Hypersensitivity Reactions
Pathology · General Pathology · lean revision notes
Hypersensitivity Reactions
Hypersensitivity is an exaggerated or inappropriate immune response to an antigen (allergen, self-antigen, or microbe) that results in tissue injury rather than protection. The Gell and Coombs classification (Types I–IV) remains the backbone of NEET PG immunopathology, with Type II vs Type III distinctions and prototypical examples being among the highest-yielding facts.
High-yield: Mnemonic for the four types — ACID: Type I Allergic (Anaphylactic), Type II Cytotoxic (antibody-mediated), Type III Immune Complex (Immune-complex), Type IV Delayed (cell-mediated). Types I–III are antibody-mediated (humoral); Type IV is T-cell mediated.
Classification overview (Gell & Coombs)
| Type | Name | Immune mediator | Antibody/cell | Reaction time | Prototype disease |
|---|---|---|---|---|---|
| I | Immediate / Anaphylactic | IgE on mast cells | IgE | Seconds–minutes (early); 2–8 h (late) | Anaphylaxis, atopy, allergic asthma |
| II | Antibody-mediated / Cytotoxic | IgG/IgM vs cell-surface or matrix antigen | IgG, IgM (+complement) | Variable (hours–days) | Autoimmune haemolytic anaemia, Goodpasture, ITP |
| III | Immune complex | Circulating Ag-Ab complexes deposit | IgG, IgM | 3–10 h (Arthus); days (serum sickness) | SLE, post-streptococcal GN, serum sickness |
| IV | Delayed / Cell-mediated | T lymphocytes (Th1, Th17, CTL) | CD4+/CD8+ T cells, no antibody | 24–72 h | TB granuloma, contact dermatitis, Mantoux |
High-yield: Only Type IV is independent of antibody and complement; it cannot be transferred by serum but can be transferred by sensitised T cells (a classic one-liner).
Type I — Immediate (Anaphylactic) Hypersensitivity
Mechanism (stepwise)
First exposure (sensitisation) → allergen processed by APC → Th2 differentiation → IL-4 and IL-13 drive B-cell class switching to IgE → IgE binds high-affinity FcεRI receptors on mast cells/basophils. Re-exposure → allergen cross-links adjacent IgE → mast cell degranulation → two phases.
- Immediate phase (minutes): preformed mediators — histamine (vasodilatation, increased permeability, bronchospasm), tryptase, heparin, chemotactic factors (ECF-A, NCF). Newly formed lipid mediators — leukotrienes C4/D4/E4 (1000x more potent than histamine as bronchoconstrictors; the old "SRS-A"), prostaglandin D2, PAF.
- Late phase (2–8 h): eosinophil, neutrophil and Th2 cell infiltration; eosinophil major basic protein causes mucosal damage. Cytokines TNF, IL-4, IL-5.
High-yield: IL-4/IL-13 = IgE class switch; IL-5 = eosinophil recruitment/activation; IL-3 + IL-4 = mast cell growth. Tryptase is the best lab marker of mast cell degranulation (raised in anaphylaxis, useful when diagnosis is uncertain).
Clinical features
- Local (atopy): allergic rhinitis, urticaria, atopic dermatitis, allergic (extrinsic) asthma, food allergy. Atopic individuals have high IgE and family history.
- Systemic (anaphylaxis): bronchospasm, laryngeal oedema, hypotension/shock, urticaria/angioedema — within minutes of antigen (penicillin, bee sting, peanut, latex).
Management — drug of choice
Adrenaline (epinephrine) IM 0.5 mg (1:1000) into anterolateral thigh is the first-line, life-saving drug of anaphylaxis. Adjuncts: oxygen, IV fluids, antihistamines (H1 ± H2), nebulised salbutamol, hydrocortisone (prevents biphasic/late reaction).
High-yield: Adrenaline acts via α1 (vasoconstriction, reverses hypotension/oedema) and β2 (bronchodilation, stabilises mast cells). Steroids and antihistamines are NOT first-line and do not replace adrenaline.
Type II — Antibody-mediated (Cytotoxic) Hypersensitivity
IgG/IgM antibodies are directed against antigens fixed on cell surfaces or extracellular matrix. Three effector mechanisms:
- Complement & Fc-mediated opsonisation/lysis → e.g. autoimmune haemolytic anaemia, transfusion reactions, haemolytic disease of newborn, ITP. Cells are phagocytosed (extravascular, spleen) or lysed by membrane attack complex.
- Complement & Fc-mediated inflammation → leucocyte recruitment and tissue injury, e.g. Goodpasture syndrome (glomerulonephritis + pulmonary haemorrhage), pemphigus vulgaris (anti-desmoglein), acute rheumatic fever (anti-streptococcal antibody cross-reacting with myocardium).
- Antibody-mediated cellular dysfunction (no necrosis) → antibody alters function:
- Graves disease — stimulatory anti-TSH receptor antibody → hyperthyroidism.
- Myasthenia gravis — blocking anti-acetylcholine receptor antibody → muscle weakness.
- Pernicious anaemia — antibody to intrinsic factor → B12 malabsorption.
High-yield: Graves and Myasthenia gravis are classic Type II without cell destruction — the antibody changes receptor signalling. This "functional" subtype is heavily tested.
| Disease | Target antigen | Effect |
|---|---|---|
| Autoimmune haemolytic anaemia | RBC membrane antigens | Haemolysis |
| Goodpasture syndrome | Type IV collagen (α3 chain) of GBM/alveolar BM | Linear IgG, crescentic GN + lung haemorrhage |
| Pemphigus vulgaris | Desmoglein 3 (desmosome) | Intraepidermal blisters, acantholysis |
| Bullous pemphigoid | Hemidesmosome (BPAG) | Subepidermal blisters |
| Graves disease | TSH receptor | Thyroid stimulation |
| Myasthenia gravis | ACh receptor | Neuromuscular blockade |
High-yield: Immunofluorescence patterns — Goodpasture = linear; post-strep GN / SLE = granular ("lumpy-bumpy") = Type III; pemphigus = fishnet/intercellular ("chicken-wire"); bullous pemphigoid = linear along basement membrane.
Type III — Immune Complex Hypersensitivity
Circulating antigen-antibody (IgG/IgM) complexes form in antigen excess, fail to be cleared, and deposit in vessel walls, glomeruli, joints and skin → complement activation (C3a, C5a) → neutrophil recruitment → lysosomal enzyme release and vasculitis.
Two classic forms
- Serum sickness (systemic): prototype. 7–10 days after foreign protein/serum (anti-venom, anti-thymocyte globulin, certain drugs). Fever, urticaria, arthralgia, lymphadenopathy, proteinuria, low serum complement (C3).
- Arthus reaction (local): intradermal antigen in a previously sensitised (high-antibody) host → localised vasculitis with oedema, haemorrhage and necrosis within 4–10 h. Experimental analogue of hypersensitivity pneumonitis.
Prototypical diseases
- SLE — DNA/anti-DNA complexes; deposition in skin, kidney (lupus nephritis), joints.
- Post-streptococcal glomerulonephritis — subepithelial "humps" on EM, granular IgG/C3.
- Polyarteritis nodosa (HBsAg complexes), reactive arthritis, hypersensitivity vasculitis, farmer's lung.
High-yield: Type II vs Type III is the single most asked discriminator. Type II antibody is against a fixed/self antigen on a specific cell (organ-specific injury, e.g. Goodpasture kidney+lung only). Type III complexes are circulating and deposit systemically at multiple sites (skin + joints + kidney), causing low complement. If the question says "lumpy-bumpy/granular deposits" or "systemic, low C3, multiple organs" → Type III; if "specific cell/tissue target, linear deposit" → Type II.
Type IV — Delayed (Cell-mediated) Hypersensitivity
No antibody. Mediated by sensitised T cells; peaks at 48–72 h. Two arms:
- CD4+ T-cell mediated (DTH): Th1 secretes IFN-γ → macrophage activation → granuloma; Th17 secretes IL-17 → neutrophil recruitment. Prototype = tuberculin/Mantoux reaction, granulomatous inflammation (TB, leprosy, sarcoidosis, fungal), contact dermatitis (poison ivy, nickel, chromate).
- CD8+ CTL mediated: direct cytotoxic killing — type I diabetes mellitus (β-cell destruction), viral hepatitis, graft rejection, tumour immunity.
Granuloma — morphology
Activated macrophages transform into epithelioid cells and fuse into multinucleate Langhans giant cells, surrounded by a rim of CD4+ lymphocytes. Central caseation in TB. This is the histological hallmark of chronic Type IV reaction.
High-yield: Mantoux/tuberculin test, lepromin test, patch test for contact dermatitis, and the Candida/mumps anergy panel are all in-vivo demonstrations of Type IV. Read at 48–72 hours, not immediately.
| Feature | Type IV (DTH) | Type I |
|---|---|---|
| Mediator | T cells, cytokines (IFN-γ) | IgE, histamine |
| Onset | 24–72 h | Seconds–minutes |
| Transfer | By T cells (not serum) | By serum (IgE) |
| Skin test read at | 48–72 h | 15–20 min (wheal & flare) |
| Example | Mantoux, contact dermatitis | Allergy prick test |
High-yield: Contact dermatitis (nickel, poison ivy/urushiol, paraphenylenediamine in hair dye) = classic Type IV. Many drug reactions are Type IV — Stevens-Johnson syndrome, DRESS, fixed drug eruption, and tuberculoid leprosy are cell-mediated.
Diagnosis & investigation of choice
| Type | Best/confirmatory test |
|---|---|
| I | Skin prick test (immediate wheal-flare); serum specific IgE (RAST); raised tryptase in anaphylaxis |
| II | Direct/indirect Coombs (antiglobulin) test for AIHA; immunofluorescence (linear); specific autoantibodies |
| III | Serum complement (low C3/C4), immune-complex assays, granular IF, tissue biopsy with vasculitis |
| IV | Patch test (contact dermatitis), Mantoux/tuberculin (read 48–72 h), lymphocyte transformation test |
High-yield: Coombs (Coombs = "Cytotoxic", Type II) detects antibody on RBC surface — direct DAT for in-vivo coating (AIHA, HDN, drug-induced), indirect for serum antibody (cross-matching). Don't confuse the test with the Gell-and-Coombs classification eponym.
Autoimmune overlap & mixed mechanisms
Many autoimmune diseases use more than one type:
- SLE — predominantly Type III (immune complex nephritis, vasculitis) but also Type II (anti-RBC/platelet causing cytopenias).
- Rheumatoid arthritis — Type III (rheumatoid factor immune complexes) + Type IV (synovial T-cell inflammation).
- Hashimoto thyroiditis — Type IV (CTL/Th1 destruction) with Type II antibodies (anti-TPO, anti-thyroglobulin).
- Type 1 DM — Type IV (CD8 β-cell killing) with antibody markers (anti-GAD, anti-islet).
High-yield: Hyperacute graft rejection = Type II (preformed anti-donor antibodies, minutes). Acute cellular rejection = Type IV (T cells, days–weeks). Chronic rejection = mixed. GVHD = Type IV (donor T cells attack host).
Complications
- Type I: fatal anaphylactic shock, status asthmaticus, biphasic reactions (recurrence after 4–12 h), airway obstruction from laryngeal oedema.
- Type II: severe haemolysis/anaemia, kernicterus in HDN, renal failure in Goodpasture, respiratory failure in myasthenic crisis.
- Type III: chronic glomerulonephritis and renal failure, necrotising vasculitis, arthritis.
- Type IV: caseating necrosis and cavitation in TB, fibrosis, scarring, persistent contact dermatitis, transplant loss, SJS/TEN with extensive skin loss.
Key differentials (how to tell them apart in the stem)
- Linear vs granular GBM immunofluorescence → linear = Goodpasture (Type II); granular = post-strep GN/SLE (Type III).
- Immediate wheal vs 48-h induration on skin testing → Type I vs Type IV.
- Organ-specific single target vs multi-organ low-complement disease → Type II vs Type III.
- Antibody-transferable vs cell-transferable → Types I–III vs Type IV.
- Hyperacute (minutes) vs acute cellular (days) graft rejection → Type II vs Type IV.
Recently asked / exam angle
- "Lumpy-bumpy" / granular deposits in glomerulus → Type III (post-streptococcal GN, lupus nephritis). Repeatedly tested.
- Goodpasture = Type II, linear IgG, anti-GBM (α3 chain of type IV collagen) — favourite "odd one out" among glomerular diseases.
- Arthus reaction is local Type III; serum sickness is systemic Type III — a classic match-the-following.
- Graves and Myasthenia gravis as Type II without cytolysis — high-frequency single-best-answer.
- Mantoux/contact dermatitis read at 48–72 h and cannot be transferred by serum (Type IV).
- Drug of choice in anaphylaxis = IM adrenaline — repeated factual recall.
- Cytokine matching: IL-5 → eosinophils, IL-4/IL-13 → IgE, IFN-γ → macrophage activation in granuloma.
- SLE involves both Type II and Type III — a common "which type(s)" question.
Rapid revision
- ACID = Anaphylactic (I), Cytotoxic (II), Immune-complex (III), Delayed (IV).
- Types I–III are antibody-mediated; only Type IV is T-cell mediated and serum-non-transferable.
- Type I early mediator = histamine; most potent bronchoconstrictor = leukotrienes (C4/D4/E4).
- Adrenaline IM is the drug of choice in anaphylaxis; steroids prevent the late phase.
- IL-4/IL-13 → IgE switch; IL-5 → eosinophils.
- Type II Coombs-positive haemolysis; Goodpasture = linear IgG anti-GBM, kidney + lung.
- Graves (stimulatory) and Myasthenia (blocking) = Type II without cell destruction.
- Type III = circulating immune complexes, low complement, granular ("lumpy-bumpy") deposits, multi-organ.
- Serum sickness = systemic, Arthus = local Type III.
- Type IV peaks at 48–72 h; granuloma = epithelioid + Langhans giant cells + IFN-γ from Th1.
- Contact dermatitis, Mantoux, TB granuloma, SJS/DRESS, type 1 DM, transplant rejection = Type IV.
- Hyperacute rejection = Type II; acute cellular rejection & GVHD = Type IV.