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Hypersensitivity Reactions — Complete Notes (MD Exam, 15 Marks)

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Definition

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Classification — Gell and Coombs

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TYPE I — Anaphylactic (Immediate) Hypersensitivity

Mechanism

1. Sensitization phase: First exposure to antigen → B cells produce IgE antibodies (driven by Th2 cells secreting IL-4, IL-5, IL-6, IL-10, and Tfh13 cells secreting IL-13).
2. IgE binds via its Fc region to high-affinity FcεRI receptors on mast cells and basophils → sensitized cells.
3. Elicitation phase: Re-exposure to antigen → antigen cross-links two adjacent IgE molecules on FcεRI → mast cell/basophil degranulation.

Mediators Released

• Histamine → vasodilation, increased vascular permeability, smooth muscle contraction, mucus secretion
• Tryptase — marker of mast cell activation
• Heparin
• Eosinophil Chemotactic Factor (ECF-A)
• Neutrophil Chemotactic Factor (NCF-A)

• Leukotrienes (LTC4, LTD4, LTE4) — formerly "Slow Reacting Substance of Anaphylaxis (SRS-A)"; powerful bronchospasm and vascular permeability
• Prostaglandin D2 (PGD2) — bronchoconstriction, vasodilation
• Platelet Activating Factor (PAF) — platelet aggregation, bronchoconstriction
• Cytokines — TNF-α, IL-4, IL-5, IL-13 (late-phase amplification)

Phases

• Early phase: within minutes — bronchospasm, urticaria, angioedema
• Late phase: 4–12 hours later — eosinophil/neutrophil infiltration, persistent inflammation (IL-5, ECF-A driven)

Clinical Examples

• Anaphylaxis (penicillin, bee sting, nuts, latex)
• Bronchial asthma (atopic)
• Allergic rhinitis (hay fever)
• Urticaria and angioedema
• Atopic dermatitis (eczema)
• Food allergies

Diagnosis

• Skin prick test / intradermal test
• Serum total IgE (elevated)
• Specific IgE (RAST / ImmunoCAP)
• Serum tryptase (confirms mast cell activation)

Treatment

• Epinephrine (adrenaline) — first-line for anaphylaxis (α1: vasoconstriction; β2: bronchodilation)
• Antihistamines (H1 blockers — diphenhydramine)
• Corticosteroids (late-phase prevention)
• Bronchodilators (salbutamol)
• Desensitization / immunotherapy (allergen-specific)

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TYPE II — Cytotoxic (Antibody-Mediated) Hypersensitivity

Mechanism

• IgG or IgM antibodies directed against cell surface antigens or antigens adsorbed onto cell surfaces.
• Cell destruction occurs via three pathways:

• Special variant — Receptor dysfunction: Antibodies against receptors may stimulate (Graves' disease) or block (Myasthenia gravis) receptor function without causing cell lysis.

Clinical Examples

• ABO-incompatible blood transfusion — anti-A/anti-B IgM → complement → intravascular hemolysis
• Autoimmune Hemolytic Anemia (AIHA) — anti-RBC IgG/IgM
• Hemolytic Disease of Newborn (HDN/Erythroblastosis fetalis) — maternal anti-Rh IgG crosses placenta
• Goodpasture syndrome — anti-GBM antibodies (IgG against type IV collagen in glomeruli and alveoli)
• Graves' disease — anti-TSH receptor antibody (stimulatory) → hyperthyroidism
• Myasthenia gravis — anti-AChR antibody (blocking) → muscle weakness
• Rheumatic fever — anti-streptococcal antibodies cross-react with cardiac myosin
• Idiopathic Thrombocytopenic Purpura (ITP) — anti-platelet IgG (anti-GpIIb/IIIa)
• Pemphigus vulgaris — anti-desmoglein IgG → skin blistering

Diagnosis

• Direct Coombs test (DAT) — detects antibody/complement on RBCs
• Indirect Coombs test — detects antibodies in serum
• Biopsy with immunofluorescence (linear IgG deposit — Goodpasture)

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TYPE III — Immune Complex–Mediated Hypersensitivity

Mechanism

1. Antigen–antibody (IgG/IgM) complexes form in circulation (systemic) or locally in tissues.
2. When complexes are formed in antigen excess, they are small and soluble → not cleared efficiently by mononuclear phagocyte system → deposit in vessel walls, glomeruli, synovium, and other sites.
3. Deposited complexes activate complement → C3a, C5a (anaphylatoxins) → mast cell degranulation, neutrophil and monocyte recruitment.
4. Activated neutrophils release lysosomal enzymes, reactive oxygen species → tissue damage (vasculitis, glomerulonephritis).
5. Platelets aggregate → microthrombi formation.

Forms

Clinical Examples

• Serum sickness — 7–21 days after foreign serum (horse anti-toxin) or drugs (penicillin, sulfonamides) → fever, urticaria, arthralgia, lymphadenopathy, proteinuria
• SLE (Systemic Lupus Erythematosus) — anti-DNA immune complexes deposit in glomeruli, vessels, skin
• Post-streptococcal glomerulonephritis — streptococcal antigen–antibody complexes → "lumpy-bumpy" IgG + C3 deposits on GBM
• Polyarteritis nodosa — hepatitis B antigen-antibody complexes
• Arthus reaction — local reaction at injection site (intradermal/subcutaneous) → erythema, induration, necrosis at 6–8 hours
• Hypersensitivity pneumonitis (Extrinsic allergic alveolitis) — farmer's lung (thermophilic actinomycetes), bird fancier's lung
• Type 2 leprosy reaction (ENL/Erythema Nodosum Leprosum) — immune complex–mediated vasculitis during leprosy treatment (Harrison's p. 5220)
• Rheumatoid arthritis — RF (IgM anti-IgG) complexes → synovitis

Key Lab/Pathological Features

• ↓ Serum complement (C3, C4, CH50) — consumption
• Immunofluorescence: granular/lumpy-bumpy deposits of IgG, IgM, C3 (vs. linear in Type II)
• Electron microscopy: subepithelial humps (post-streptococcal GN)
• ↑ Circulating immune complexes (C1q binding assay)
• ↑ ESR, CRP

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TYPE IV — Delayed (Cell-Mediated) Hypersensitivity

Mechanism

• First exposure to antigen → Antigen Presenting Cells (APCs — dendritic cells, Langerhans cells, macrophages) process antigen → present on MHC class II → activate CD4+ Th1 cells, or on MHC class I → activate CD8+ CTLs.
• Memory T cells are generated.

• Sensitized Th1 cells recognize antigen → release cytokines:
  • IFN-γ → macrophage activation → epithelioid and giant cell formation → granuloma
  • TNF-α, IL-2 → inflammation, T cell proliferation
  • IL-3, GM-CSF → monocyte/macrophage recruitment
• Activated macrophages release further cytokines, lysosomal enzymes, ROS → tissue damage
• CD8+ CTLs directly kill antigen-bearing cells (perforin/granzyme pathway)

Subtypes of Type IV (Cher classification)

Clinical Examples

• Tuberculin (Mantoux) test — 48–72 h induration; hallmark Type IV reaction
• Contact dermatitis — poison ivy (urushiol), nickel, chromate, latex; Langerhans cells are key APCs
• Granulomatous diseases — tuberculosis, sarcoidosis, leprosy (TT type), Crohn's disease, schistosomiasis
• Graft rejection (acute and chronic cellular rejection)
• Type 1 diabetes mellitus — CD8+ CTL destruction of beta cells
• Hashimoto's thyroiditis
• Multiple sclerosis
• Drug hypersensitivity — Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) (Type IVc)

Classic Test — Tuberculin Test (PPD)

• Intradermal injection of purified protein derivative (PPD)
• Read at 48–72 hours
• Positive: ≥10 mm induration (≥5 mm in HIV/immunocompromised)
• Histology: perivascular infiltrate of lymphocytes and macrophages

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Comparison Table — All Four Types

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Passive Transfer of Hypersensitivity

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Important Points for Exam

1. Type I is the only type mediated by IgE; all others by IgG/IgM (II, III) or T cells (IV).
2. Types I, II, III are antibody-mediated → can be passively transferred by serum.
3. Type IV is cell-mediated → only transferable by cells (lymphocytes).
4. Complement is activated in Types II and III, not in I or IV.
5. Arthus reaction = local Type III; Serum sickness = systemic Type III.
6. Graves' disease and Myasthenia gravis are Type II but involve receptor dysfunction (not cell lysis).
7. SJS/TEN = Type IVc (CD8+ CTL-mediated).
8. Erythema nodosum leprosum (ENL/T2R) = Type III immune complex reaction (Harrison's p. 5220).
9. Tuberculin reaction = classic Type IV; maximal at 48–72 hours.
10. SRS-A (Slow Reacting Substance of Anaphylaxis) = LTC4 + LTD4 + LTE4 (Type I, most potent bronchoconstrictors).

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Memory Aids

• Type I → IgE → Immediate → Itching, anaphylaxis
• Type II → II antibodies attack II = cells (surface antigens)
• Type III → IIIangle of IgG + Ag + Complement = complex problem
• Type IV → IV = IVolves T cells = IVery Delayed (48–72 h)

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