Hypersensitivity reactions occur when the immune system mounts an exaggerated or inappropriate response to an antigen, causing tissue damage rather than protection. The Gell and Coombs classification divides hypersensitivity into four types.
Type I: Immediate Hypersensitivity (Allergy)
Type I reactions are mediated by IgE antibodies bound to mast cells and basophils. Upon re-exposure to allergen, cross-linking of surface IgE triggers degranulation within minutes. Mediators released include histamine (vasodilation, bronchoconstriction, pruritus), leukotrienes (sustained bronchoconstriction), prostaglandins, and platelet-activating factor (PAF). Clinical manifestations range from mild (allergic rhinitis, urticaria, conjunctivitis) to severe systemic anaphylaxis (hypotension, airway obstruction, shock). Common allergens include pollen, dust mites, animal dander, insect venom, foods (peanuts, shellfish, eggs), and drugs (penicillin). Diagnosis is performed via skin prick testing, serum-specific IgE (ImmunoCAP), and basophil activation tests. Treatment involves antihistamines (H1 blockers), corticosteroids, epinephrine (for anaphylaxis), and allergen-specific immunotherapy (desensitization).
Type II: Antibody-Mediated Cytotoxicity
Type II reactions involve IgG or IgM antibodies directed against cell surface or extracellular matrix antigens. The antibodies bind to target cells, leading to their destruction through complement activation (MAC formation), antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and opsonization leading to phagocytosis. Examples include autoimmune hemolytic anemia (anti-RBC antibodies), Goodpasture syndrome (anti-glomerular basement membrane antibodies), myasthenia gravis (anti-acetylcholine receptor antibodies), transfusion reactions (ABO incompatibility), and drug-induced hemolytic anemia, which occurs when drugs adsorb to RBC surfaces and elicit antibody responses.
Type III: Immune Complex-Mediated Hypersensitivity
Type III reactions result from deposition of soluble antigen-antibody immune complexes in tissues, particularly blood vessel walls, renal glomeruli, and joints. Immune complexes activate complement, generating C5a and C3a (anaphylatoxins) and recruiting neutrophils, which release lysosomal enzymes and reactive oxygen species causing tissue damage. Serum sickness is a systemic immune complex disease following administration of foreign proteins (antisera, certain drugs), with symptoms including fever, rash, arthritis, and glomerulonephritis. The Arthus reaction is a localized immune complex vasculitis at an injection site. Autoimmune examples include systemic lupus erythematosus (anti-nuclear antibody complexes in kidneys, skin, joints), rheumatoid arthritis (IgM anti-IgG complexes in joints), and post-streptococcal glomerulonephritis.
Type IV: Delayed-Type Hypersensitivity (DTH)
Type IV reactions are T cell-mediated, occurring 24-72 hours after antigen exposure. They do not involve antibodies; instead, sensitized T cells release cytokines that recruit and activate macrophages. Contact dermatitis occurs when poison ivy (urushiol), nickel jewelry, and certain chemicals (haptens) penetrate skin and are presented by Langerhans cells to memory T cells, causing local inflammation and blistering. The tuberculin reaction involves intradermal injection of purified protein derivative (PPD) from M. tuberculosis, causing induration at 48-72 hours in sensitized individuals (Mantoux test for TB exposure). Granulomatous hypersensitivity occurs when persistent antigens (M. tuberculosis, M. leprae, fungi) induce granuloma formation with epithelioid macrophages and multinucleated giant cells.
Other Hypersensitivity Classifications
In addition to the four main types, Type V (Stimulatory) involves antibodies that stimulate receptor function rather than blocking it, as seen with thyroid-stimulating immunoglobulins in Graves disease, which bind the TSH receptor and cause hyperthyroidism. Type VI (ADCC) is sometimes grouped with Type II and emphasizes NK cell-mediated killing of antibody-coated target cells.
Clinical Relevance of Hypersensitivity
Drug hypersensitivity reactions can mimic all four types and require careful clinical diagnosis. Understanding the underlying type guides treatment: antihistamines for Type I and immunosuppression (corticosteroids, cyclophosphamide) for Types II through IV. Pre-screening (G6PD deficiency before primaquine, HLA-B*5701 before abacavir) can prevent severe hypersensitivity.
