Classify hypersensitivity reactions. Describe the mechanism of each type with examples.

Definition

• The immune mechanism is normal; it is the response that is excessive or misdirected
• Requires prior sensitisation — the first exposure causes no reaction
• Classified by Gell and Coombs into four types

The Four Types at a Glance

• Mnemonic — acid: Anaphylactic, Cytotoxic, Immune complex, Delayed
• Types I to III are antibody-mediated; type IV is cell-mediated — the single most useful division

Type I — Immediate Hypersensitivity

First exposure — antigen presented, TH2 response, IL-4 and IL-13 drive B cells to make IgE → IgE binds FcεRI receptors on mast cells and basophils — the person is now sensitised → Re-exposure — antigen cross-links two adjacent IgE molecules → Mast cell degranulation → immediate phase (5–30 minutes) — preformed histamine: vasodilatation, increased permeability, bronchospasm, mucus → late phase (2–24 hours) — newly synthesised leukotrienes, prostaglandins, cytokines; eosinophil infiltration and tissue damage

• The late phase causes the tissue damage, and is why asthma is treated with steroids rather than antihistamines alone
• Atopy — a genetic predisposition to exaggerated IgE responses; familial, with raised serum IgE and eosinophils

Type II — Antibody-mediated

Type III — Immune Complex Disease

Antigen–antibody complexes form in the circulation → Complexes of intermediate size in slight antigen excess are the pathogenic ones — too small to be cleared, too large to pass → Deposit where there is filtration or turbulence: glomeruli, joints, skin, small vessels, pericardium → Complement is activated → C3a and C5a → neutrophils are recruited and release lysosomal enzymes and radicals → fibrinoid necrosis and vasculitis

Type IV — Delayed (cell-mediated)

• No antibody is involved, so type IV cannot be transferred by serum — only by lymphocytes. This is the classical experimental proof
• Persistent antigen converts a delayed reaction into a granuloma after two to three weeks

Applied Aspects

• Anaphylaxis is treated with intramuscular adrenaline, which reverses every effect of the mediators; antihistamines and steroids are adjuncts only
• Skin prick testing demonstrates type I; the Mantoux test demonstrates type IV, read at 48–72 hours
• Direct and indirect Coombs tests detect type II antibody on or against red cells
• Rh haemolytic disease is a type II reaction prevented entirely by anti-D immunoglobulin — one of the great successes of applied immunopathology
• Serum sickness is now seen with antivenom and antithymocyte globulin, appearing 7–10 days after the first exposure
• Contact dermatitis to nickel, chromate and rubber is a type IV reaction diagnosed by patch testing
• Desensitisation (allergen immunotherapy) shifts the response from IgE toward blocking IgG and regulatory T cells, and is the only treatment that alters the natural history of allergy
• Asthma is a type I reaction with a dominant late phase, which is why inhaled corticosteroids are the mainstay and bronchodilators alone are inadequate
• Transfusion reactions — acute haemolytic reactions are type II and ABO-related; febrile non-haemolytic reactions are caused by donor leucocytes and are prevented by leucodepletion
• Hyperacute graft rejection is a type II reaction, and acute cellular rejection a type IV one — the same classification applies throughout transplantation
• Tuberculin conversion indicates infection, not disease, and its interpretation must allow for BCG vaccination, which is universal in India
• Corticosteroids suppress all four types, which is why they are so widely used and so readily abused
• Penicillin can cause all four types — anaphylaxis (I), haemolytic anaemia (II), serum sickness (III) and contact dermatitis (IV); a single drug illustrating the entire classification
• Eosinophilia points to type I or to parasitic infestation, and both are common in India
• Total and specific IgE support a diagnosis of atopy, but skin prick testing remains more sensitive and far cheaper
• Latex allergy is an occupational hazard for health workers, and may be type I or type IV; the two require different tests
• Hypersensitivity is the mechanism behind much of clinical medicine — asthma, drug reactions, autoimmune disease, transplant rejection and the tuberculin test all belong to this single classification
• Omalizumab, an anti-IgE antibody, is used in severe allergic asthma and acts precisely at the first step of the type I pathway
• Type II and type III are distinguished by where the antigen is — fixed on a cell surface in type II, and free in the circulation forming complexes in type III. That single question separates them reliably