Hypersensitivity Reactions — Gell and Coombs Types I to IV, Examples and Tests

A hypersensitivity reaction is an exaggerated or dysregulated immune response to an antigen that injures the host's own tissue. These reactions usually occur in someone previously sensitised to the antigen — the first exposure primes the immune system, and a later exposure triggers the damage. The antigen may be foreign (pollen, a drug, a vaccine, antivenom) or self (as in autoimmune disease).

Gell and Coombs grouped these reactions into four types according to the immune mechanism that does the damage. The first three are antibody-mediated and develop quickly; type IV is T-cell mediated and delayed. The classification is a mechanism map, not a list of diseases: many real illnesses involve more than one type at once.

Type I has two phases. In sensitisation, antigen-presenting cells activate T-helper cells, which drive B cells to make allergen-specific IgE. That IgE binds the high-affinity FcεRI receptor on mast cells and basophils. On re-exposure, the allergen cross-links the bound IgE and the cells degranulate within minutes, releasing histamine, leukotrienes, prostaglandins and other mediators.

• Site decides the disease — skin: urticaria, angioedema, atopic dermatitis; nose: allergic rhinitis; airway: asthma; gut: food allergy; systemic: anaphylaxis.
• Late-phase response — type I can produce a second, later wave of inflammation and chronic allergic inflammation after the immediate reaction.
• Risk factors — genetic predisposition (atopy), environmental triggers and the hygiene hypothesis (less early microbial exposure, more allergy).
• Treatment ladder — allergen avoidance, antihistamines, corticosteroids, bronchodilators, epinephrine for anaphylaxis, and allergen immunotherapy.

StatPearls now treats 'anaphylactic' (IgE-mediated) and 'anaphylactoid' (IgE-independent) reactions as one diagnosis — anaphylaxis — because the clinical picture and the treatment are identical. An old-style option that says 'anaphylactoid reactions need different treatment' is wrong.

In type II, IgG or IgM binds antigens fixed on a cell surface or in the extracellular matrix. Damage follows by three routes: opsonisation with complement- and Fc receptor-mediated phagocytosis; complement-driven inflammation; and antibody-mediated disruption of cell signalling — where the antibody does not kill the cell but switches a receptor on or off.

Treatment follows the mechanism: stop the offending drug, suppress antibody production (corticosteroids), and in severe disease remove or neutralise antibody with plasmapheresis or IVIG in severe cases. Complications include organ failure and life-threatening bleeding or pulmonary haemorrhage — the reason Goodpasture syndrome is an emergency.

In type III the antigen is soluble. Antibody binds it in the circulation (or locally), forming antigen–antibody complexes that deposit in vessel walls, joints, skin and glomeruli. The complexes activate the classical complement pathway; the fragments C3a and C5a draw in neutrophils and macrophages, whose enzymes and reactive oxygen species damage the tissue. The disease appears where the complexes lodge, not where the antigen came from.

• Serum sickness (systemic) — classically after heterologous antiserum; today mostly drugs. Fever, rash and polyarthritis or polyarthralgia appear 1–2 weeks after exposure and settle within weeks once the agent is stopped. Self-limited, excellent prognosis.
• Arthus reaction (local) — antigen injected into someone with high circulating IgG (e.g. a tetanus toxoid booster given too often). Complexes form in situ in dermal vessels → local vasculitis, pain, swelling, induration, sometimes necrosis. Develops over 6–12 hours, peaks at 12–36 hours.
• Systemic lupus erythematosus — immune complexes in kidney, skin and joints.
• Post-streptococcal glomerulonephritis — complexes in glomeruli after group A streptococcal infection.
• Hypersensitivity vasculitides — IgA vasculitis (Henoch–Schönlein purpura), cryoglobulinaemia.

Type IV is the only type with no antibody. Antigen-presenting cells activate sensitised T lymphocytes — CD4+ Th1 and Th17 cells and CD8+ cytotoxic T cells — which release cytokines, recruit macrophages or kill target cells directly. Because enough T cells must be activated and recruited, the reaction typically appears 48–72 hours after exposure and can take weeks.

• Allergic contact dermatitis — nickel, poison ivy; tested with patch testing.
• Tuberculin (Mantoux) test — 0.1 mL PPD intradermally; induration (not erythema) read at 48–72 hours.
• Granulomatous disease — tuberculosis, sarcoidosis.
• Transplant rejection (cell-mediated).
• Severe cutaneous drug reactions — SJS/TEN, DRESS (DIHS), AGEP, SDRIFE, drug fever.

Delayed hypersensitivity is also the body's defence against intracellular pathogens — mycobacteria, fungi and some parasites — and part of tumour immunity. When CD4+ T cells are depleted, as in AIDS, macrophages engulf mycobacteria but fail to eliminate them, so infection persists and progresses.

Antihistamines blunt the skin prick test (it reads a histamine-driven wheal) but do not interfere with patch testing, because a type IV reaction does not depend on histamine.

The 2023 EAACI position paper extends Gell and Coombs to nine types: antibody-mediated I–III, cell-mediated IVa–c (matching T1, T2 and T3 responses), tissue-driven V–VI — type V = epithelial barrier defects, type VI = metabolic-induced immune dysregulation — and type VII, direct cellular and inflammatory responses to chemicals. It also stresses that mixed types are common in practice.

• Contact dermatitis is type IV, not type I — even though it itches like an allergy. Atopic dermatitis is listed under type I.
• Goodpasture is type II (antibody against a fixed basement-membrane antigen), not type III — its defining biopsy finding is diffuse linear IgG along the glomerular basement membrane on immunofluorescence.
• Serum sickness and Arthus are both type III — systemic (1–2 weeks) vs local (hours).
• Tuberculin test and granulomas are type IV; measure induration, not erythema, at 48–72 hours.
• Graves and myasthenia are type II — antibodies alter receptor function without killing the cell.
• Haemolytic disease of the newborn is type II; free antibody in maternal serum is found with the indirect Coombs, antibody already coating red cells with the direct Coombs.
• SJS/TEN and DRESS are T-cell (type IV) drug reactions — not IgE.
• First drug in anaphylaxis is IM adrenaline — not IV, not antihistamine, not steroid.

• Match the disease to the type — the commonest format; know two or three examples per type cold.
• Mechanism stem — 'antibody against receptor, no cell lysis' (II), 'complement C3a/C5a, neutrophils, vasculitis after injection' (III), 'reaction peaks at 48–72 h' (IV).
• Test identification — direct vs indirect Coombs; prick vs patch test; how and when the Mantoux is read.
• Clinical vignette — fever, rash, joint pains 10 days after a new drug or antivenom = serum sickness; swelling and necrosis hours after a booster = Arthus.
• Emergency management — dose and route of adrenaline in anaphylaxis.

Revise the year-wise papers on NEET PG PYQs and INI-CET PYQs — immunology matching questions recur almost every year.