS IsG ATAU IgM TERHADAP ANTIGEN
YANG MERUPAKAN BAGIAN SEL PEJAMU. ANTIBODI TERSEBUT
DAPAT MENSENSITISASI SEL K SEBAGAI EFEKTOR ANTI-BODY
DEPENDENT CELL CYTOTOXITY (AADC). ATAU MENGAKTIFKAN
KOMPLEMEN DAN MENIMBULKAN LISIS

REAKSI TIPE III

DISEBUT REAKSI KOMPLEKS IMUN TERJADI AKIBAT

PENIMBUNAN KOMPLEKS ANTIGEN-ANTIBODI DALAM
JARINGAN ATAU PEMBULUH DARAH. ANTIBODI DISINI
BIASANYA JENIS IgG. KOMPLEKS TERSEBUT MENGAKTIFKAN
KOMPLEMEN YANG KEMUDIAN MELEPAS MACROPHAGE
CHEMOTAC-TIC FACTOR.

REAKSI TIPE IV

ADA 4 JENIS TIPE IV

SEBAGAI BERIKUT :
1. REAKSI JONES MOTE
2. HIPERSENSITIVITAS
KONTAK
3. TIPE TUBERKULIN
4. REAKSI GRANULOMATA

REAKSI JONES MOTE

DITANDAI OLEH ADANYA INFILTRASI LEUKOSIT
BASOFIL DIBAWAH EPIDERMIS YANG SERING
DISEBUT HIPERSENSITIVITAS BASOFIL KULIT BILA
DICETUSKAN PADA BINATANG PERCOBAAN. HAL
TERSEBUT BIASANYA DITIMBULKAN ANTIGEN
YANG LARUT

DERMATITIS KONTAK
DERMATITIS

YANG TIMBUL PADA KULIT

TEMPAT KONTAK DENGAN ALERGEN
REAKSI MAKSIMAL 48 JAM DAN MERUPAKAN
REAKSI EPIDERMAL
SEL LANGERHANS SBG ANTIGEN
PRESENTING CELL (APC) MEMEGANG
PERANAN

TIPE TUBERKULIN
ADALAH REAKSI DERMAL YANG BERBEDA
DENGAN REAKSI DERMATITIS KONTAK DAN
TERJADI 20 JAM SETELAH TERPAPAR OLEH
ANTIGEN. REAKSI TERDIRI ATAS INFILTRASI SEL
MONONUKLEAR (50% ADALAH LIMFOSIT DAN
SISANYA MONOSIT)
SETELAH 48 JAM, TIMBUL INFILTRASI LIMFOSIT
DALAM JUMLAH BESAR SEKITAR PEMBULU DARAH
YANG MERUSAK HUBUNGAN SERAT-SERAT
KOLAGEN KULIT

REAKSI GRANULOMATA
MERUAPAK REAKSI TIPE IV YANG DIANGGAP
PALING PENTING OLEH KARENA MENIMBULKAN
BANYAK EFEK PATOLOGIS. AL TERSEBUT TERJADI
OLEH KARENA ADANYA ANTIGEN YANG PERSISTEN
DI DALAM MAKROFAG YANG BIASANYA BERUPA
MIKROORGANISME YANG TIDAK DAPAT
DIHANCURKAN ATAU KOMPLEKS IMUN YANG
MENETAP MISALNYA PADA ALVEOLITIS ALERGIK

TIPE

JONES

KONTAK

TUBERKULIN

GRANULOMA

WAKTU
REAKSI

24 JAM

48 JAM

48 JAM

4 MINGGU

BENTUK
KLINIS

PEMBENGKAKAN
KULIT

EKSIM

INDURASI LOKAL INDURASI KULIT

DAN BENGKAK
PANAS

GAMBARA
N
HISTOLOGI
K

LEUKOSIT
BASOFIL,
LIMFOSIT SEL
MONONUKLEAR

ANTIGEN

Ag INTRADEMAL
mis. OVALBUMIN

SEL MONONUKLEAR, SEL

EDEMA, EPIDERMIS MONONUKLEAR,
MENIMBUL
LIMFOSIT,
MONOSOT,
MAKROFAG
MENURUN
EPIDERMAL
DERMAL :
mis, nikel, karet dsb TUBERKULIN DAN
MIKRO
BAKTERIUM,
LEISMANIA

SEL EPITELOID,
SEL RAKSASA
MAKROFAG,
FIBROSIS,
NEKROSIS
AG ATAU
KOMPLEKS Ag/Ab
ATAU TALK DALAM
MAKROFAG YANG
PERSISTEN