Immunology - 4 - Innate Effector Mechanisms

Question 1

various pathogen pattern recognition receptors.

Answer 1

Innate immunity

• Specific recognition
  
  • molecular patterns - structures shared by classes of microbes
• Receptors - limited diversity
  
  • Toll-like receptors (TLR)
  • N-formyl methionyl receptor
  • Mannose receptor
• Distribution
  
  • nonclonal
  • identical receptors on all cells of same lineage
• Discrimination of self/non-self
  
  • Yes - host cells NOT recognized

Adaptive Immunity

• Specific recognition
  
  • Ag - diff on each microbe
• Receptors - great diversity
  
  • TCR
    
    • recombination of gene segments
• Distribution:
  
  • clonal
  • clones of lymphocytes w/ distinct specificities express diff receptors
• Discrimination:
  
  • Yes - based on selection against self-reactive lymphocytes
    
    • may be imperfect = autoimmune issues

Question 2

Non-immune cell-mediated innate effector mechanisms

Answer 2

BARRIERS

• Mechanical
  
  • epithelial cells w/ tight jxns
  • longitudinal flow of air/fluid (skin/gut)
  • movement of mucus via cilia (lungs)
  • tears/nasal cilia (eyes/nose)
• Chemical
  
  • FA - skin
  • Antibacterial peptides (skin/gut/lungs)
  • low pH/enzymes (gut)
  • enzymes in tears (lysozymes - eyes)
• Microbiological
  
  • normal flora (skin/gut)

DEFENSINS

• alpha; made in..
  
  • neutrophils, monocytes, macrophages, B/T cells, NK
  • paneth cells in GI & vaginal tract
    
    • constitutive & induced by STI
• beta; made in…
  
  • epithelial cells
  • monocytes, macrophages, dendritic cells, keratinocytes
    
    • constitutive & induced by infection

Question 3

process of extravasation

Answer 3

Leukocyte migration

1. Rolling
   
   • selectin ligand on leukocyte = slows roll
2. Integrin activation by chemokines
   
   • binds integrin on leukocyte w/ high affintiy = stops cell
     
     • chemokines produced by endothelial & macrophages
       
       • TNF & IL-1
3. Stable adhesion
   
   • Ig superfamily
     
     • ICAM-1/VCAM
4. Migration thru endothelium

Components:

• Selectins
  
  • bind carbs;
  • initiate leukocyte-endothelial interaction
• Integrins
  
  • bind to cell-adhesion molecules + ECM
  • strong adhesion
• Ig superfamily
  
  • various roles in cell adhesion
  • ligand for integrins

Question 4

process of phagocytosis

Answer 4

1. bacterium = phagocytosed
   
   • neutrophil
2. phagosome = fuses w/ azurophilic & specific granules
3. pH of phagosome rises
   
   • antimicrobial response = activated
   • bacterium killed
4. pH of phagosome decreases
   
   • fusion w/ lysosome
     
     • allows acid hydrolysis to degrade the bacterium completely
5. Neutrophil dies by apoptosis
   
   • phagocytosed by macrophage

Mechanisms of killing:

• acidification
• toxic O2 products
• toxis NO
• antimicrobial peptides
• enzymes
• competitors

Question 5

mechanisms of activation and inhibition of NK cells.

Answer 5

Activation / Inhibition

• MHC I on normal cells = recognized by inhibitory receptor
  
  • inhibits signals from activating receptors
  • NK does not kill normal cell
• Altered or absent MHC I = cannot stimulate negative signal
  
  • NK is triggered by signal from activating receptors
  • Activated NK cell releases granule contents
    
    • induces apoptosis in target cell

Question 6

cytokines involved in innate immunity

Answer 6

1. Activation of dendritic cells, macrophages, NK cells
   
   • IL-12
   • IFN-y
   • TNF, IL-1, cytokines released
     
     • inflammation
2. Cytokines
   
   1. TNF = tumor necrosis factor
      
      • macrophages/T cells
        
        • endothelial cells –> activation of inflammation, neutrophils, fever, acute phase proteins, cachexia, apoptosis
   2. Interleukin (IL-1)
      
      • macrophages, endothelial cells, epithelial cells
        
        • endothelial cells –> activation of inflammation, fever, acute phase proteins
   3. Chemokines
      
      • macrophages, dendritic cells, endothelial cells, T cells, fibroblasts, platelets
        
        • leukocytes = increased integrin affinitiy; chemotaxis, activation
   4. Interleukin-12 (IL-12)
      
      • dendritic cells, macrophages
        
        • NK & T cells = IFN-y production, increased cytotoxic activity, TH1 differentiation
   5. Interferon-y (IFN-y)
      
      • NK, T cells
        
        • activation of macrophages; stimulation of Ab responses
   6. Type I interferon (alpha & beta)
      
      • alpha = dendritic cells, macrophages
      • beta = fibroblasts
        
        • All cells = anti-viral state, increased class I MHC expression; NK activation
   7. Interleukin-10 (IL-10)
      
      • macrophages, dendritic cells, T cells
        
        • inhibition of IL-12; reduced expression of MHC II molecules; ANTI-INFLAMMATORY

Question 7

cytokines involved in adaptive immunity

Answer 7

• Macrophage + dendritic cell (innate immunity)
  
  • co-stimulator (B7) expression
  • cytokine production
    
    • —>
• Naive T lymphocyte (adaptive immunity)
  
  • B7 – CD28
  • cytokind receptor
    
    • —>
• T cell proliferation & differentiation
  
  • cell-mediated immunity

• Microbes (innate)
  
  • complemement activation
• CR2 receptor on B lymphcytes (adaptive)
  
  • B cell proliferation & differentiation
    
    • humoral immunity