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• Hypersensitivity
  •  excessive response ® significant tissue damage
• Autoimmunity
  •  immunoreactivity against "self" antigens
• Immunodeficiency
  •  diminished reactivity

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Hypersensitivity

Classification:determined by time required for expression of clinical symptoms following antigen exposure: Immediate, Delayed

Immediate Hypersensitivity

• Immediate Hypersensitivity: antibody mediated; symptoms occurring within minutes to a few hours following antigen exposure -- Three Categories:

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  • Type I:
    • Characteristics type I:
      • antigen cross-linking of membrane-bound IgE on blood basophils or tissue mast cells
    • Consequences type I:
      • Cellular Degranulation: releasing histamine, leukotrienes, and other mediators)
      • These mediators may induce:
        • asthma
        • hives
        • hay fever
  • Type II:
    • Characteristics-type II:
      • antigen-antibody complex formation between foreign antigen +IgM or IgG immunoglobulins
      • examples:
        • Hashimoto's thyroiditis-slide A
        • Hashimoto's thyroiditis-slide B
    • Occurrence-type II:
      •  Blood transfusion reactions
      •  Newborn: hemolytic disease
        • Mechanism:
          • antibodies formed «foreign erythrocyte membrane antigens
      •  Drug Induced
    • Consequences-type II:
      • Complement cascade activation
      •  Generation of membrane attack complex ® destroys red blood cells
    • Newborn hemolytic disease:
      •  anti-Rh IgG antibodies (produced by an Rh negative mother):
        1. Cross the placenta
        2. Bind to erythrocytes of Rh-positive fetus;damage fetal erythrocytes
      • Prevention:
        • Administration of anti-Rh antibodies to the mother; 24-48 hours after delivery of the first Rh+ child
    • Drug Induced: Examples --
      •  penicillin administration to allergic patients
        • Mechanism: penicillin binds to erythrocytes or other host tissue ® neoantigen production of antibodies ® induction complement-mediated cell lysis
        •  Repeat administration may cause ® systemic anaphylaxis

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  • Type III:
    • Characteristics-type III:
      •  presence of increased antigen-antibody complex concentrations ® tissue damage
      • example: polyarteritis
      • complexes activate complement producing components with:
        • anaphylatoxic / chemotactic actions (C5a, C3a, C4a) which:
          1.  increase vascular permeability
          2.  attract neutrophils to the site of complex deposition
             •  complex deposition; neutrophil-release of lytic enzymes may cause:
               1. skin rash
               2. glomerulonephritis
               3. arthritis

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Delayed Hypersensitivity

• Cell-mediated;
• Responses: 2-3 days after sensitizing antigen exposure
• Tissue Characteristics:
  •  local inflammatory response
  •   significant damage associated with influx of antigen-nonspecific inflammatory cells especially neutrophils and macrophages

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• Macrophage/Neutrophil Recruitment -- mediation:
  • TH1-produced cytokines cause:
    1. extravasation and chemotaxis of neutrophils and circulating monocytes
    2. induction of myelopoiesis
    3. macrophage activation causing enhanced:
       • phagocytic
       • microbicidal activity
       • antigen-presenting functions
       • digestive enzyme release, contributing to extensive tissue damage

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•  Delayed-type hypersensitivity however are very effective in combating/eliminating infections caused by intracellular pathogens:
  • M. tuberculosis
  • Leishmania

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Autoimmunity

• Introduction
  • Failure to distinguish "self" tissues and cells from foreign ("nonself") antigens
  • Caused by activation of self-reactive T and B lymphocytes which induce:
    • Cell-mediated responses against self antigens
    • Humoral immune responses against self antigens

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• Clinical Pathologic Consequences, Autoimmune Disease:Examples --
  • Rheumatoid arthritis
    • IgM antibodies (rheumatoid factors) react with Fc IgG component to form immune complexes.
      • Immune complexes ® split complement components ® joint and kidney inflammation
  • systemic lupus erythematosus
    • Antibodies produced against:
      • self DNA
      • red blood cells
      • platelets
      • histones
  • Insulin-dependent diabetes mellitus
    • Cell-mediated autoimmune attack destroys:
      • insulin-producing pancreatic B cells
      • Activated CD4+ T_DTH :
        • infiltrate islets of Langerhans
        • recognize self islet B-cell peptides

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• Possible Explanations for Autoimmune Disease:
  • Self-reactive T cell exposure to previously unseen antigens (e.g. myelin basic protein, lens protein)
  • Molecular mimicry in which immune responses are directed against pathogenic antigenic determinants sharing identical or very similar epitopes with normal host tissue -- example:
    •  rheumatic fever following Streptococcus pyrogenes infection-- heart muscle damage secondary to host-immune responses against streptococcal antigenic determinants shared with myocardial tissue
    •  in the case of viral etiology -- cell-mediated and humoral immune responses are directed against viral epitopes mimicking sequestered self antigens
  • Inappropriate class II MHC molecular expression on cell membranes that should not and normally do not expressed class II MHC (pancreatic islet B cells)
    • B cells then present "self" peptides to helper T cells ® induce CTL, T_DTH, and B lymphocyte cells ® react against self antigens

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