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104 Cards in this Set
- Front
- Back
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What are the barrier fcts of the innate IS?
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Local inflammation (C5a)
Local TNF-a |
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What is the innate response to intracellular bacteria?
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Activated NK-dependent mac activation
IL-1, IL-6, TNF-a, IL-12 |
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What is the innate response to virus infected cells?
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IFN-a and B
IL-12 activated NK cells |
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What do viral factors do to alter inflammatory responses?
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-Block chemotaxis: reduce infiltration by inflam cells
-Block actions of IFNs -Bind host cyto/chemokines that activate leukocytes and lymphocytes -Alter complement binding and activation (neuraminidase activity inc complement fixation, C3b binding) -Inc C' control ptns: degrades C3b, reduce cytolysis and ADCC |
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What do viroceptors and viromitigators do?
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Inhibit IFN and their cellular actions
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What do viral IFN receptors do?
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NEutralize host IFNs
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Why do viruses inhibit TNA-dependent ptn kinase PKR?
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Because PKR induces cell stasis and apoptosis
(viruses want cells to live ) |
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Why do viral factors block the activation of RNaseL?
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Because RNaseL degrades vRNA
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What cells and other things are/can be inhibited during viral infection?
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Inhibit:
MHC expression APCs NK cells Anti-viral fcts |
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Why does the virus inhibit/block/neutralize all these immune fcts?
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Increase chance of viral survival
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What do viral chemokines (CK) do once they enter the host?
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1) Virus makes soluble CK binding ptns that neutralize the host CKs
2) Virus makes vCK-R that bind and neutralize host CKs 3) Lack of host CKs reduces infiltration and activation of monocytes, TH1/2 lymphocytes 4) vCK agonists **deviate host T-cell response to Th2, reduce Th1** |
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How does Cow pox virus interfere with complement?
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It has a vFactor I homologue
-->Degrades C3b, C4b |
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How does herpes virus saimiri (HVS) interfere with complement?
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Has a viralCD59
Binds C8, C9 .: can't form mb-attack complex |
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How doe Vaccinia virus and HVS interfere with C'?
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Have a vMCP homologue
Like cow pox, also degrades C3 and C4 |
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How can viruses inhibit/fool NK cells?
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Virus suppresses host cell MHC expression and express viral MHC homologues instead
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How do viruses suppress host MHC expression?
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Reduction of polymorphic class 1A MHC expression
Increase monomorphic class 1B MHC expression Expression of viral MHC homologue |
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What is the end result of this change in the host MHC?
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Reduced CMI
Reduced NK activity |
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How do viruses evade attack by innate cells and factors?
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They hide inside cells
Some priviliged sites protect viral pathogens (ex: neural tissues) |
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What can happen when a virus hides inside macs, lymphocytes etc?
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-May block critical fcts of the cell (i.e Ag processing, presentation, activation of mac fcts)
This can cause impaired innate and acquired specific immune responses |
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What part of C' do viruses block?
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Block C' activation
Degrade activated C' factors (C3b) Disrupt Mb Attack Complex (by blocking C8, C9) |
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Why do viruses produce receptors and binding ptns that compete for IFN, Chemo and cytokines?
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Want to prevent their activation
Allows virus to live longer |
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How can viruses evade NK cells?
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Suppressing the expression of surface target ptns for NK cells
Can hide even better if they express an MHC homologue that can interact with the NKIRs on NK cell and .: inactivate the killing of the infected cell |
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Why do viruses block apoptosis of the cellsthey infect?
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Make these infected cells immortal
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When does the adaptive response start?
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Late (after 96 hours)
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What is the barrier fct of the adaptive IR?
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IgA Ab in luminal spaces
IgE Ab on mast cells Local inflammation |
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What is the adaptive response to extracellular pathogens?
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IgG Ab and Fc receptor bearing cells
IgG, IgM Ab + classical C' path |
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What is the adaptive response to intracellular pathogens?
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T cell activation of macs by IFN-y
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What is the adaptive response to virus infected cells?
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Cytotoxic T cells
IFN-y |
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What do neutralizing Ab do?
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Prevent virus receptors from binding to target cell ligand
Blocks viremia **only works on viral particles that have NOT YET entered the cell** |
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What is viremia?
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Spread of infection in the blood
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How can Ab mediate lysis?
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Ab-dependent C'-mediate lysis of infected cells by MAC
C' can perforate viral envelope so that serum enz can contact and degrade the nucleocapsid and/or viral genome |
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How can Ab be used in opsonization?
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IgG and C3b bind the surface of infected cells
Activate ADCC and phagocytosis Inactivation of virus particles and infected cells |
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What happens in cell-mediated cytolysis?
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Activated cytotoxic T-cells specifically kill infected cells in a MHC restricted manner and completely terminate active infections
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How migh Igs and C3b help viruses enter cells? (this mechanism known as Enhancement)
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Can help viruses enter and infect phagocytic cells that express FcR and C3bRs
(ex: CMV does this) |
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How can the virus evade specific host defenses?
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1) Host is genetically deficient
2) Lack of presentation of viral Ag by host cells 3) No/low immunogenicity 4) Shedding of excess viral Ag 5) Shedding soluble Ag:Ab immune complexes 6) Suppression 7) Host acquires immune deficiency |
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How can the host be genetically deficient?
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Host doesn't have vital immune cells or resistance factors
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Why is lack of presentation a problem for the host?
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Latent viruses aren't actively transcribes and .: invisible to the host defense system (HSV, varicella-chicken pox/shingles)
Host cells are temporarily non-permissive |
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Why is low/no immunogenicity of the virus a problem for the host?
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Virus is trascribed but not seen by IS because of moleular mimicry of autologous epitopes or eurotropism (privileged site)
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How can viruses evade the immune system by shedding excess viral Ag?
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Ag excess can interfere with the targeting of the innate and immune respose to the site of infection
It can delete/anergize T or B cells, via APCs without B7 (hepatitis) |
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How does shedding soluble Ag-Ab immune complexes inhibit host defenses?
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Inhibits ADCC and NK cytotoxicity by blockig Fc-y receptors (Hepatitis, EBV)
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How ca the virus suppress the IS?
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Can directly make immunosuppressive factors that actively inhibit the host innate resistance and acquired IR
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How ca viruses evade host defenses if the host acquires an immune deficiency?
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Virus infects and inactivates cells of the specific host defense system, causing an immunodeficiency (HIV)
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What are the specific mechanisms of blocking Ag processing and presentation?
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1) Inhibition of MHC class I expression
2) Inhibition of peptide trasport by TAP |
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What is the result of the virus inhibiting MHC I expression?
Ex? |
Impaired recognition of infected cells by cytotoxic T cells
EX: herpes simplex, Cytomegalovirus |
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What is the result of a virus inhibiting peptide transport by TAP?
Ex? |
Blocks peptide's association with MHC I
Ex: Herpes simplex |
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What is the specific mechanism of host immunosuppression?
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Virally encoded cytokine homologue of IL-10
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What is the result of virally encoding a homologue of IL-10?
Ex? |
Inhibits Th1 lymphocytes
Reduces IFN-y production ex: epstein Barr virus |
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What happens during a viral infection of ineffective host IR?
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Mild/no inflam response (not seen as foreign => prions)
No IR: agent is invisible to host defences (prion) Humoral response only: Th2 bias in the host response. No CMI attack of intracellular virus (CMV) IR too slow: virus establishes broad infection (CV) Low affinity IR: many infected cells esape killing Ab response non-neutralizing vs internal ptns Low lvl neutralizing Ab: many viral particles escape **Ab response enhaces disease: virus enters by FcR and C3b, escape from phagosome and replicate inside the cell Infected cell not killed: Infeted cells resist cytotoxic attack due to a block of apoptosis so that infected cells may become immortal |
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What are some molecular mimics?
What do they do? |
C' activation: reduced opsonization, lysis of infected cells
IFN-a/B: reduced activation of anti-viral effetors IFN-y: reduced mac ativation, less MHC expression IL-1: reduced inflammation and fever IL-6: Reduced T and B cell prolif IL-8: Reduced chemotaxis ad inflammation IL-10: Suppression of Th1 and Tcyt CMI IL-12: Blocks activation of NK-cells and Th1 cells IL-17: Augments IL-6 production, T cell growth, increasing infection IL-18: blocks production of IFNy reducing activation Th1, macs TGF-B: suppress Th1 and Tcyt CMI Tumor necrosis factor: inactiviting TNF induced apoptosis and growth Anti-apoptosis: v-bcl2, vFLIP, vSERPIM: prevent apoptosis Chemokines: inactivate inflammation and parts of IR Hormones: inc expression of steroid may inhibit inflam and immunity Hormones: increased expression of steroids may inhibit inflam and immunity |
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What are Th1 cells for?
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Activates macs
Induces B cells to produce opsonizing Ab |
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What are the Th2 cells for?
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Actiates B cells to make neutralizing Ab
Has various effects on macs |
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What are the Th1 cytokines for?
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IL-2
IL-3 IFN-y: suppresses Th2, activates macs |
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What are the Th2 cytokines?
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IL3/4/5
IL-10: suppresses Th1 TGF-B: suppresses Th1 GM-CSF |
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What do the virokines vIL6, vIL10, vIL17?
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Activation of Th2
Supression of Th1 Reduced CMI cytotoxicity Activation of infected cells Increased virus production |
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What do soluble cytokine receptors (viroceptors) do?
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Block IFN-y receptors
Block IFN-a/B receptors Block TNF receptor ==>Block these things so that the chemokines can't bind their receptors on the host |
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What are the viroceptors for TNFs?
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CPV-CrmB/C/D/E
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Why would the virus want to make its own soluble receptors for TNF?
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TNF is associated with apoptosis
TRAIL: TNF related apoptosis inducing ligand vFLIP (viroceptor) has Fas/FLICE linked inhib ptn -->Inhibits Fas or TNF induced apoptosis |
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What is apoptosis?
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Programmed cell death
->Get nuclear and cellular fragmentation |
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What happens during apoptosis?
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Activation of CASPASE cascade
Activation of endogenous DNAse Cleavage of host cell DNA Inactivation of host cell gene fct Phagocytosis and disposal of enclosed cellular debris without releasing intracellular ptns (this reduces the chance of autoimmunization and autoimmunity) |
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What are the viromitigators of apoptosis for?
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Blocking pro-apoptosis receptors
Inactivation of apoptosis signal transduction Inactivation of caspases (cysteine protease) Stabilization of mitochondrial mbs Cells essentially immortal while infected .: Virus cannot be eliminated |
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What do viromitgators inhibit?
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Different Caspases
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What does CPV-CrmA inhibit?
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ICE family of caspases including ICE (casp-1) and FLICE (Casp-8)
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What are viromitigators?
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Viral inhibitors of apoptosis
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What are the 3 types of of viromitigators?
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1)vCASPASE inhiitors
2) vp53 inhibitors 3) vBCL-2 homologues |
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What can the virus do to induce immune suppression?
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-Suppress or alter MHC expression: less CMI and less Tc
-Inactivation of mac: impair APC activation, phagocytosis, cytotoxicity -Depletion of Th: less Th= less activation of Tc/B cells -Modulation of Th1/2: more Th2= less Th1 .: less CMI -Suppression of specific B cells: less APC .: less Ig prod'n -Polyclonal activation of B cells: less specific antiviral Ag Induction of suppressive cytokines: less prolif and activation -Activation of host suppressive cells: Tregs suppress cell activation -Viral inactivation of NKs: impairs host resistance and reduces IFNy prod impairing Th1help for anti-viral immunity |
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What can viromitigators do?
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Reduce MHC expression
Less Tc cell activation |
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How can viromitigators reduce Th1 activation?
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Viruses can cause:
-Impaired proteasome fct: can't degrade Ag -Reduced expression of MHC-2 -Reduced loading of peptide (vTAP) -Reduced Th cell activation -Ineffective CMI, less Tc-cells |
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How can viruses reduce Tc-cell activation?
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Inhibit proteasome fct (can't properly degrade ptn)
Activate MHC-1 and CD4 endocytosis Increased lysosomal degradation of MHC-I Reduced CTL recognition of virus Ags |
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What do the Ab inhibitor type of viromitigators do?
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Herpes virus has a vFcR homolog
Virus FcRs can bind immune complexes --> vFcR and vC3bR activate cell growth (don't activate cellular resistance) |
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What are virokines?
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Viral chemokine mimics that activate cells to permit viral replication (makes cells permissive)
-They directly activate cell metabolism and viral replication -Activate the expression of endogenous cytokines that activate cellular metabolism and viral replication |
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What do viroceptors do?
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Neutralize IFNs and factors preventing viral survival
-Neutralize cytokines essential for immune fct -Block/compete with FcR necessary for Ab fcts and ADCC -Neutralize pro-apoptotic factors |
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What do viromitigators do?
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Activate/block the expression of factors to permit viral replication (makes cells permissive)
-Block MHC expression, blocking immune fct -Express MHC mimics that don't present Ag -Block apoptosis, making infected cells immortal |
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How can viruses be associated with cell death?
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Virolysis by the direct action of the virus
Immune lysis by the IS |
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What residual post-viral immuno-pathology can remain after the infection?
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Acute inflam pathology (ulcers, papules)
Chronic inflammatory pathology (cell death, scar) Autoimmunity |
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How do viruses cause cancer?
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Neoplastic transformation by viral vOnc
Mutation of host genomes activates cellular cOnc |
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What are some infection-ass't autoimmune injuries?
What kind of damage do they cause? |
Inflammation targeting infected tissues: non-specific damage
Cytolysis of infection: loss of essential tissue cells Autoimmunity |
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What can happen in autoimmunity?
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-Cellular autoAgs are released after tissue damage, and lymphocytes are activated, causing persistent cytotoxicity
-Induction of co-stimulatory molec on non-prof APCs, leading to activation of low affinity Th cells -Polyclonal activation of B cells by viral oncogenes, superAg and trans-activating factors to induce auto-Ab -Molecular mimicry that causes immunity to viral ptn that cross reacts with the homologous host ptn -Cytokine transactivation/dysregulation activates Th1/Tc cells (release of T cell regulation, breaking of tolerance) -Bystander killing of normal cells by active Tc cells |
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Why is immunity a double edged sword?
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Th1/Tc CMI is important for complete elimination of viruses
Tcyt CMI to viruses can harm normal host tissues AutoAb production might create immune complexes and ADCC that harms the host cell ->CMI response might kill the host |
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What is the effect of LCM (virus) on neonatal mice?
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Immune complex disease
->The mice can live for a while and tolerate the viral ptns, but develop long term immmune complex disorder. No CMI |
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What is the effect of LCM on adult mice?
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Death
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What happens to adult mice infected with LCM and then treated with cyclo-phosphamide?
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Persistent infection
-->The cyclophosphamide stops the CMI inflammation .: the mice live |
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What happens to adult mice that are infected with LCM, treated with cyclophosphamide and then spleen cells from an adult mouse that died of the LCM infection (and was untreated)?
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The mouse dies because the immune response is too strong
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What happens to the immune system during a LCMV infection?
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Activation of T cells
Prod'n of IFNy Activation of macs ==>Results in massive mononuclear cell infiltration of the mbs of the brain and fatal meningitis |
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How can viruses cause autoimmune self injury
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-Lysis of cells can release cryptic Ag that cause an autoimmune response
-Costimulatory activation of Th Cells--> many tissue macs don't have B7 and can't activate Th cells. Viruses may induce B7 expression and Macs activate a Th1/2 cell response to autoAg |
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What can happen when a cell/tissue barrier is disrupted?
Ex? |
Release of sequestered self Ag
Activation of nontolerized cells Ex: Sympathetic ophthalmia |
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What can happen when an APC is infected?
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Induction of costimulatory activity on APCs
ex: effect of adjuvants in induction of EAE |
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What happens when there is increased accessory adhesion molecult on the APC?
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Get inc avidity of the Th-cell:APC binding and promote activation
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Do active Th cells require B7 to be stimulated?
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No
(Not due to affinity maturation) |
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Do non professional APCs have B7?
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No
.: if T cells recognize something on them, get induction of anergy |
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What other kind of autoimmune self injury can take place?
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1) Ag complexes: binding of pathogen to self ptn
-->Pathogen acts as a carrier to get anti-self response 2) Molecular mimcry: prod'n of cross reactive Ab/T cells 3) Super Ag: polyclonal activation to autoreactive T cells |
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Can cross reaction with foreign species cause autoAb production?
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Yes
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How could you tell if acute juvenile onset insulin-dependent diabetes is caused by a viral induced autoimmune response?
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Express a viral ptn in the Beta cells in the islets of langerhans
Infect the mouse with the virus Monitor insulin production and glucose levels in the blood and urine |
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What happens to a mouse that that has grown in the presence of LCMV-NP gene (the gene has been hybridized to the insulin promoter)?
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Mouse has it inherently .: no IR
--> NP only expressed in the pancreatic Beta cells |
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What happens if thsi mouse is subsequently infected with LCMV?
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See development of diabetes
->CTL killed all the virus infected cell and then went on to kill all the cells expressing NP --> the CD8 cells has to get into the islets and kill B-cells that expressed NP ->This resulted in diabetes (autoimmunity) |
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Can Th1 cytokines alone cause pathology?
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Yes
Can make cytokines to eliminate the virus infecting a specific tissue Local cytokines might activate local Tcyts or macs that would normally bind to normal tissue Ag peptides with low affinity The autoimmune Tc-cells couls then destroy the normal host tissue causing autoimmune pathology |
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How would you design an experiment to regulate Th1 cytokine expression?
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Use a specific tissue promoter in the Beta cells in islets of Langerhans
Monitor insulin production and glucose levels in blood and urine |
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What does chronic local activation of Th1 cytokines do?
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Augments CMI to auto-Ag
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What can the activation of Th cells by superAg do?
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Can activate B cells and cancer
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How can superAg activation of Th cells cause cancer?
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Virus induces persistent cellular activation and prolif, increasing the risk of mutation and malignant transformation
--> Cancer |
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What are some other adverse effects of viral infection?
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Inflammation: nonspecific PMN/Mono infiltration and tissue damage
Granulomatous lesions: Tissue infiltration by B and T cells and prod'n of IR in the tissues Immune complex: IgG:Ag activates C' and ADCC leading to local inflam and tissue damage Cytolysis: Tc cells kill cells vital to normal organ fct Chroninc, prgv or persistent disease: exhaustion of defenses and chronic cell loos requiring continuous replacement favors cancer Chronic fatigue: peristent cytokine activation, hyperplasia Birth defect: dev'p morphogenetic defects in embryo/fetal dev'p Organ dysfct: organ damage Neoplastic transformation: viral oncogens cause transactivation of host cellular fcts inc cell replication and neoplastic transformation Death: acut, rapid, systemic disease and multi organ failure |
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What is required by the host to totally eliminate virus?
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Death of all infected cells
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What can happen if there is chronic over prod'n of virokines?
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Induce tissue specific autoimmunity
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What happens when there is corss reactive Tcyt activation?
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Tissue speciic autoimmunity
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What can be used to minimize pathology?
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Preventive vaccinations
Prompt treatment with antiviral drugs |
