Hypersensitivity Reactions

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### Introduction to Hypersensitivity - **Definition:** Exaggerated or inappropriate immune responses damaging host tissues. - **Classification:** Gell and Coombs classification divides hypersensitivity into four main types (Type I, II, III, IV), based on the immune mechanism involved and the time course of the reaction. | Type | Immune Mechanism | Examples | Onset | |---|---|---|---| | I | IgE-mediated | Anaphylaxis, allergic asthma | Immediate (minutes) | | II | Antibody-mediated (IgG, IgM) | Transfusion reactions, autoimmune hemolytic anemia | Minutes to hours | | III | Immune complex-mediated | Serum sickness, Arthus reaction, SLE | Hours to days | | IV | Cell-mediated (T-cells) | Contact dermatitis, TB test, MS | Delayed (24-72 hours) | ### Type I Hypersensitivity (Immediate) - **Mechanism:** Allergen exposure triggers IgE production by B cells. IgE binds to Fc receptors on mast cells and basophils. Subsequent exposure to the same allergen cross-links IgE on these cells, leading to degranulation and release of inflammatory mediators (histamine, leukotrienes, prostaglandins). - **Key Mediators:** Histamine (vasodilation, increased vascular permeability, smooth muscle contraction), leukotrienes (prolonged bronchoconstriction), prostaglandins (vasodilation, bronchoconstriction). - **Clinical Manifestations:** - **Local:** Allergic rhinitis (hay fever), allergic asthma, atopic dermatitis (eczema), food allergies. - **Systemic (Anaphylaxis):** Widespread mast cell degranulation leading to systemic vasodilation, increased vascular permeability, bronchoconstriction, and shock. Can be life-threatening. - **Treatment:** Antihistamines, corticosteroids, epinephrine (for anaphylaxis), desensitization (allergy shots). ### Type II Hypersensitivity (Cytotoxic) - **Mechanism:** Antibodies (IgG or IgM) bind to antigens on the surface of target cells, leading to cell destruction. 1. **Complement-mediated lysis:** Antibodies activate complement cascade, forming Membrane Attack Complex (MAC) and lysing cells. 2. **Opsonization and phagocytosis:** Cells coated with antibodies (and/or complement C3b) are recognized and phagocytosed by macrophages and neutrophils. 3. **Antibody-Dependent Cell-mediated Cytotoxicity (ADCC):** Fc portion of antibodies on target cells is recognized by NK cells, which then kill the target cells. - **Examples:** - **Transfusion reactions:** Incompatible blood transfusions. - **Hemolytic disease of the newborn:** Rh incompatibility between mother and fetus. - **Autoimmune hemolytic anemia:** Antibodies target red blood cells. - **Goodpasture's syndrome:** Antibodies target basement membrane in kidneys and lungs. - **Myasthenia gravis:** Antibodies block acetylcholine receptors at neuromuscular junctions. - **Graves' disease:** Antibodies stimulate thyroid-stimulating hormone (TSH) receptors, leading to hyperthyroidism. - **Treatment:** Immunosuppressants, plasmapheresis, corticosteroids. ### Type III Hypersensitivity (Immune Complex) - **Mechanism:** Formation of immune complexes (antigen-antibody complexes) in the circulation. These complexes deposit in tissues (e.g., blood vessel walls, glomeruli, joints), activating complement and recruiting inflammatory cells (neutrophils), leading to tissue damage. - **Key Features:** Deposits in small blood vessels (vasculitis), glomeruli (glomerulonephritis), and joints (arthritis). - **Examples:** - **Serum sickness:** Reaction to foreign proteins (e.g., antitoxins, antivenoms) leading to fever, rash, arthralgia, glomerulonephritis. - **Arthus reaction:** Localized immune complex vasculitis following subcutaneous antigen injection in sensitized individuals. - **Systemic Lupus Erythematosus (SLE):** Autoantibodies form complexes that deposit in various tissues. - **Post-streptococcal glomerulonephritis:** Immune complexes deposit in kidney glomeruli after streptococcal infection. - **Rheumatoid arthritis:** While primarily Type IV, immune complexes can contribute. - **Treatment:** Anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants. ### Type IV Hypersensitivity (Delayed-Type, Cell-Mediated) - **Mechanism:** Unlike other types, Type IV is mediated by T-cells, not antibodies. Sensitized T-helper (CD4+) cells recognize antigens, release cytokines (e.g., IFN-$\gamma$), which activate and recruit macrophages, leading to inflammation and tissue damage. Cytotoxic T-lymphocytes (CD8+) can also directly kill target cells. - **Onset:** Delayed, typically 24-72 hours after antigen exposure. - **Examples:** - **Contact dermatitis:** Reaction to poison ivy, nickel, latex, etc. - **Tuberculin skin test (PPD test):** Diagnostic test for tuberculosis exposure. - **Granuloma formation:** Chronic inflammation in response to persistent antigens (e.g., tuberculosis, sarcoidosis). - **Multiple Sclerosis (MS):** T-cells attack myelin sheath in the central nervous system. - **Type 1 Diabetes:** T-cells destroy pancreatic beta cells. - **Graft rejection:** T-cell mediated rejection of transplanted organs. - **Treatment:** Corticosteroids, immunosuppressants.