The Body's Defenses

1. Surface defenses
2. Nonspecific (innate) immunity
   • Based on PATTERN RECOGNITION
     • pathogen-associated molecular patterns (PAMP)
       • Peptidoglycan
       • lipoteichoic acid
       • lipopolysaccharide
       • mannose/carbohydrates
       • fMLP
       • flagellin
       • RNA/DNA
     • pattern recognition receptors (PRR)
       • Toll-like receptors (TLR)
       • NOD-like receptors (NLR): cytoplasmic
       • RIG-like receptors: dsRNA
       • C-type lectin receptors (CLR)
3. Adaptive immunity
   • based on ANTIGEN RECOGNITION
     • antigen-presenting cells (APC)
     • B-cells: ANTIBODY
     • T-cells: T-cell receptor (TCR)

The immune system

1. White blood cells (leukocytes)
   1. Lymphocytes
      • B-cells: antibody production
        • MHC-II, C3b & C3d receptors, Immunoglobulins in membrane
      • T-cells: cell-mediated immunity
        • CD-4: initiate or regulate immune response
          • TH1: local responses (inflammation, antibody, DTH)
          • TH2: systemic antibody production
          • TH17: activate neutrophil responses
        • CD-8: cytotoxic
          • Kill virally infected cells, foreign tissue, tumor cells
          • suppress immune respones
      • Natural Killer cells: cancer/virus cell surveillance
        • Fc receptor; antibody-mediated response
   2. Mononuclear cells
      • Monocytes: precursors of macrophages
      • Macrophages: phagocytosis, antigen presentation, cytokine release
        • M-2 macrophages: tissue repair, phagocytosis (remove debris)
        • M-1 macrophages: antibacterial, phagocytic, inflammatory
          • MHC-II antigen, IgG receptor, C3b receptor
          • Secrete IL1, IL6, IL12, TNF-a
          • activated by INF-gamma
   3. Granulocytes
      • Neutrophils (PMN): phagocytosis, inflammation; pus
      • Eosinophils: defense vs. parasites
      • Basophils: histamine release
2. Tissue (resident) cells
   1. Mast cells
   2. Resident (tissues) macrophages
      • Kupffer cells (liver)
      • Microglia
      • Alveolar macrophages
      • Intraglomerular mesangial cells
   3. Dendritic cells (skin, liver, lymph nodes, spleen, blood, thymus)
      • phagocytosis
      • antigen presentation (MHC-II)
      • cytokine release
3. Immune system organs
   1. Thymus
   2. Bone marrow

      Differentiation of immune system cells

   3. Lymph nodes: filter lymph
   4. Spleen: filter; remove encapsulated bacteria; stores RBCs
   5. MALT: appendix, tonsils, Peyer's patches

      Resident B cells, T cells, dendritic cells

      Antigen response: proliferation & swelling

      Homing receptors (addressins) for B & T cells

Innate Immunity

A. Complement

• Serum proteins (at least 25 different proteins)
  • synthesized by the liver in response to IL-6
• Inactive state when in serum
  • Host cells & plasma have protective factors
• Activated by 3 different pathways
  1. Classical pathway - specific immunity
     • Mediated by aggregated antibody (IgG, IgM)
     • Activates C1 → C2 + C4 → C2a4b
  2. Alternative pathway - activated by
     1. Endotoxins (LPS)
     2. Polysaccharides
     3. Teichoic acids
        • Requires properdin (protein)
        • Fast response, independent of antibody or complement
        • Factor D → Factor B → Bb + C3b = C3bBb
  3. Lectin pathway via macrophages + mannose binding protein
     • antibacterial & antifungal
     • MBL → MASP → C2 + C4 → C2a4b
• C3 convertase cleaves protein C3 into C3a and C3b
  • C3a recruits inflammatory response (chemotactic) & stimulates mast cells
  • C3b also promotes phagocytosis (opsonin)
• C3b binds to pathogen membrane
• Factor B binds to C3b = C3bBb
• C3b binds to C3 convertase → C5 convertase
• C5 convertase splits C5 into C5a and C5b
  • C5a: chemotactic & activates mast cells
• C5b + C6 + C7 bind to pathogen membranes
• C8 and C9 join = membrane attack complex
  • Primarily vs. Gram-negative bacteria
• Other complement functions
  • Initiate inflammation (bind to mast cells - histamine): C3a, C4a, C5a
  • Attract leukocytes: C3a, C5a
  • Promote phagocytes (opsonization): C3b
  • activate B-cells directly: C3d
  • activate clotting pathway (C5a)

B. Phagocytosis 

• Neutrophils, macrophages, eosinophils, dendritic cells
• Two mechanisms
  • opsonin-dependent
  • opsonin-independent

1. Opsonization
   • C3b on pathogen surface recognized by C3b receptors
   • Antibodies on pathogen surface recognized by Fc receptors
   • Mannose binding protein receptors
2. Opsonin-independent mechanisms
   • receptors for LPS, TA, mannose, FHA
   • hydrophobic interactions

• Phagocytosis engulfs pathogens into phagosome
• Phagosome fuses with lysosome (or PMN granules)
• Pathogens are destroyed by enzymes & other compounds
  • peroxide, superoxide, hydroxyl, halides, NO
  • acids, lysozyme, defensins, proteases, cathepsin G
  • activated macrophages can kill intracellular pathogens
• Neutrophils release inflammatory mediators (PGs, LTs) and form pus
• Macrophages in the spleen remove encapsulated pathogens

Phagocytes respond to chemoattractant mediators, e.g. C5a

C. Inflammation

1. Signs:
   • swelling, redness, warmth, pain
2. Causes
   1. Tissue damage (wound/trauma): endothelial cells --> IL-1, 6
   2. Pathogens (via macrophages, complement)
3. Inflammatory Response
   • Damage causes tissue cells to release chemical mediators (chemokines)
   • Vascular endothelium responds by expressing selectins
   • Neutrophils in blood are slowed down and attach to selectins
   • Neutrophils squeeze through capillary wall
   • Inflammatory mediators are also activated, s.a. bradykinin
     • Bradykinin activates mast cells to release histamine
     • Bradykinin and histamine cause capillary walls to become leaky
     • Bradykinin causes release of prostaglandins from nearby cells
     • Prostaglandins & bradykinin enhance swelling and stimulate pain receptors
   • Inflammation is enhanced by cytokines s.a. IL1, IL6, IL12, IFN-gamma and by C3a & C5a
   • Neutrophils also release prostaglandins & leukotrienes
4. Results of inflammation
   • Phagocytic cells are attracted to the infection site
   • Antimicrobial serum proteins also get to the infection site
   • Temperature increase stimulated local immune response

D. Fever

1. Pathogen engulfed by macrophage
2. Macrophage releases cytokines s.a. IL-1 and TNF-a
3. IL-1 & TNF-a  stimulate hypothalamus via prostaglandin synthesis to increase temperature
4. Increased temperature stimulates immune system and inhibits pathogens

E. Cytokines

1. Cytokines are chemical mediators released by immune system cells
2. Cytokines have several important functions
   • Stimulate bone marrow
   • Stimulate WBC differentiation and division (e.g. Interleukins)
   • Chemoattraction of phagocytes, lymphocytes 
   • Induce fever
   • Produce inflammation/tissue swelling
   • Destroy tumor cells
3. Many cytokines are released by macrophages
4. 3 major classes:
   • Interleukins (IL1 - IL18)
   • Tumor necrosis factors
   • Interferons

F. Interferon

1. IFN-a and IFN-b
2. Produced by virally infected cells and lymphocytes
3. Stimulate neighboring cells to produce anti-viral proteins

G. Chemotaxis

1. Attraction of phagocytes to site of infection
   • Complement C3a, C5a
   • Chemokines (alpha, beta)
   • Bacterial components s.a. fMLP

H. Acute Phase Response

1. Triggered by IL1, IL6, TNF-a, inflammation, tissue injury, PGE2, INF
2. Promotes host defense
   • fever
   • anorexia
   • sleepiness
   • metabolic changes
   • protective protein production (clotting, complement, antigen-binding, etc)

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