Virus-Induced Immunopathology

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Virus-Induced Immunopathology
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Cell mediated Immunopathology
Antibody-mediated Immunopathology
Virus-initiated Immunopathology
Cell mediated immunopathology
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Contact between CTL (CD8+) and
target
TCR recognizes cognate peptide
presented by MHC I
Activation of CTL; release of
membrane granules with perforin
and granzyme
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Perforin: Pore formation in target
cells resuting in cytolysis
Granzyme B: induction of
apoptosis
Release of Inflammatory
cytokines (TNF-a, IFN-g, ILs)
CD4+ T cells can enhance CD8mediated immunopathology
NK Cell
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Non-specific of “non-self”
ADCC
Effector Cell
CTL
TCR
Viral antigen
MHC Class I
Target Cell
Cell-mediated Immunpathology:
LCMV, an experimental model
Inflammatory Cytokines
Cytopathic attack on
choriodal cells can
damage meninges
Convulsions (?)
Effector Cell
Nitric Oxide
CTL
TCR
Viral antigen
MHC Class I
NOS
Inflammatory Macrophage
Infected Choriodal Cells
Cell-mediated Immunpathology: LCMV,
an experimental model

Lymphocytic Choriomeningitis Virus causes fatal
choriomeningitis (inflammation of meninges) in
immunocompetent mice, but not in immunosuppressed
mice
Intracerebral Innoculation
e.g. via Cyclophosphamide Rx,
or irradiation
Adoptive Transfer:
Syngeneic normal mice
“immunized” IP with LCMV.
Anti-serum or lymphocytes
then adoptively transferred

Log10 Virus Titer

Serum GLDH

A: Perforin is required for
CTL effector function
B: Perforin, hence CTL
function, is required for virus
clearance (IV challenge)
C: Perforin, CTL activity,
mediates fatal
choriomeningitis (IC
infection)
D: CTL is also involved in
hepatopathology (liver
damage) by hepatotropic
LCMV
Percent Alive

% Cr51 release
CTL activity is required for
LCMV immunopathology
Immune mediated disease: Tissue
destruction in addition to
inflammation
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Hepatotropic LCMV
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Liver destruction
Cerebellar involution in newborn rats
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Pathogenic consequences: severe ataxia
Immunosuppressed
Non-Immunosuppressed
CD4+ T cells can enhance immune
pathology
(N.B. in the book, should be RSV should be Respiratory Syncytial Virus, NOT Rous Sarcoma Virus)
Respiratory Syncytial Virus: virus induced immunopathology
(bronchioaveolitis) is more dependent on CD4 T lymphocytes
Im m uniz ation
(day 0)
Formal i n i nacti vated
RSV
(all grou ps)
Depletion
days 18, 20, 23
None
C D8
C D4
C D8 + CD4
In tranasal
RSV in fe ction
day 21
YES
YES
YES
YES
Alve ol i tis
(% l u ng area)
day 25
9.6%
3.9%
0.5%
0.3%
Complement Fixation
(neg.)
IgG3>IgG1>IgG3>>>(IgG4)
Depletion is usually
accomplished by infusing
mice with antibodies
(complement-fixing)
against the specific cellsurface molecule
Passsive transfer of antibodies (from RSV infected animals)
cannot re-produce aveolitis
Conclusion: alveolitis is mediated mainly by CD4+ effector cells
Cell-mediated Immunopathology:
Human disease
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Clinical disease associated
with development of hightiter antibodies
Presence of high titer virus
(viremia) in the absence of
clinical disease (hepatitis)
suggest that the disease is
not caused by infection per
se
Anti-HBsAg may contribute
to transient acute hepatitis,
but may synergize with CTL
mediated clerance of virus
from hepatocytes
CTL response itself can
result in acute hepatitis
% Maximum
Hepatitis B Virus infection
% Maximum

HBV
All three particles contain HBsAg (also known as the major protein)
The L(large) and M(middle) are also contained in the Dane particles
The L protein when expressed alone gets trapped in ER
~45 nm “Dane”particles
(infectious)
~20 nM spheres
HBsAg (major) and middle proteins and host lipids;
No nucleic acid, non-infectious
Present in 103 to 106 fold excess over Dane particles
Can reach 1012 particles/ml in infected patients
Highly immunogenic, original source of
1st generation HBV vaccine
~20 nM in diameter filaments
(contains the L protein, but lack nucleic acids;
Non-infectious)
Cell-mediated Immunopathology:
Human disease
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Evidence from mice model
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Transgenic mice can be made to express large, middle or major
envelope proteins
Wt. Mice can be vaccinated with envelope proteins and Ag-specific
CTL clones can be made directed against specific epitopes in large,
middle or major envelope proteins
System allows dissection of which immune response, targeted
against which epitope, that is responsible for the immunopathology
Cell-mediated Immunopathology:
Human disease
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Evidence from mice model
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Transgenic mice expressing HbsAg
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Adoptive transfer of CTL specific for a HepB
envelope protein results in acute hepatitis
Direct cytotoxic effects of CTLs is limited to
small numbers of hepatocytes (why? If all
liver cells express the HBsAg)
However, IFNg secreted by CTLs can attract
other WBCs (phagocytes, PMNs) leading to
necroinflammatory foci
However, these cytokines are also involved
in viral clearance; down regulates viral
transcription
Transgenic mice expressing large
Hep B envelope protein (intracellular
accumulation)
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Adoptive transfer of CTL specific for a
HepB large envelope protein results in
progessive inflammation and liver
necrosis
ER accumulation of L protein may be
cytotoxic resulting in activation of
liver macrophages (Kupffer cells)
Antibody-mediated Immunopathology
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Ab-Ag complex formation during
viremic infections
Deposition of immune complex in
glomerulus can initiate complement
cascade and cause inflammation,
scarring and eventual kidney failure
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Large complexes get trapped at the
basement membrane
Mesangial cells enlarge into the
subepithelial (mesangial) space in an
attempt to remove accumulating
immune complexes
Long term: glomerular capillary gets
constricted foot processes of
podocytes (glomerular endothelial
cells) get fused; basement membrane
gets leaky but filtering is blocked
Result: Impaired
glomerular function,
kidney failure (no urine
production)
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Antibody-mediated
Immunopathology
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Ab-Ag complex formation during
viremic infections
Deposition of immune complex in
glomerulus can initiate
complement cascade and cause
inflammation, scarring and
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Infectious Ab-Ag complex
Can be demonstrated by
reduction in infectious titer
using antibodies against

mouse IgG
virus
eventual kidney failure
Y = anti-LCMV
Y
Y
Y
Y = anti-mouse IgG
Y
Y
Tre atmen t of se ra
From mice persisten tly
i nfected wi th LC MV
LCMV titer
(log10 LD50 per 0.02 m l)
An ti-mouse imm u noglobu l i n
<1.0
Controls
Normal rabbi t se rum
An ti-mouse albu m i n
3.7
3.5
Antibody-Mediated Immunopathology:
Human Disease

Dengue hemorrhagic fever
 Dengue virus, flavivirus transmittted by mosquitoes
 4 serotypes (1-4)
 Disease is usually self-limiting but small percentage
develop hemorrhagic fever and shock
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DHF/DSS occurs most commonly in
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children previously infected with a different serotype
infants with primary infection but with maternal anti-dengue
antibodies against another serotype
Abs against one serotype can enhance infection by second
serotype (Antibody-Dependent Enhancement)
Y Y
Enhancement is dependent on the titer of the Abs
(Heterotypic
anti-Dengue Ab)
Fc Receptor
monocyte
Enhancement is dependent on Fc portion of Abs
(Fab fragments from immune sera do not have
Enhancing ability)
Y
ADE
Y
Total IgG
F(ab)2
+++
-
Enhancement is dependent on the
titer of the Abs
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At high concentrations of
virus-specific Ab (low Ab
dilution), percent occupancy
of antibody binding sites is
sufficiently high to inhibit
critical steps in the viral life
cycle
As antibody becomes more
dilute, its inhibitory activity
becomes attentuated, at some
point below the neutralization
end-point, antibody binding at
subneutralizaing
concentrations (High Ab
dilution) enhances viral
infectivity
Neutralization
end-point
Enhanced attachment,
free envelope spikes
available to mediate fusion
Y YY
No free envelope
spikes to
mediate fusion
Y Y
Y
Y
(Heterotypic
anti-Dengue Ab)
Fc Receptor
Fc Receptor
monocyte
monocyte
(Heterotypic
anti-Dengue Ab)
Enhancement is dependent on the titer of the Abs
Enhancement is dependent on Fc portion of Abs
(Fab fragments from immune sera do not have
Enhancing ability)
Y
ADE
ADE
Y
Total IgG
F(ab)2
+++
+++
YYY
[+anti-F(ab)2]
Fc
How does ADE in secondary Dengue
virus infection lead to DHF/DSS?
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Increased entry/replication in target cells
(Monocytes/Macrophages) results in secretion of
inflamatory cytokines (TNF-a, IFNg and IL-2) that
also have vasoactive properties
In 2º Dengue infection, pre-existing Ag-specific
CD8 and CD4 T cells are activated, and also
secrete similar vasoactive cytokines
Resulting “cytokine” storm can capillary fragility
(associated with hemorrhage) and permeability
(associated with shock--loss of intravascular
osmotic pressure)
Anti-viral antibodies: the good,
the bad, and the useless
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LCMV immunopathogenesis:
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A: Slowly replicating Armstrong strain
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Ab slows hematogenous spread of LCMV, and
prevents robust CTL response; protects animals
against CTL mediated choriomeningitis
B: Intermediate replicating WE strain
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Virus infected meningeal cells become target for CTLs-resulting in choriomeningitis
CTLs are made due to hematogenous spread to spleen
and other lymphoid tissues
Too high a level of viral replication in lymphoid tissue
can lead to immune exhaustion: activation induced
apoptosis of Ag-specific CTLs
Ab did not slow spread of LCMV sufficiently to
affect disease outcome
C: High replicating strain

Usually causes immune exhaustion (“high-dose
paralysis”); Ab slows down virus enough for
robust CTL response, which results in fatal
choriomeningitis
Virus-initiated autoimmunity:
Molecular mimicry
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Immune response against a viral
antigen cross-reacts with a host
protein
Cross-reactivity doesn’t
necessarily result in autoimmune
disease
Experimental Allergic Encephalitis
(EAE)
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Myelin Basic Protein immunization
results in EAE (demyelination);
“encephalitogenic” epitope confined to
10 amino-acid stretch in MBP
HBV polymerase contains similar
10 aa stretch; immunization with
this peptide can cause encephalitis
in rabbits
IMMUNOLO GIC AL
C RO SS
REAC TIVITY
DEMONSTRATED
PROTEIN
SEQUENC E
Poliovirus VP2
Acetylcholi ne re ceptor
STTKESRGTT
TVIKESRGTK
YES
Papil loma virus E2
Insulin re ceptor
SLHLESLKDS
VYGLESLKDL
YES
Rabie svirus glycoprotein
Insulin re ceptor
TKESLVIIS
NKESLVISE
YES
HIV p24
IgG constant re gion
GVETTTPS
GVETTTPS
YES
Me asle s virus P3
C orticotrophin
LECIRALK
LECIRACK
NO
Virus-Induced Immunopathology
Defensive Effects
Destructive Effects
---CTL removal of
infected cells
---CTL mediated
destruction
---Ab neutralization
---ADE;
Immune Complex Disease
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