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1、Virus-Induced Immunopathology,Cell mediated ImmunopathologyAntibody-mediated ImmunopathologyVirus-initiated Immunopathology,Cell mediated immunopathology,Contact between CTL(CD8+)and targetTCR recognizes cognate peptide presented by MHC IActivation of CTL;release of membrane granules with perforin a
2、nd granzymePerforin:Pore formation in target cells resuting in cytolysisGranzyme B:induction of apoptosisRelease of Inflammatory cytokines(TNF-a,IFN-g,ILs)CD4+T cells can enhance CD8-mediated immunopathologyNK CellNon-specific of“non-self”ADCC,MHC Class I,Cell-mediated Immunpathology:LCMV,an experim
3、ental model,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 Transf
4、er:Syngeneic normal mice“immunized”IP with LCMV.Anti-serum or lymphocytes then adoptively transferred,CTL activity is required for LCMV immunopathology,A:Perforin is required for CTL effector functionB:Perforin,hence CTL function,is required for virus clearance(IV challenge)C:Perforin,CTL activity,m
5、ediates fatal choriomeningitis(IC infection)D:CTL is also involved in hepatopathology(liver damage)by hepatotropic LCMV,Immune mediated disease:Tissue destruction in addition to inflammation,Hepatotropic LCMVLiver destructionCerebellar involution in newborn ratsPathogenic consequences:severe ataxia,
6、Immunosuppressed,Non-Immunosuppressed,CD4+T cells can enhance immune pathology,Respiratory Syncytial Virus:virus induced immunopathology(bronchioaveolitis)is more dependent on CD4 T lymphocytes,Passsive transfer of antibodies(from RSV infected animals)cannot re-produce aveolitisConclusion:alveolitis
7、 is mediated mainly by CD4+effector cells,(N.B.in the book,should be RSV should be Respiratory Syncytial Virus,NOT Rous Sarcoma Virus),Depletion is usually accomplished by infusingmice with antibodies(complement-fixing)against the specific cell-surface molecule,IgG3IgG1IgG3(IgG4),(neg.),Complement F
8、ixation,Cell-mediated Immunopathology:Human disease,Hepatitis B Virus infectionClinical disease associated with development of high-titer antibodiesPresence of high titer virus(viremia)in the absence of clinical disease(hepatitis)suggest that the disease is not caused by infection per seAnti-HBsAg m
9、ay 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,%Maximum,45 nm“Dane”particles(infectious),20 nM spheresHBsAg(major)and middle proteins and host lipids;No nucleic acid,non-infe
10、ctiousPresent in 103 to 106 fold excess over Dane particlesCan reach 1012 particles/ml in infected patientsHighly immunogenic,original source of 1st generation HBV vaccine,20 nM in diameter filaments(contains the L protein,but lack nucleic acids;Non-infectious),HBV,All three particles contain HBsAg(
11、also known as the major protein)The L(large)and M(middle)are also contained in the Dane particlesThe L protein when expressed alone gets trapped in ER,Cell-mediated Immunopathology:Human disease,Evidence from mice modelTransgenic mice can be made to express large,middle or major envelope proteinsWt.
12、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 proteinsSystem allows dissection of which immune response,targeted against which epitope,that is responsible for the immunopathology,Cell-mediated
13、 Immunopathology:Human disease,Evidence from mice modelTransgenic mice expressing HbsAgAdoptive transfer of CTL specific for a HepB envelope protein results in acute hepatitisDirect cytotoxic effects of CTLs is limited to small numbers of hepatocytes(why?If all liver cells express the HBsAg)However,
14、IFNg secreted by CTLs can attract other WBCs(phagocytes,PMNs)leading to necroinflammatory fociHowever,these cytokines are also involved in viral clearance;down regulates viral transcriptionTransgenic mice expressing large Hep B envelope protein(intracellular accumulation)Adoptive transfer of CTL spe
15、cific for a HepB large envelope protein results in progessive inflammation and liver necrosisER accumulation of L protein may be cytotoxic resulting in activation of liver macrophages(Kupffer cells),Antibody-mediated Immunopathology,Ab-Ag complex formation during viremic infectionsDeposition of immu
16、ne complex in glomerulus can initiate complement cascade and cause inflammation,scarring and eventual kidney failureLarge complexes get trapped at the basement membraneMesangial cells enlarge into the subepithelial(mesangial)space in an attempt to remove accumulating immune complexesLong term:glomer
17、ular capillary gets constricted foot processes of podocytes(glomerular endothelial cells)get fused;basement membrane gets leaky but filtering is blockedResult:Impaired glomerular function,kidney failure(no urine production),Antibody-mediated Immunopathology,Ab-Ag complex formation during viremic inf
18、ectionsDeposition of immune complex in glomerulus can initiate complement cascade and cause inflammation,scarring and eventual kidney failure,Infectious Ab-Ag complexCan be demonstrated by reduction in infectious titer using antibodies against mouse IgG,Antibody-Mediated Immunopathology:Human Diseas
19、e,Dengue hemorrhagic feverDengue virus,flavivirus transmittted by mosquitoes4 serotypes(1-4)Disease is usually self-limiting but small percentage develop hemorrhagic fever and shockDHF/DSS occurs most commonly in children previously infected with a different serotypeinfants with primary infection bu
20、t with maternal anti-dengue antibodies against another serotypeAbs against one serotype can enhance infection by second serotype(Antibody-Dependent Enhancement),Enhancement is dependent on the titer of the Abs,Enhancement is dependent on the titer of the Abs,At high concentrations of virus-specific
21、Ab(low Ab dilution),percent occupancy of antibody binding sites is sufficiently high to inhibit critical steps in the viral life cycleAs antibody becomes more dilute,its inhibitory activity becomes attentuated,at some point below the neutralization end-point,antibody binding at subneutralizaing conc
22、entrations(High Ab dilution)enhances viral infectivity,Neutralization end-point,(Heterotypic anti-Dengue Ab),Y,Y,Y,No free envelope spikes to mediate fusion,Enhanced attachment,free envelope spikes available to mediate fusion,Enhancement is dependent on Fc portion of Abs(Fab fragments from immune se
23、ra do not have Enhancing ability),Y,Y,Total IgG,F(ab)2,ADE,+,-,Enhancement is dependent on the titer of the Abs,+anti-F(ab)2,+,ADE,Fc,How does ADE in secondary Dengue virus infection lead to DHF/DSS?,Increased entry/replication in target cells(Monocytes/Macrophages)results in secretion of inflamator
24、y cytokines(TNF-a,IFNg and IL-2)that also have vasoactive propertiesIn 2 Dengue infection,pre-existing Ag-specific CD8 and CD4 T cells are activated,and also secrete similar vasoactive cytokinesResulting“cytokine”storm can capillary fragility(associated with hemorrhage)and permeability(associated wi
25、th shock-loss of intravascular osmotic pressure),Anti-viral antibodies:the good,the bad,and the useless,LCMV immunopathogenesis:Virus infected meningeal cells become target for CTLs-resulting in choriomeningitisCTLs are made due to hematogenous spread to spleen and other lymphoid tissuesToo high a l
26、evel of viral replication in lymphoid tissue can lead to immune exhaustion:activation induced apoptosis of Ag-specific CTLsA:Slowly replicating Armstrong strainAb slows hematogenous spread of LCMV,and prevents robust CTL response;protects animals against CTL mediated choriomeningitisB:Intermediate r
27、eplicating WE strainAb did not slow spread of LCMV sufficiently to affect disease outcomeC:High replicating strainUsually causes immune exhaustion(“high-dose paralysis”);Ab slows down virus enough for robust CTL response,which results in fatal choriomeningitis,Virus-initiated autoimmunity:Molecular
28、mimicry,Immune response against a viral antigen cross-reacts with a host proteinCross-reactivity doesnt necessarily result in autoimmune diseaseExperimental Allergic Encephalitis(EAE)Myelin Basic Protein immunization results in EAE(demyelination);“encephalitogenic”epitope confined to 10 amino-acid stretch in MBPHBV polymerase contains similar 10 aa stretch;immunization with this peptide can cause encephalitis in rabbits,Virus-Induced Immunopathology,-CTL removal of infected cells,-CTL mediated destruction,-Ab neutralization,-ADE;Immune Complex Disease,Defensive Effects,Destructive Effects,
