Hypersensitivity Reactions • Gell and Coombs classification: – Type I – IgE mediated (allergy) – Type II – Antibody-mediated cytotoxic – Type III – Immune Complex mediated – Type IV – Delayed-Type Hypersensitivity (DTH) • Types I, II and III are “immediate” • Type IV is delayed
Type I Hypersensitivity • Antigens are called “allergens” • Unknown why people get allergies, but there is a strong genetic predisposition (called atopy) • Hallmark is inappropriate production of IgE against allergens that cause mast cell degranulation (see fig 15-2) • Normally IgE/mast cell activity should be directed against parasitic infections
Type I Hypersensitivity • Mediators of Type I hypersensitivites – Mast cell granule contents (early effects) • Histamine and Heparin - ↑ vascular permeability, smooth muscle contraction (intestines, bronchi), mucus secretion • Chemotactic factors – attract eosinophils and neutrophils • Proteases – mucus secretion, complement activation, degradation of blood vessel basement membrane – Later Effects • Leukotrienes and prostaglandins – secreted after tissue disruption caused by mast cell degranulation, effects are similar to histamine • Arrival of proinflammatory eosinophils and neutrophils
Clinical Manifestations of Type I • Systemic anaphylaxis – Allergen gets into the blood stream – Dyspnea, ↓ BP, bronchole constriction, GI and bladder smooth muscle contration, shock, death within minutes if untreated – Treatment - epinephrine • Allergic rhinitis (hay fever) – Inhaled allergen triggers reaction in nasal mucosa – Watery exudate from nose, eyes, upper respiratory tract, sneeezing and coughing
Clinical Manifestations of Type I • Asthma – Allergic asthma – due to inhaled airborne allergens (pollens, dust, fumes, etc) – Intrinsic asthma – triggered by cold, exercise – Reaction develops in lower respiratory tract – Bronchoconstriction, airway edema, mucus secretion, inflammation • Food allergies – Ingestion of allergen – Vomiting and diarrhea – If allergens are absorbed into bloodstream, reactions can occur where allergen deposits • asthma-like symptoms • Urticaria (hives, wheal & flare response)
Clinical Manifestations of Type I • Atopic Dermatitis (allergic eczema) – Often occurs in young children – Red skin rash – Strong hereditary predisposition
Type I Hypersensitivity • Skin testing – Potential allergens are injected or scratched into the skin – If the patient is allergic a wheal & flare response occurs • RIST – radioimmunosorbent test – similar to RIA, non- invasive way to identify allergies
Type I Hypersensitivity • Treatment – Avoid allergen if possible – Antihistamines, or anti-prostaglandins – Hyposensitization – injections of low doses of allergen may cause a shift from IgE to IgG as the dominant antibody formed.
Type II Hypersensitivity • Antibody-mediated Cytotoxic HS – Antibodies (IgM or IgG) bind to cell surface antigens. Antigen/antibody complex may lead to: • Complement activation lysis • ADCC • Opsonization phagocytosis – These are normal reactions, but when they cause unwarranted tissue damage, they are considered a hypersensitivity.
Type II Hypersensitivity • Examples of Type II HS: – Transfusion reactions • To ABO blood groups • To other RBC blood groups – Hemolytic disease of the newborn (erythroblastosis fetalis) – Drug-induced hemolytic anemia (penicillin)
Type III Hypersensitivity • Immune Complex Disease – Antibody (IgG) / attaching to soluble antigen leads to complex formation – Immune complexes may deposit in: • Blood vessel walls (vasculitis) • Synovial joints (arthritis) • Glomerular basement membrane (glomerulonephritis) • Choroid plexus
Type III Hypersensitivity • Damage occurs due to: – Anaphylatoxin release due to complement activation (C3a, C5a) which then attracts neutrophils, and causes mast cell degranulation – Neutrophils have trouble phagocytosing “stuck” immune complexes so they release their granule contents leading to more inflammation – Platelet aggregation also results from complement activation • These effects are also known as the Arthus reaction
Type III Hypersensitivity • Localized reactions – edema and redness (erythema) and tissue necrosis of the affected tissue – Can occur in the skin following insect bites – Can occur in the lungs • E.g. “farmer’s lung” from inhaling particles from moldy hay
Type III Hypersenstivity • Generalized reactions: – Serum sickness (following treatment with antiserum to a toxin) – Autoimmune diseases • SLE • Rheumatoid arthritis – Drug reactions (penicillin) – Infectious diseases • Meningitis, hepatitis, malaria, mono etc.
Type IV Hypersensitivity • Delayed type hypersensitivity (DTH) – T H cells that have been “sensitized” by an antigen develop a T H 1 and (sometimes a T C response) leading to macrophage recruitment and activation. – First noticed with reaction to tuberculosis bacteria (tuberculin reaction) – Hallmarks of type IV is the large number of macrophages at the reaction site, and that it takes an average of 24 hrs to manifest after repeat exposure.
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