Hypersensitivity Reactions

Gell and Coombs Classification

Type I

Sensitization phase (2-3 wk gap): APC → allergen presented → CD4 TH → TH2 → IL-4 → B cell → IgE → coats mast cell/basophil (FcεR1, high affinity).

Effector phase: re-exposure → IgE cross-link → degranulation. Primary mediators (preformed): histamine, heparin, serotonin, ECF-A, NCF-A, proteases. Secondary mediators (synthesized on stimulation): leukotrienes (SRS-A), prostaglandins, PAF, bradykinin.

Actions: vasodilation, smooth muscle contraction, ↑vascular permeability.

Manifestations:

• Systemic anaphylaxis: dyspnea, hypotension, vascular collapse. Triggers: venom, penicillin, insulin, antitoxins, seafood, nuts. DOC = epinephrine.
• Localized/atopy (>20% people, familial): Allergic rhinitis (commonest, 10%), Asthma (2nd commonest — allergic vs intrinsic), Food allergy, Atopic dermatitis, Drug allergy.

Late phase (4-6hr after immediate, lasts 1-2 days): eosinophils (ECF-A/IL-5/GM-CSF, 30% infiltrate — chronic asthma) + neutrophils (NCF-A/IL-8, 30% infiltrate) → tissue damage, basement membrane thickening.

Factors: Genetics (50% risk both parents atopic, 30% one parent). Allergen dose (small repeated = persistent IgE; large = transient IgE→IgG shift). TH1 (IFN-γ, inhibits) vs TH2 (promotes) balance.

Detection: Skin prick test (wheal-flare <30min, cheap, screens many, risk of new sensitization/rare anaphylaxis). Total/specific IgE (EIA, FEIA/ImmunoCAP, multiplex immunoblot).

Treatment: Avoidance. Hyposensitization (repeated ↑ SC doses → IgE→IgG shift or TH2→TH1 shift). Monoclonal anti-IgE (only if IgE not receptor-bound yet). Drugs: Antihistamines (block H1), Epinephrine (↑cAMP, bronchodilation), Corticosteroids, Theophylline, Cromolyn sodium (blocks mast cell Ca2+).

Type II

IgG (rare IgM) binds cell-surface/matrix/adsorbed antigen. Fc triggers 3 mechanisms:

Complement-dependent: Cytolysis (MAC C5-C9) / Inflammation (C3a, C5a chemoattractants) / Opsonization (C3b, C4b). Examples: ABO transfusion reaction, Rh incompatibility (erythroblastosis fetalis), Autoimmune hemolytic anemia/agranulocytosis/thrombocytopenia, Drug-induced hemolytic anemia (quinine, penicillin), Pemphigus vulgaris (anti-desmosome).

ADCC: IgG (Fab) coats target, Fc engages effector (NK cell) → destroys large targets (parasites, tumors, grafts).

ADCD (Antibody-dependent Cellular Dysfunction) — anti-receptor Ab:

• Activation: Graves’ disease (LATS Ab stimulates thyroid)
• Inhibition: Myasthenia gravis (anti-ACh receptor blocks)
• Others: Goodpasture (anti-type IV collagen), Pernicious anemia (anti-intrinsic factor), Rheumatic fever (anti-strep cross-reacts cardiac), Chagas myocarditis

Type III

Excess Ag-Ab complex forms (normally cleared by complement+phagocytosis; excess in chronic infection/autoimmune disease/repeated exposure).

Ab excess or Ag-Ab equivalence → large insoluble complex → localizes near site → LOCALIZED reaction. Ag excess (esp. monovalent) → small soluble complex → circulates → deposits systemically → GENERALIZED reaction.

Mechanism: Classical complement → C3a/C5a (anaphylatoxin + chemoattractant) → neutrophil recruitment → frustrated phagocytosis (can’t engulf large complex) → lytic enzyme release. + Platelet activation (Fc receptor → aggregation, microthrombi). + Hageman factor → kinin → vasodilation/edema.

Localized/Arthus reaction: NM Arthus 1903. Antigen injected into pre-immunized animal skin → local complex + complement → necrotizing vasculitis. Human examples: insect bites, repeated desensitization injections, extrinsic allergic alveolitis (Farmer’s lung = Saccharopolyspora/moldy hay; Bird-fancier’s disease = dried pigeon feces dust).

Generalized/systemic: deposits in vessels (vasculitis), GBM (glomerulonephritis), synovium (arthritis). Diseases: SLE (anti-DNA), Rheumatoid arthritis, PAN, Post-strep glomerulonephritis, Lepra reaction type 2, Hepatitis B/C arthritis, Dengue arthritis, Hyperacute graft rejection.

Serum sickness: historical, foreign (horse) antiserum. Symptoms at 7-8 days: fever, weakness, vasculitis, edema, erythema. Resolves as complexes clear. Not seen now.

Type IV (Delayed)

Cell-mediated, 24-72 hr delay. Mediator: TDTH cell (usually TH1-derived; occasionally CD8+/TH17). Injury: activated macrophages.

Sensitization phase (1-2wk): APC + MHC-II → TH → TDTH. Effector phase: re-exposure → TDTH cytokines:

• IFN-γ (KEY cytokine) — activates macrophage: ↑MHC-II, ↑TNF receptors, ↑O2 radicals, ↑NO
• IL-2 — autocrine TDTH proliferation
• MCAF, TNF-β — recruit monocytes
• MIF — inhibits macrophage migration AWAY (traps them at site)
• IL-3, GM-CSF — local monocyte synthesis

Protective (pathogen cleared, minimal damage) vs Tissue-damaging (microbe escapes killing → persistent macrophage activity → nonspecific destruction).

Granuloma formation (persistent/nondegradable antigen): macrophage → epithelioid cell (large, flat, eosinophilic) → fusion (IFN-γ) → multinucleated giant cell. Structure: epithelioid cell core + lymphocyte collar + fibroblast/connective tissue rim. Classic: TB, leprosy tubercle.

Tuberculin (Mantoux) test = DTH prototype. Intradermal tuberculin → induration+erythema at 48-72hr (sensitized). Similar tests: Lepromin test, Montenegro test (leishmaniasis), Frei test (LGV).

Contact dermatitis: nickel, poison ivy/oak, picryl chloride = haptens + skin protein → immunogenic → Langerhans cell → TH → TDTH reaction.

Other DTH conditions: Type 1 DM, Multiple sclerosis, Peripheral neuropathies, Hashimoto’s thyroiditis, Crohn’s disease, Chronic transplant rejection, GVH disease, Lepra reaction type I.

Definition and the Gell and Coombs Framework

Hypersensitivity (allergy) describes the injurious consequences a sensitized host suffers on renewed contact with a specific antigen — the normally protective immune response turned destructive. Gell and Coombs classified these reactions into four types by two features: whether the underlying abnormality is humoral or cell-mediated, and whether the reaction is immediate or delayed. Types I, II, and III are immediate (minutes to hours, antibody-driven); type IV is delayed (24–72 hours, cell-mediated).

Type I Hypersensitivity

Mechanism

Type I reactions run through two phases separated by 2–3 weeks. In the sensitization phase (first exposure, most effective parenterally but possible by any route), an APC presents allergen to CD4 TH cells, which differentiate into TH2 cells; TH2-derived IL-4 drives B cells to produce IgE, which coats mast cells and basophils via high-affinity Fcε receptors, leaving them “primed.” In the effector phase, re-exposure (the “shocking dose”) cross-links IgE on sensitized mast cells, triggering degranulation in two waves: primary mediators (preformed — histamine, heparin, serotonin, eosinophil/neutrophil chemotactic factors, proteases) release immediately; secondary mediators (synthesized on stimulation — leukotrienes, prostaglandins, platelet-activating factor, bradykinin) follow. Together these cause vasodilation, smooth-muscle contraction, and increased vascular permeability — the basis of both localized (atopic) and systemic (anaphylactic) manifestations.

Manifestations

Systemic anaphylaxis is an acute emergency — severe dyspnoea, hypotension, vascular collapse, potentially fatal within minutes — triggered by insect venom, drugs (penicillin, insulin), antitoxins, seafood, or nuts. Epinephrine is the drug of choice.

Localized anaphylaxis (atopy) affects >20% of people, runs in families, and stays confined to the entry-site epithelium: allergic rhinitis/hay fever (commonest atopic disorder, ~10% of the population), asthma (second commonest; allergic vs intrinsic/exercise-or-cold-triggered), food allergy (GI symptoms or distant urticaria), atopic dermatitis/eczema, and drug allergy.

A late-phase reaction follows the immediate phase by 4–6 hours, lasting 1–2 days, driven by recruited eosinophils (via ECF-A, IL-5, GM-CSF — ~30% of the infiltrate, contributing to chronic asthmatic inflammation) and neutrophils (via NCF-A, IL-8 — another ~30%), producing genuine tissue damage and basement-membrane thickening.

Genetic makeup (50% child risk if both parents atopic, 30% if one), allergen dose (repeated small doses → persistent IgE; larger doses → transient IgE, shift to IgG), and the TH1/TH2 balance (TH1’s IFN-γ inhibits type I reactions; TH2 promotes them) all shape an individual’s susceptibility.

Detection and Management

The skin prick test — allergen introduced intradermally or by scratch, read for wheal-and-flare within 30 minutes — is cheap and screens many allergens at once, but can itself sensitize or rarely trigger systemic anaphylaxis. Total and allergen-specific serum IgE can be measured by enzyme immunoassay, fluoro-enzyme immunoassay (ImmunoCAP), or multiplex immunoblot.

Management: allergen avoidance where feasible; hyposensitization (repeated increasing subcutaneous allergen doses, shifting the response from IgE toward blocking IgG antibody, or from TH2 toward TH1); monoclonal anti-IgE (effective only if IgE isn’t already receptor-bound); and drugs — antihistamines (block H1 receptors), epinephrine (raises mast cell cAMP, relaxes bronchial smooth muscle), corticosteroids, theophylline, cromolyn sodium (blocks mast cell Ca²⁺ influx).

Type II Hypersensitivity

IgG (rarely IgM) binds host cell-surface antigens, extracellular matrix antigens, or exogenous antigens adsorbed onto host cells, and the Fc region then triggers injury by three broad routes.

Complement-dependent reactions: cytolysis (membrane attack complex, C5-C9, pores the target), inflammation (C3a/C5a as chemoattractants), and opsonization (C3b/C4b coating the target for phagocytic uptake). Clinical examples: ABO-incompatible transfusion reaction, Rh incompatibility/erythroblastosis fetalis, autoimmune hemolytic anaemia/agranulocytosis/thrombocytopenia, drug-induced hemolytic anaemia (quinine, penicillin — drug adsorbs onto RBC, antibody binds it), and pemphigus vulgaris (autoantibodies against desmosomal proteins).

ADCC: IgG coats the target via Fab; Fc engages an effector cell’s (typically NK cell) Fc receptor, destroying targets too large to phagocytose (parasites, tumours, grafts).

Antibody-dependent cellular dysfunction (ADCD): autoantibodies against a receptor either activate it (Graves’ disease — LATS antibody stimulates thyroid) or block it (myasthenia gravis — anti-acetylcholine-receptor antibody). Other examples: Goodpasture syndrome (anti-type-IV-collagen), pernicious anaemia (anti-intrinsic-factor), rheumatic fever (anti-streptococcal antibody cross-reacting with cardiac antigen), Chagas myocarditis.

Type III Hypersensitivity

Excess immune complexes (Ag-Ab) form and, instead of being cleared efficiently by complement-mediated phagocytosis (the normal fate), accumulate — in chronic infection, autoimmune disease, or repeated environmental exposure — and deposit in tissue. Antibody excess or antigen-antibody equivalence produces large, insoluble complexes that localize near the injection/deposition site (localized reaction); antigen excess (especially monovalent antigen) produces small, soluble complexes that circulate and deposit systemically.

Tissue injury follows classical complement activation: C3a/C5a act as anaphylatoxins (local mast cell degranulation) and chemoattractants (neutrophil recruitment); neutrophils attempt but fail to phagocytose the oversized complexes, instead releasing lytic enzymes through frustrated phagocytosis. Platelet activation (Fc-receptor binding → aggregation, microthrombi, vasoactive amine release) and Hageman factor activation (→ kinin → vasodilation, oedema) compound the damage.

Localized (Arthus) reaction: NM Arthus (1903) demonstrated this by injecting antigen into a previously immunized animal’s skin — circulating antibody meets antigen locally, forming complexes that fix complement and produce localized necrotizing vasculitis. In humans: insect bites, repeated desensitization injections, and inhalational lung disease (extrinsic allergic alveolitis — farmer’s lung from Saccharopolyspora in mouldy hay, bird-fancier’s disease from dried pigeon faeces dust).

Generalized (systemic) reactions deposit complexes in blood vessels (vasculitis), glomerular basement membrane (glomerulonephritis), and synovium (arthritis) — implicated in SLE (anti-DNA), rheumatoid arthritis, polyarteritis nodosa, post-streptococcal glomerulonephritis, lepra reaction type 2, hepatitis B/C-associated arthritis, dengue arthritis, and hyperacute graft rejection. Serum sickness — the historical prototype, from foreign (horse) antiserum therapy, now essentially obsolete — produces fever, weakness, vasculitis, oedema, erythema roughly 7–8 days after exposure, resolving as complexes clear.

Type IV (Delayed) Hypersensitivity

This is cell-mediated (not antibody-driven), delayed by 24–72 hours, and mediated principally by TDTH cells (usually TH1-derived, occasionally CD8+ or TH17), with tissue injury from activated macrophages.

Sensitization phase (1–2 weeks): APCs present antigen with MHC-II to TH cells, which differentiate into TDTH cells. Effector phase: on re-exposure, TDTH cells secrete cytokines — IFN-γ (the key cytokine, activating macrophages to upregulate MHC-II, TNF receptors, oxygen radicals, nitric oxide), IL-2 (autocrine TDTH proliferation), MCAF/TNF-β (recruit monocytes to the site), MIF (inhibits macrophage migration away from the site, concentrating them), IL-3/GM-CSF (local monocyte synthesis).

This response is genuinely protective when it clears the pathogen (activated macrophages killing efficiently with minimal collateral damage) but becomes tissue-damaging when the microbe escapes macrophage killing — the resulting persistent macrophage activity and enzyme release causes nonspecific destruction. Continued DTH against persistent, non-degradable antigen produces granuloma formation: macrophages transform into epithelioid cells (large, flat, eosinophilic), which occasionally fuse (IFN-γ-induced) into multinucleated giant cells, surrounded by a lymphocyte collar and an outer fibroblast/connective-tissue rim — the classic tubercle of tuberculosis and leprosy.

The tuberculin (Mantoux) test is the prototype DTH skin test: intradermal tuberculin antigen produces induration with erythema at 48–72 hours in a sensitized individual. Analogous tests exist for other organisms (lepromin test, Montenegro test for leishmaniasis, Frei test for LGV). Contact dermatitis (nickel, poison ivy/oak, picryl chloride) follows the same mechanism — these are haptens that complex with skin protein to become immunogenic, internalized by Langerhans cells and presented to TH cells. Beyond infection and contact allergens, DTH also underlies several noninfectious conditions — type 1 diabetes, multiple sclerosis, peripheral neuropathies, Hashimoto’s thyroiditis, Crohn’s disease, chronic transplant rejection, graft-versus-host disease — and lepra reaction type I.

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