🔬 Overview
Hypersensitivity refers to tissue injury caused by an exaggerated or misdirected immune response. The first encounter with an antigen sensitizes the immune system; subsequent exposure triggers a damaging reaction. The four Gell & Coombs types are classified by the effector mechanism and the type of immune response.
⚡ Type I · Immediate (IgE‑mediated)
fast mast cells atopy Response within minutes of re‑exposure. Mediated by IgE bound to FcεRI on mast cells, basophils, and eosinophils.
Pathophysiology
- Sensitization: first exposure → Th2 cells produce IL‑4 and IL‑13 → B cells class‑switch to IgE.
- Effector phase: allergen cross‑links IgE on mast cells → degranulation → histamine, proteases, prostaglandins, leukotrienes.
- Late‑phase: 2–4 hours later, arachidonic acid metabolites and cytokines cause inflammation, leukocyte recruitment.
Clinical examples
- Allergic rhinitis (hay fever)
- Asthma (bronchoconstriction, mucus)
- Anaphylaxis (insect stings, drugs)
- Food allergies (urticaria, GI)
- Wheal‑and‑flare skin tests
Mediators: histamine (vasodilation, smooth muscle), heparin, prostaglandin D₂, leukotrienes C₄/D₄/E₄ (bronchospasm), LTB₄ (neutrophil chemotaxis).
🧬 Type II · Antibody‑mediated (cytotoxic / non‑cytotoxic)
IgG/IgM cell surface ECM Antibodies against cell‑surface or extracellular matrix antigens. Tissue damage localised to the antigen‑bearing tissue.
Mechanisms
- Opsonisation & complement‑mediated lysis: Fc receptor phagocytosis, MAC formation.
- Inflammatory cell recruitment: C3a, C5a, and FcγR trigger neutrophil/macrophage infiltration.
- Functional alteration: antibody binding to receptor (e.g., TSH receptor) or enzyme (e.g., AChR) alters signalling without cell death.
Cytotoxic examples
- Autoimmune hemolytic anemia (anti‑RBC)
- HDNB (Rh incompatibility)
- Goodpasture syndrome (anti‑collagen IV)
- Transfusion reactions (ABO)
Non‑cytotoxic examples
- Myasthenia gravis (anti‑AChR → muscle weakness)
- Graves disease (anti‑TSHR → hyperthyroidism)
- Pernicious anemia (anti‑intrinsic factor)
🌀 Type III · Immune complex‑mediated
soluble Ag–Ab vasculitis nephritis Circulating immune complexes deposit in small vessels → complement activation, neutrophil recruitment, tissue injury. Usually systemic.
Key diseases
- SLE (dsDNA, Sm, nucleoproteins) → nephritis, arthritis, malar rash
- Post‑streptococcal glomerulonephritis (planted streptococcal Ag) → “lumpy‑bumpy” deposits
- Serum sickness (foreign proteins) → arthritis, vasculitis, nephritis
- Polyarteritis nodosa (HBV Ag) → systemic vasculitis
🛡️ Type IV · T‑cell mediated (delayed)
CD4+ Th1/Th17 CD8+ CTL 48–72 h No antibody involvement. Tissue damage from cytokine‑activated macrophages, neutrophils, or direct cytotoxicity.
Th1 / Th17 mediated
- Tuberculin test (PPD) – induration
- Contact dermatitis (poison ivy, nickel)
- Rheumatoid arthritis (synovial inflammation)
- Crohn disease (Th1/Th17 driven)
- Type 1 diabetes (β‑cell destruction)
CD8+ CTL mediated
- Viral infections (hepatitis)
- Graft rejection
- Some autoimmune diseases (e.g., DM1)
⚖️ Autoimmunity · pathogenesis
Autoimmunity arises from failure of central (thymus, bone marrow) and peripheral tolerance. Self‑reactive lymphocytes escape deletion and become activated.
Breakdown of tolerance
- Anergy: self‑antigen recognition without co‑stimulation → lymphocyte inactivation.
- Deletion: apoptosis via Fas/FasL or caspase pathways.
- Suppression: Treg cells secrete IL‑10, TGF‑β; high CTLA‑4 sequesters B7 (CD80/86).
- B cell tolerance: anergic B cells express high IgD, excluded from follicles → apoptosis.
Genetics & environmental triggers
HLA associations are the strongest genetic risk factors. Examples:
| Disease | HLA allele |
|---|---|
| Rheumatoid arthritis | DR4 |
| Type 1 diabetes | DR3 / DR4 |
| Ankylosing spondylitis | B27 |
| Celiac disease | DQ2 / DQ8 |
| SLE | DR2 / DR3 |
Non‑HLA genes (e.g., PTPN22, CTLA‑4, IL‑2R) also contribute. Infections (molecular mimicry) and tissue injury expose self‑antigens, driving chronic progression.
💎 Clinical Pearls & High‑Yield Facts
- Bee sting anaphylaxis → type I. Urticaria, bronchospasm, hypotension. First‑line: epinephrine.
- Hashimoto thyroiditis → type IV (T‑cell mediated) with autoantibodies as markers (anti‑TPO, anti‑thyroglobulin).
- Goodpasture syndrome → type II: anti‑collagen IV antibodies → linear immunofluorescence on kidney/lung biopsy.
- Serum sickness → type III: fever, rash, arthralgias ~1‑2 weeks after antiserum or drug.
- Contact dermatitis (poison ivy) → type IV. Treat with topical steroids.
- HDNB prevention: RhoGAM at 28 weeks and within 72h of delivery/termination.
- Autoimmunity associations: female preponderance, HLA‑linked, often relapsing‑remitting.
USMLE Tip: Distinguish type II (antibody to cell surface) from type III (soluble immune complexes). Type II is localised to the target tissue; type III is systemic (vessels, glomeruli). Type IV has no antibody involvement — DTH or CTL.