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Microbiology 1.1b Immunology - Dr. Fontanilla
Microbiology 1.1b Immunology - Dr. Fontanilla
ADAPTIVE
IMMUNITY
I.
CELL-‐MEDIATED
IMMUNITY
A.
Development
of
T-‐Cells
• T-‐cell
progenitor
cells
undergo
differentiation
in
the
thymus
• Under
the
influence
of
thymic
hormones,
T-‐cells
differentiate
into
committed
cells
expressing
a
specific
T-‐cell
receptor
(TCR)
• Most
T-‐cells
with
TCR
become
positive
for
both
CD4
and
CD8
(co-‐
receptor
molecules)
• T-‐cells
undergo
selection
process
that
result
in
the
retention
only
of
those
cells
with
antigen
receptors
for
nonself
or
foreign
antigens
–
99%
die
in
the
thymus
• Those
that
survive
undergo
final
maturation
process
which
express
either
CD4
or
CD8
• Exit
into
the
periphery
to
mature
into
effector
cells
Figure
1.
Activation
of
Naïve
T-‐cell.
The
red
triangle
is
the
antigen,
together
with
MHC
II
on
the
surface
of
APC.
On
the
surface
of
Naïve
T
helper
cell
is
the
T-‐
B.
T-‐cell
Receptor
for
Antigen
cell
receptor
(TCR)
and
a
co-‐stimulatiry
receptor,
CD28.
• T-‐cell
receptor
proteins
have
variable
and
constant
regions
similar
to
antibodies
II.
T-‐EFFECTOR
CELL
FUNCTION
• Variable
regions
are
located
at
the
amino
terminals
of
the
A.
CD4
Effector
Cells
polypeptide
chain
farthest
away
from
the
cell
membrane
• Both
chains
contribute
to
the
variable
domain
that
interact
with
Table
1.
CD4
Effector
Cells
antigen
presented
by
MHC
complex
Th1
Cells
• Differentiate
in
the
presence
of
IFN-‐γ
• CD4
and
CD8
function
as
co-‐receptors
• Activate
macrophages
• During
recognition
of
antigen,
the
CD4
and
CD8
molecules
interact
• Cause
B
cells
to
switch
to
produce
different
subclasses
with
T-‐cell
receptor
complex
and
MHC
molecules
on
the
APC
of
IgG
• CD4
binds
to
MHC
class
II
and
CD8
binds
to
MHC
class
I
• Promote
clearance
of
bacteria
by
direct
destruction
in
the
IFN-‐γ
activated
macrophage
or
by
destruction
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MICROBIOLOGY 1.1b
after
phagocytosis
of
opsonized
particles
• Produce
IL-‐2
and
IFN-‐γ
Th2
Cells
• Predominate
in
the
presence
of
IL-‐4
• Activate
mast
cells
and
eosinophils
and
cause
B
cells
to
synthesize
IgE
• Respond
to
helminthic
infections
• Secrete
IL-‐4,
IL-‐5,
IL-‐9
and
IL-‐1
Th17
Cells
• Produced
when
TGF-‐β
and
IL-‐6
come
together
• Produce
IL-‐17
and
IL-‐22
• IL-‐17
–
cytokine
that
induces
stromal
and
epithelial
cells
to
produce
IL-‐8
• IL-‐8
–
a
potent
chemokine
that
recruits
neutrophils
and
macrophages
to
infected
tissues
Regulatory
• CD4
T
cells
become
Treg
when
exposed
to
TGF-‐β
T
• Function
by
suppressing
T-‐cell
responses
(Treg)
• Produce
TGF-‐β
and
IL-‐10
which
suppress
immune
Cells
responses
Figure
3.
HIV
infects
CD4+
T
helper
cells
which
acts
on
the
dentritic
cell
which
in
turn
stimulates
the
development
of
CD8+
T
cells;
end
result
of
HIV
is
immunosuppression
because
of
impaired
release
of
cytokines,
chemokines,
and
delayed
lysis
of
infected
cells.
Figure
2.
T-‐cell
Proliferation
and
Differentiation
to
different
CD4
Effector
cells
and
its
secretions.
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MICROBIOLOGY 1.1b
• These
three
pathways
lead
to
release
of
C5
convertase
which
breaks
Table
5.
Clinical
Application
down
C5
into
C5a
and
C5b
Biomarkers
of
• Provide
clues
for
mechanisms
of
disease
• C5a
is
an
anaphylatoxin
as
well
as
a
chemotactic
factor
disease
• Pro-‐inflammatory
cytokines
TNF-‐α,
Il-‐1
and
IL-‐6
can
• C5b
binds
to
C6
and
C7
to
form
a
complex
that
inserts
into
the
be
detected
in
the
sera
of
patients
with
septic
shock
membrane
bilayer
Measurement
• Useful
monitor
of
immune
status
• C8
then
binds
to
the
C5b-‐C6-‐C7
complex
followed
by
polymerization
of
cytokine
• T-‐cell
function
can
be
monitored
by
the
ability
of
T-‐
of
up
to
16
C9
molecules
to
produce
MAC
production
in
cells
to
produce
• The
MAC
generates
a
channel
pore
in
the
membrane
cytolysis
by
vitro
IFN-‐γ
(eg.
Identify
TB
reactivity)
allowing
free
passage
of
water
across
the
cell
membrane
Recombinant
• Key
therapeutic
agents
cytokines
• INF-‐α
–
hepatitis
C
infection
B.
Regulation
of
The
Complement
System
• INF-‐β
–
multiple
sclerosis
• C1
inhibitor
binds
to
and
inactivates
the
serine
protease
activity
of
Targets
of
• Cytokine
receptor
antagonists
and
anti-‐cytokine
C1r
and
C1s
therapeutics
monoclonal
antibodies
• Factor
I
cleaves
C3b
and
c4b
–
reducing
amount
of
C5
convertase
• Downgrade
pathogenic
responses
to
exaggerated
available
cytokine
production
• Factor
H
enhances
the
effect
of
factor
I
on
C3b
• Eg.
TNF-‐α
inhibitors
–
used
to
manage
rheumatoid
• Factor
P
(properdin)
protects
C3b
and
stabilizes
the
C3
convertase
of
arthritis
the
alternative
pathway
IL-‐2
and
IL-‐15
inhibitors
–
for
transplantation
and
• Decay-‐accelerating
factor
–
a
membrane
ound
protein
found
on
cancer
most
blood
cell
surfaces
–
accelerate
the
dissociation
of
C3
convertase
on
all
3
pathways
V.
HYPERSENSITIVITY
• A
condition
in
which
an
immune
response
results
in
exaggerated
or
Table
3.
Complement
Deficiencies
inappropriate
reactions
that
are
harmful
to
the
host
C2
Deficiency
Serious
pyogenic
infections
• The
first
contact
with
an
antigen
induces
a
sensitization
to
that
MAC
components
deficiency
Enhances
susceptibility
to
Neisserial
allergen
infection
• The
second
contact,
a
hypersensitivity
reaction
can
occur
Properdin
deficiency
Susceptibility
to
meningococcal
disease
A.
Type
I:
Immediate
Hypersensitivity
(Allergy)
C1
inhibitor
protein
deficiency
Hereditary
angioedema
• Occurs
within
seconds
after
antigen
combines
with
the
specific
IgE
o Intravenous
administration
–
systemic
C.
Pathogen
Evasion
o Atopic
allergy
–
local
reaction
• Some
microbes
have
developed
surfaces
that
interfere
with
opsonization
by
C3b
or
interfere
with
insertion
of
the
MAC
• Complement
activation
inhibited
by
presence
of
microbial
generated
proteins
o Protein
A
and
Protein
C
both
bind
IgE
Fc
• Microbes
can
generate
enzymes
that
degrade
complement
component
IV.
CYTOKINES
• Potent
low-‐molecular-‐weight
protein
cell
regulators
• Produced
transiently
and
locally
by
numerous
cell
types
• Multifunctional
proteins
o Hematopoiesis,
immunity,
infectious
disease
tumorigenesis,
homeostasis,
tissue
repair
and
cellular
development
and
growth
• Act
as
signaling
molecules
by
binding
to
their
own
glycoprotein
receptors
on
cell
membranes
Figure
4.
Pathogenesis
of
Type
I
Hypersensitivity
Allergen
on
the
antigen-‐
• Followed
by
a
relay
of
the
signal
to
the
cell
nucleus
presenting
cell
àinteraction
triggers
memory
cells
to
produce
plasma
cells,
which
produce
immunoglobulins
à
stimulate/sensitize
mast
cells
by
second
Table
4.
Classification
and
Functions
exposure
to
allergen
à
release
of
vasoactive
amines
which
affect
smooth
CLASSIFICATION
FUNCTION
muscle,
blood
vessel,
mucous
glands,
platelets,
sensory
nerve
endings,
Immunoregulatory:
IFN-‐γ
Role
in
antigen
presentation
eosinophils.
Proinflammatory:
IL-‐11,
IL-‐6,
Seen
in
infectious
diseases
TNF-‐α
and
IFNs
Table
6.
Mediators
of
Type
I:
Immediate
Hypersensitivity
Anti-‐inflammatory:
TGF-‐β,
IL-‐10,
Down
regulate
an
overactive
HISTAMINE
PROSTRAGLANDINS
&
IL-‐11
and
IFN-‐β
inflammatory
response
LEUKOTRIENES
Growth
and
Differentiation
Colony
stimulation
factor
(CSFS)
• Primary
mediator
• Secondary
mediators
and
stem
cell
factor
• Causes
vasodilation,
• Derived
from
arachidonic
acid
via
increased
capillary
cyclooxygenase
pathway
permeability,
and
smooth
• PG
à
bronchoconstriction
muscle
contraction
causing
• Leukotrienes
à
increased
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MICROBIOLOGY 1.1b
bronchospasm
permeability
of
capillaries
Systemic
Ex:
Acute
Poststreptococcal
glomerulonephritis
Immune
Complex
Treatment
Prevention
disease
• Reverse
action
of
mediators
by
• Prevention
by
identification
maintaining
airway,
artificial
of
allergen
ventilation,
supporting
cardiac
• Avoidance
function
• Give
epinephrine,
antihistamines,
and
corticosteroids
• Atopy
–
strong
familial
predisposition;
elevated
IgE
levels
o Symptoms
induced
by
exposure
to
specific
allergens:
pollen,
house
dust,
food
(shellfish)
o Manifestations:
Hay
fever,
asthma,
eczema,
urticarial
Table
7.
Two
Major
Forms
of
Type
III:
Immune
Complex
Hypersensitivity
Arthus
reaction
• local,
typically
elicited
on
skin
when
a
low
dose
of
antigen
is
injected
and
immune
complex
form
locally;
occurs
within
12
hours
Figure
7.
Type
4
Hypersensitivity
Reaction
• IgG
is
formed;
activation
of
complement
leads
to
activation
of
mast
cells
and
neutrophils,
mediator
release
and
vascular
permeability
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MICROBIOLOGY 1.1b
VI.
DEFICIENCIES
OF
THE
IMMUNE
RESPONSE
• HIV
–
uses
CD4
molecules
as
the
virus
receptor
and
chemokine
A.
Primary
Immunodeficiency
receptor;
progressive
loss
of
CD4
T-‐cells
o Develop
multiple
opportunistic
infections
(TB,
oral
candidiasis,
• Disorders
of
the
immune
system
in
which
the
defect
is
intrinsic
to
cryptococcocis,
pneumocystis
jirovecii)
the
cells
of
the
immune
system
• Have
a
genetic
basis
D.
Malignancy
• Loss
of
number
or
function
of
b
cells,
t
cells
or
phagocytic
cells,
complement
components,
cytokines
or
tlrs
lead
to
increased
• Leukemias:
Deficiency
in
functional
neutrophils,
loss
of
phagocytosis
susceptibility
to
infections
(increased
production
of
non-‐functional
leukocytes)
• Example:
Chronic
Granulomatous
Disease
(CGD)
o Increased
infections
with
bacteria
and
fungi
o Impaired
phagocytic
function
• Lymphomas
and
multiple
myeloma
o Normal
levels
of
igs,
t-‐
and
b-‐
cells
and
phagocytic
cells
• Some
tumors
secrete
high
levels
of
tgf-‐β
that
suppress
a
variety
of
o Genetic
defect
in
cytochrome
b-‐558
responses
including
th1
responses
o Defect
in
the
ability
of
phagocytes
to
produce
peroxide
and
superoxide,
which
in
turn
calls
on
other
macrophages
and
they
E.
Drugs
coalesce
to
become
multi-‐nucleated
• Cytotoxic
drugs
used
to
treat
cancer
(cisplatin)
o Usually
seen
in
areas
with
lymph
nodes
(cervical,
axillary,
• Immunosuppressive
drugs
(cyclosporine)
–
transplantation
inguinal
areas)
• Treatment
of
autoimmune
diseases
(ra)
• Patients
become
more
prone
to
infection
B.
Secondary
Immunodeficiency
• Disorders
of
immune
system
in
which
the
defect
is
induced
by
external
factors
such
as
viruses
(HIV,
Herpes),
malignancy
and
drugs
C.
Infections
• Viral
infections
:
Measles
(Rubeola)
and
Ebstein
Barr
Virus
(EBV)
• You
become
more
susceptible
to
secondary
bacterial
infections
(bacterial
pneumonia
in
children
with
measles)
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