Immune Response to Pathogens

Question 1

Innate immune response to extracellular pathogen

Answer 1

• LPS activates complement → opsonization and MAC
• LPS activates TLR4 in macrophages → macrophage secretion of IL-1 and IFN-gamma → macrophage activation → macrophage secretion of IL-1 & TNF-alpha → neutrophil recruitment → neutrophils phagocytose pathogen and destroy it by releasing antimicrobial toxins
• Macrophages can directly engulf pathogens → production of cytokines → recruitment of others from blood

Question 2

How do extracellular pathogens evade the innate immune response?

Answer 2

• Chemical changes to LPS and surface antigens over time
• Decoy membranes (e.g., w/ sialic acid)
• Molecular mimicry

Question 3

Adaptive immune response to extracellular pathogens I

Answer 3

• LPS binds TLR4 → DC activation
• DC activates naive T cells:
  
  • Th1 cells produce IFN-gamma → macrophage activation → phagocytosis/killing of pathogen by macrophage
  • Th17 cells produce IL-17 and antimicrobial factors like IL-21 that target pathogen
• Antigen cross-links BCRs of marginal zone B cells → TI activation of B cells → differentiation of plasma cells that produce of low affinity IgM
• Antigen bound to BCRs on B cells will be processed and presented to activated Th cells → differentiation into plasma cells that secrete high affinity IgM (IgG, IgA, IgE) and memory B cells
• Antibodies bind to antigens → form immune complexes which can:
  
  • activate complement
  • Or be taken up by macrophages thru Fc-Rs

Question 4

Adaptive immune response to extracellular pathogens II

Answer 4

• Need both** a Th1- and a Th2-mediated B cell response**
• Mature naive T cells found in mesenteric lymph are activated by DC presentation of bacterial antigenic peptide in MHCII
  
  • Th1 activation → release of IFN-gamma and IL-2 → ⇡macrophage phagocytosis/pro-inflammatory cytokine release and ⇡CTL activation (respectively)
  • Th1 activation of B cells → SHM, affinity maturation, and class switching to IgG1 and IgG3
  • Th2 activation → release of IL-4
  • Th2** activation of B cells → SHM, affinity maturation, and class switching to **IgG4** and **IgA

Question 5

Immune response to intracellular pathogen (e.g., live-attenuated Sabin Poliovirus vaccine)

Answer 5

• Recognition of virus mediated by TLR3 and TLR7/TLR8 → signal transduction that results in activation of NFkB → production of type 1 interferons (INF-alpha and INF-beta) by pDCs → IFNalpha/beta upregulation of genes whose products:
  
  • Block viral protein translation
  • Initiate host cell apoptosis before virions can be release
  • Degrade viral RNA
  • Activate macrophages, NK cells, pDCs, and cDCs
• cDCs present antigen on MHCI to CD8+ T cells → CTL killing of virus infected cells

Question 6

Innate response to intracellular virus

Answer 6

• Complement:
  
  • opsonizes virions that have burst out for phagocytosis by activated macrophages
  • MAC kills enveloped viruses
• Virus-infected cells w/ low MHCI → directly detected by NK cells → NK cells release perforin and granzyme → virus-infected cell apoptosis
  
  • NK cells also release IFN-gamma → activates macrophages → macrophages release IL-12 → activates more NK cells
• Activated macrophages kill virus-infected cells

Question 7

NK cells & ADCC

Answer 7

ADCC = Antibody-Dependent Cell-mediated Cytotoxicity

• Antibodies react w/ epitopes on the virus-infected cell membrane
• NK cells bind to the Fc portion of the antibodies → NK cells release pore-forming perforins & serine proteases called granzymes → granzymes pass through the pores and activate the infected cell’s caspase enzymes for apoptosis → destruction of cytoskeleton & chromosomal degradation → virus-infected cell lysis

Question 8

ADCC vs Opsonization

Answer 8

• Opsonization flags up pathogens w/ antibodies for phagocytosis by phagocytes (neutrophils, macrophages)
• ADCC is similar in that the pathogen is flagged up by antibody, but the receptor cell is cytotoxic cell (NK cell) that will release cytotoxic granules and kill the flagged cell.

Question 9

How do intracellular pathogens evade the innate immune system?

Answer 9

• Inhibit MHC class I presentation of antigens
• Activate inhibitory costimulation receptors of NK cells with their MHCI
• ⇣expression of “stressed” molecules on their surface to prevention activation of NK

Question 10

Adaptive response to intracellular virus

Answer 10

• Uptake of viral antigen by pDCs → Virus binds to endosomal TLRs [TLR3 (dsRNA), TLR7/8 (ssRNA), TLR9 (DNA)] or RIGs → pDCs activated and migrate to lymphoid tissue to prime naive T cells:
  
  • CD4+:
    
    • IFN-gamma released by DCs → Th1 → IFN-gamma and TNF-alpha → activated CTLs and IgG1/3 antibody secretion by B cells and inhibition of Th2
      
      • Note: TNF-alpha also directly damages virus-infected cells
    • RARE: IL-4 released by DCs → Th2 → IL4 & IL5 → IgG1 antibody secretion by B cells & inhibition of Th1
  • CD8+: IFN-gamma and IL-2 released by DCs → CTLs → IFN-gamma, perforin, & granzyme → apoptosis of virus-infected cells