Hypersensitivity reactions

The four types (Gell and Coombs)

• The order is Anaphylactic, Cytotoxic, immune Complex, Delayed. Complement fragments C3a and C5a (anaphylatoxins) degranulate mast cells and raise vascular permeability; C5a also attracts neutrophils.

Type I: IgE and mast cells

• Sensitisation: first exposure drives Th2 cells (IL-4, IL-13) to switch B cells to IgE, which coats mast cells by the high-affinity receptor FcεRI. IL-5 recruits eosinophils. On re-exposure, cross-linking releases histamine and tryptase (preformed), then leukotrienes and prostaglandins.
• Late phase: eosinophils and Th2 cytokines sustain inflammation. Anaphylaxis can recur hours later without re-exposure (biphasic reaction), so patients are observed for several hours (often 6–12) after treatment. A mast cell tryptase taken 1–2 hours after the event confirms anaphylaxis.
• Treatment: adrenaline 0.5 mg IM (0.5 mL of 1 in 1,000) into the anterolateral thigh in adults, repeat after 5 minutes if needed; airway, oxygen, IV fluids; antihistamines and steroids are second-line. A clear history of hives or swelling within minutes of amoxicillin is IgE allergy: avoid all penicillins.
• Venom immunotherapy gives increasing doses of venom; it induces IgG4 "blocking" antibodies that intercept the allergen before it reaches IgE, plus regulatory T cells (IL-10, TGF-β) that damp the Th2 response.
• Desensitisation: when penicillin is essential (syphilis in pregnancy with past anaphylaxis), graded oral desensitisation produces temporary tolerance. It works only for IgE-mediated allergy, never for SJS/TEN.
• Variants to recognise:

• Angioedema without urticaria or itch is usually bradykinin, not histamine, so adrenaline, antihistamines and steroids barely work:

Type II: antibody against a fixed antigen

• ITP: IgG-coated platelets are removed by splenic macrophages through Fc receptors (extravascular, no complement lysis, so no haemoglobinuria or fibrinogen fall). IVIG works within days by blocking those Fc receptors.
• ABO incompatible transfusion (usually a bedside identity error): preformed IgM anti-A or anti-B fix complement and cause intravascular haemolysis within minutes: fever, rigors, loin pain, red-brown urine, shock, DIC. The kidney is injured by free haemoglobin, hypotension and microthrombi causing acute tubular necrosis. Stop the transfusion immediately.
• Haemolytic disease of the newborn (erythroblastosis fetalis): maternal IgG anti-D crosses the placenta and coats Rh-positive fetal red cells. A first sensitising pregnancy rarely affects the baby; the next one does.
• Anti-D prophylaxis: given at 28 weeks (routine antenatal) and within 72 hours of delivering an Rh-positive baby, and after miscarriage, amniocentesis or abdominal trauma. The injected antibody coats and clears fetal red cells before the mother's B cells can respond, so she never makes her own anti-D.
• Goodpasture syndrome: antibodies to the α3 chain of type IV collagen in glomerular and alveolar basement membranes: haemoptysis and crescentic GN with linear IgG.
• Receptor antibodies: myasthenia (blocks acetylcholine receptors), Graves (stimulates TSH receptors). Hyperacute transplant rejection (minutes after reperfusion) is type II from preformed antibody. The direct Coombs test detects antibody on red cells.

Type III: immune complexes

• Complexes formed with slight antigen excess are small enough to escape the liver and spleen but large enough to lodge in vessel walls; very large complexes are cleared and cause little harm.
• They deposit where blood is filtered under high pressure or flow is turbulent: glomeruli, synovium, skin and small vessels, choroid plexus. The brain is protected by the blood–brain barrier.
• Damage comes from complement and neutrophils: low C3 in active disease (SLE, PSGN, membranoproliferative GN, cryoglobulinaemia) and granular ("lumpy-bumpy") immunofluorescence.
• Post-streptococcal GN: 1–3 weeks after a throat (or 3–6 weeks after skin) infection; cola urine, oedema, hypertension, low C3; electron microscopy shows subepithelial humps.
• Serum sickness: 1–2 weeks after foreign protein (antivenom) or drugs: fever, rash, arthralgia, proteinuria. Arthus reaction: local necrotising reaction hours after injecting antigen into a person with high IgG (a booster given too soon).
• Hypersensitivity pneumonitis (farmer's lung from mouldy hay, bird fancier's lung from pigeons): cough, fever and breathlessness 4–8 hours after exposure, better away from it. The acute reaction is type III (precipitating IgG, which shows exposure, not necessarily disease); chronic disease is type IV with lymphocytic interstitial inflammation and poorly formed granulomas.

Type IV: T cells

• Mantoux test: intradermal tuberculin read at 48–72 hours as induration, the memory Th1 response. 5 mm or more is positive in HIV, immunosuppression or recent contacts (exclude active TB, then treat latent infection); 10 mm or more in other people.
• False-negative Mantoux (anergy): miliary or overwhelming TB, malnutrition, advanced HIV, measles, steroids, sarcoidosis. It may turn positive after treatment and refeeding.
• Contact dermatitis: haptens (nickel, hair dye, chromate) bind skin proteins, are presented by Langerhans cells, and elicit Th1 reactions; confirm with patch testing.
• Granulomas: Th1 cells release IFN-γ, turning macrophages into epithelioid and giant cells (TB, leprosy, sarcoid, Crohn disease).
• Stevens–Johnson syndrome and TEN (allopurinol, carbamazepine, sulfonamides, lamotrigine): drug-specific CD8 cytotoxic T cells kill keratinocytes (granulysin, Fas ligand), giving full-thickness epidermal necrosis with a sparse infiltrate, mucosal erosions and a positive Nikolsky sign. Over 30% detachment is TEN.

Transplant rejection

Remember Name the effector: IgE (I), antibody on a cell (II), floating complexes (III), T cells (IV).

Exam trap Myasthenia, Graves and haemolytic disease of the newborn are type II; SLE and PSGN are type III; contact dermatitis is type IV, not type I.

Exam trap Angioedema without itch or weals is bradykinin-mediated (ACE inhibitor or C1 inhibitor deficiency); adrenaline and antihistamines fail.

How FCPS asks about this

• Erythroblastosis fetalis and transfusion reactions: type II; anti-D clears fetal cells before the mother responds; ABO kidney injury is from free haemoglobin and shock.
• PSGN: type III, low C3, subepithelial humps; SLE spares the brain because complexes lodge in filtering vessels.
• Anaphylaxis: IgE on mast cells; IM adrenaline 0.5 mg; observe for biphasic reaction; tryptase confirms.
• Mantoux: type IV at 48–72 hours; 5 mm positive in HIV; zero in miliary TB is anergy.
• Farmer's or pigeon breeder's lung: symptoms 4–8 hours after exposure; type III then IV.
• SJS/TEN: CD8 T cells killing keratinocytes; venom immunotherapy works through IgG4 and Tregs.
• Hereditary angioedema: C1 esterase inhibitor deficiency, low C4; icatibant or C1 inhibitor.