Classify hypersensitivity reactions. Describe each type with its mechanism and examples.

Definition and Classification

• Types I, II and III are antibody-mediated and can therefore be transferred by serum; type IV is cell-mediated and can be transferred only by cells. This is the single most useful way to hold the classification
• A type V (stimulatory) is sometimes added for antibodies that stimulate rather than destroy — the TSH-receptor antibody of graves disease

Type I — Immediate Hypersensitivity

First exposure — antigen drives a Th2 response with IL-4 → B cells class-switch to produce IgE → IgE binds high-affinity FcepsilonRI receptors on mast cells and basophils — the person is now sensitised but has no symptoms → second exposure — antigen cross-links adjacent IgE molecules → degranulation within seconds → preformed mediators — histamine, tryptase, heparin, chemotactic factors → newly synthesised mediators — leukotrienes (the old SRS-A), prostaglandins, platelet-activating factor, cytokines → early phase (minutes) — vasodilatation, increased permeability, bronchospasm, itch; then a late phase at 4–12 hours with eosinophil infiltration and sustained inflammation

• Examples — anaphylaxis, atopic asthma, allergic rhinitis, urticaria and angio-oedema, food and drug allergy, insect sting reactions
• Tests — skin prick test, intradermal test, serum specific IgE (RAST), and total IgE
• Treatment — adrenaline intramuscularly in anaphylaxis; antihistamines, corticosteroids and mast cell stabilisers for lesser reactions; allergen avoidance; and desensitisation (immunotherapy) in selected patients

Type II — Cytotoxic Hypersensitivity

• Mechanism — IgG or IgM binds an antigen on a cell surface or basement membrane, and damage follows by (1) complement activation and lysis, (2) opsonisation and phagocytosis, (3) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells
• Examples — ABO-incompatible transfusion reaction; haemolytic disease OF the newborn (Rh incompatibility); autoimmune haemolytic anaemia and immune thrombocytopenia; goodpasture syndrome (anti-glomerular basement membrane antibody affecting kidney and lung); rheumatic carditis (molecular mimicry with streptococcal M protein); drug-induced cytopenias; and hyperacute graft rejection
• Antibodies that block or stimulate rather than destroy — myasthenia gravis (blocking the acetylcholine receptor) and graves disease (stimulating the TSH receptor)
• Test — the COOMBS (antiglobulin) test: direct detects antibody already on the patient’s red cells; indirect detects free antibody in the serum, and is used in cross-matching and antenatal screening

Type III and Type IV

Diagnostic Tests in Hypersensitivity

Applied Aspects

• In tuberculosis and leprosy, much of the tissue damage is type IV hypersensitivity rather than the organism itself — which is why corticosteroids are given in tuberculous meningitis and pericarditis, and in type 1 lepra reactions to save nerve function
• The Mantoux test measures exposure, not disease, and in a country with universal BCG and high background infection its positive predictive value is limited; a negative test does not exclude tuberculosis, particularly in miliary disease, HIV or malnutrition, where anergy occurs
• Give anti-D immunoglobulin to Rh-negative mothers after delivery of an Rh-positive infant and after any sensitising event; it prevents haemolytic disease of the newborn by removing fetal cells before the mother can respond
• Ask about previous reactions before giving heterologous serum — antivenom, antitoxin — and have adrenaline drawn up; but never withhold antivenom from an envenomated patient for fear of a reaction, since the alternative is death
• Adrenaline is the only drug that reverses every feature of anaphylaxis, and antihistamines and steroids must never delay it
• Contact dermatitis is a common occupational problem — nickel, chromate in cement, rubber accelerators, and topical antibiotics; patch testing identifies the agent and avoidance is the treatment
• Read the Mantoux as induration, not erythema, at 48 to 72 hours; measuring redness is a common and consequential error
• Desensitisation (allergen immunotherapy) works by shifting the response from IgE toward IgG blocking antibody and regulatory T cells; it is effective for venom and pollen allergy but must be done where anaphylaxis can be treated
• Type II and type III are distinguished by where the antigen is — fixed on a cell surface in type II, soluble and forming circulating complexes in type III; the mediators overlap but the pattern of damage differs entirely
• Serum sickness is now seen chiefly with antivenom, antitoxin and some monoclonal antibodies, appearing 7 to 10 days after administration with fever, rash, arthralgia and proteinuria
• Atopy runs in families and tends to march — infantile eczema, then food allergy, allergic rhinitis and asthma; recognising the pattern allows earlier and better management
• Hypersensitivity pneumonitis is occupational and preventable — farmer’s lung, bagassosis, bird fancier’s lung; identifying and removing the exposure prevents irreversible fibrosis
• Type IV reactions to drugs may be severe — Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with particular HLA types and with carbamazepine, allopurinol, sulphonamides and nevirapine
• Transfusion reactions span several types — acute haemolytic (type II, from ABO incompatibility and usually a clerical error), febrile non-haemolytic, allergic and anaphylactic (type I, notably in IgA deficiency)
• Check the identity of patient and unit at the bedside; ABO-incompatible transfusion is a preventable type II reaction and the fault is almost always administrative rather than immunological
• Latex allergy is an occupational hazard for healthcare workers, and cross-reacts with banana, avocado and kiwi; powder-free and synthetic gloves have greatly reduced it
• Anaphylaxis to antivenom must never prevent its use in an envenomated patient; adrenaline is drawn up first, the reaction treated, and the antivenom continued