MBI - 414 Immunology Principles
MBI - 415 Immunology Principles and Practice

Hypersensitivity

General Characteristics

• Hypersensitivity refers to "inappropriate" or "harmful" immune-mediated reactions that cause damage to the host as a result of immune responses against allergens (immunogens that induce hypersensitivity sensitization) that may or may not be pathogenic
• Hypersensitivities all have two phases:
  • Sensitization - induction and development of immune responses that lead to generation of conditions that can lead to the tissue-damaging reactions we call hypersensitivity
  • Elicitation - antigenic triggering of hypersensitivity reactions that cause damage to the host
• Two major groups of hypersensitivities based on the time required for elicitation (after the sensitization has occurred)
  • Immediate hypersensitivities occur within minutes to a few hours after secondary antigen exposure (typically antibody mediated)
  • Delayed hypersensitivities typically occur 48-72 hours after secondary antigen exposure (typically T cell mediated)

Immediate Type Hypersensitivity

• Type I Hypersensitivity ... IgE Mediated
  • Sensitization
    • IgE antibody response specific for the allergen is generated as a result of IL-4 and/or IL-13 predominance that leads to B cell Ig-switching from IgM to IgE Ig-gene activation
      • Th2 cells respond preferentially as a result of the cummulative action of allergen quality and quantity, route of immunogen entry, and whether or not the "first" responders" (NK cells, eosinophils, basophils, mast cells and other Th2 cells) that secrete IL-4 and/or IL-13
      • Th2 cells predominate as a result of continued secretion of IL-4 and/or IL-13
    • Mast cells and basophils bind IgE antibodies via Fcε-RI
  • Elicitation ... reaction can occur in a few minutes
    • Allergen crosslinks IgE molecules bound to FcE-RI on the surface of mast cells and basophils (mast cells have ~10 times as many FcE-RI as basophils, so they are the most important in this response)
    • Fcε-RIs signal the cell to:
      • release preformed mediators as a result of degranulation:
        • histamine, which triggers:
          • dilitation of capillaries in the immediate area, leading to increased blood flow into the affected (local) region of the body
          • increased vascular permeability of capillaries in the area, leading to enhanced "delivery" of chemical and cellular factors from the bloodstream into the region
          • constriction of venules and veins in the area (due to smooth muscle contraction), which leads to decreased blood flow out of the affected (local) region, thus enhancing local vascular permeabililty effects
        • serotonin, which triggers the same three effects as histamine
        • heparin, which blocks blood coagulation in the local area
        • proteases, which trigger:
          • bronchial mucus secretion
          • vascular basement membrane damage
          • complement activation
      • generate more histamine that can be secreted if allergen stimulation continues
      • generate and release lipid mediators as a result of activating:
        • aracadonic acid pathways:
          • cyclooxygenase pathway generates:
            • prostaglandins, which enhance vascular permeability and vascular dilitation, and foster neutrophil chemotaxis
            • thromboxanes, which cause vasoconstriction and platelet aggregation
          • lipooxygenase pathway generates leukotrienes:
            • leukotrienes C4, D4 and E4, which cause bronchial smooth muscle contraction (the "factor" thought to cause these effects was originally called slow-reacting factor of anaphylaxis or SRS-A)
            • leukotriene B4, which fosters neutrophil chemotaxis
        • lyso-PAF pathway to generate platelet-activating factor (PAF) which aggregates platelets, fosters eosinophil chemotaxis and activates neutrophils
      • generate and secrete cytokines and chemokines:
        • IL-4, IL-13 ... which foster Th2 development and cytokine secretion
        • IL-3, IL-5, GM-CSF ... which foster eosinophil development and activation
        • TNF-α ... which promotes inflammation
        • MIP-1α ... attracts monocytes, macrophages and neutrophils
        • eosinophil chemotactic factor (ECF-A), which attracts eosinophils into the affected (local) region of the body
        • neutrophil chemotactic factor (NCF-A), which attracts neutrophils into the affected (local) region of the body
    • Examples of disease conditions caused by these mechanisms include allergic rhinitis (hayfever), food allergies resulting in urticaria (rashes), Asthma
• Type II Hypersensitivity ... ADCC and/or Cytotoxic Antibody Mediated
  • Sensitization
    • IgG antibody response specific for the allergen
    • Binding of IgG antibodies to host cells or platelets
  • Elicitation
    • Binding of antigen-specific antibodies to host cells leads to damage by:
      • complement mediated lysis (IgG or IgM)
• phagocytes, which engulf and digest the host cells sensitized by IgG antibody
• natural killer cells, eosinophils, macrophages or neutrophils, which lyse host cells sensitized by IgG antibody via release of various lytic factors
  • NK cells release perforin and granzymes
  • eosinophils release perforin and lytic enzymes
  • macrophages and neutrophils release lysosomal enzymes
• Examples of diseases caused by these mechanisms include autoimmune hemolytic anemia, autoimmune thrombocytopenia, transfusion reactions, and erythroblastosis fetalis
• Type III Hypersensitivity ... Immune Complex Mediated
  • Sensitization
    • IgG and/or IgM antibody response specific for the allergen
  • Elicitation
    • Immune complex formation via IgG and/or IgM crosslinking of antigen
    • Accumulation of immune complexes capable of activating complement in various tissues leads to accumulation of neutrophils attracted by C5a chemotactic activity
    • These neutrophils bind to the complexes (because they are opsonized by IgG-Fc and/or C3b bound to them) and try to engulf them
    • Because the complexes are typically much larger than the neutrophils, the phagocytes cannot engulf them; instead, they release lysosomal enzymes, and these damage the host tissues
    • Two types of immune complex hypersensitivity:
      • Arthus reactions are restricted to localized areas where antigen is introduced (or produced) in the presence of high concentrations of antibody
      • Serum sickness reactions are disemminated reactions that occur when antigen is introduced systemically in the presence of low concentrations of antibody
    • Examples of disease conditions caused by these mechanisms include rheumatoid arthritis (Arthus) and glomerulonephritis (serum sickness) in chronic streptococcal or hepatitis B infections

Delayed Type Hypersensitivity

• Type IV Hypersensitivity ... T Cell Mediated
  • Sensitization
    • Activation and proliferation of sensitized T helper cells specific for allergen
  • Elicitation
    • Antigenic stimulation of sensitized T helper cells leads to their prolilferation and release of cytokines that lead to recruitment, retention and activation of macrophages at the site of allergen introduction (or production)
    • Granuloma formation occurs as a result of the accumulation and activation of macrophages at sites where allergen is localized
    • Granulomas can lead to tissue replacement and/or damage as a result of release of cytokines and lysosomal enzymes ... particularly when macrophage accumulations are so extensive that the cells in the centers of the granulomas cannot obtain oxygen and/or toxic by-products cannot be efficiently removed
    • Examples of disease conditions caused by these mechanisms include poison ivy, poison oak, tuberculosis, schistosomiasis, and tuberculoid leprosy