ImmunologyTier 1Medical Sciences concept

Gell and Coombs hypersensitivity classification (types I-IV)

Core concept

	Type I	Type II	Type III	Type IV
Name	Immediate / anaphylactic	Antibody-mediated cytotoxic	Immune complex	Delayed, cell-mediated
Mediator	IgE on FcepsilonRI	IgG or IgM against a CELL-SURFACE or MATRIX antigen	IgG/IgM + SOLUBLE antigen -> circulating complexes	T cells (+ macrophages, eosinophils, neutrophils)
Effector	Mast cell / basophil degranulation - histamine, tryptase, leukotrienes, PGD2	Complement lysis, opsonisation/phagocytosis, ADCC, or receptor stimulation/blockade	Deposition -> complement -> neutrophil influx	Cytokines, cytotoxic CD8, granzyme/perforin
Timing	Minutes (biphasic up to 12 h)	Hours-days	7-21 days (or 1-3 d if pre-sensitised)	48-72 h to weeks
Test	Skin prick, specific IgE, tryptase	Direct/indirect Coombs, tissue immunofluorescence	Complement consumption (low C3/C4), immune complexes, biopsy	Patch test, tuberculin/IGRA, lymphocyte transformation

Mnemonic - ACID: Allergic / Cytotoxic / Immune complex / Delayed
*The key discriminator between II and III is where the antigen is - type II antigen is fixed to a cell or membrane; type III antigen is soluble and the complex forms in the circulation before depositing*

Type I

Sensitisation -> IgE bound to FcepsilonRI -> re-exposure cross-links -> degranulation
Preformed: histamine, tryptase, heparin | Newly synthesised: leukotrienes C4/D4/E4 (the slow-reacting substance of anaphylaxis), PGD2, PAF | Late: IL-4, IL-5, IL-13
Examples: anaphylaxis, allergic rhinitis/conjunctivitis, allergic asthma, atopic dermatitis, food and venom allergy, acute urticaria, wheal-and-flare
Late-phase response at 4-8 h explains biphasic anaphylaxis and the eosinophilic infiltrate in asthma

Type II - by effector mechanism

Destruction: autoimmune haemolytic anaemia, ITP, haemolytic disease of the newborn, ABO-incompatible transfusion, drug-induced cytopenias, hyperacute transplant rejection
Basement membrane injury: Goodpasture (anti-GBM, alpha-3 chain of type IV collagen), pemphigus vulgaris (desmoglein 3), bullous pemphigoid (BP180)
Receptor stimulation or blockade (type V in some schemes): Graves (TSH receptor agonist), myasthenia gravis (AChR blocking), pernicious anaemia (intrinsic factor), insulin-receptor antibodies
Rheumatic fever - molecular mimicry with streptococcal M protein

Type III

Serum sickness - 7-21 days after a foreign protein or drug: fever, urticarial or morbilliform rash, arthralgia/arthritis, lymphadenopathy, +/- glomerulonephritis and low C3/C4
- Classic causes: heterologous antisera, anti-thymocyte globulin, rituximab and other mAbs, cefaclor, penicillins, minocycline, infliximab
- "Serum sickness-like reaction" in children after cefaclor is clinically identical but without demonstrable complexes
Others: post-streptococcal glomerulonephritis, active SLE, cryoglobulinaemic vasculitis, hypersensitivity pneumonitis (Arthus-type, farmer's lung), polyarteritis nodosa with HBV, Arthus reaction after booster vaccination
Complex size and antigen:antibody ratio determine deposition - slight antigen excess makes intermediate-size complexes that neither clear nor precipitate, and lodge in glomeruli, joints and small vessels

Type IV

Contact dermatitis (nickel, poison ivy), tuberculin/Mantoux, granuloma formation (TB, sarcoid), coeliac disease, type 1 diabetes islet destruction, chronic transplant rejection, most drug exanthems including SJS/TEN and DRESS
Contact dermatitis, not urticaria, is the type IV skin reaction - the wheal-and-flare is type I

The classification tells you which test to send and which treatment works
- Type I -> adrenaline, tryptase, skin prick testing; antihistamines are adjunctive only
- Type II -> Coombs test, immunofluorescence; steroids, IVIg, rituximab, plasma exchange
- Type III -> complement levels and biopsy; withdraw antigen, steroids, plasma exchange
- Type IV -> patch testing; steroids, T-cell-directed immunosuppression; skin prick testing is useless
Anaphylaxis vs anaphylactoid - identical clinically; anaphylactoid (radiocontrast, vancomycin, opioids) needs no prior exposure and is not IgE-mediated, but the emergency treatment is the same: IM adrenaline**
Hereditary angioedema fits none of the four - bradykinin-mediated: no urticaria, normal tryptase, no response to adrenaline, steroid or antihistamine
One drug can cause several types - penicillin: anaphylaxis (I), haemolytic anaemia (II), serum sickness (III), maculopapular rash or AGEP (IV)
The scheme is a teaching framework, not a complete taxonomy - autoinflammatory disease, complement-mediated reactions and p-i drug reactions sit outside it

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