Hypersensitivity Study Guide

📖 Core Concepts Hypersensitivity – an immune response that damages tissue or disrupts physiology after re‑exposure to a specific antigen. Gell‑Coombs classification – four mechanistic types: Type I (Immediate) – IgE on mast cells/basophils → degranulation. Type II (Cytotoxic) – IgG/IgM bind cell‑surface antigens → complement or ADCC. Type III (Immune‑complex) – Soluble Ag‑Ab complexes deposit → complement → neutrophils. Type IV (Delayed) – Antigen‑specific T cells (CD4⁺ or CD8⁺) release cytokines → tissue injury. Allergy vs. Allergen – “Allergy” = any hypersensitivity reaction; “allergen” = an antigen that binds IgE. Key cells & receptors – Mast cell FcεRI, basophil FcεRI, FcγR (Type II), CD4⁺ Th subsets, CD8⁺ CTL, neutrophils, eosinophils. Mediator families – Histamine, leukotrienes, prostaglandins (Type I); complement C3a/C5a (Types II–III); IFN‑γ, IL‑4/5/13, IL‑17, IL‑8 (Type IV subtypes). --- 📌 Must Remember Four types are defined by antigen type and immune mechanism (Gell‑Coombs). IgE‑mediated degranulation requires cross‑linking of FcεRI‑bound IgE → calcium influx via ORAI1. First‑line anaphylaxis treatment = IM epinephrine (counteracts bronchoconstriction, vasodilation, mast‑cell activation). Skin prick test → sensitization only; must be paired with compatible clinical history. Double‑blind placebo‑controlled food challenge = gold‑standard for food allergy diagnosis. Direct Coombs detects RBC‑bound IgG/IgM; Indirect Coombs detects circulating antibodies. Immune‑complex size: intermediate Ag:Ab ratios → small‑to‑medium complexes → most pathogenic (deposit in vessels). Type IV subtypes: IVa – Th1 → IFN‑γ/TNF‑α → macrophage activation, granulomas. IVb – Th2 → IL‑4/5/13 → eosinophilia. IVc – CD8⁺ CTL → perforin/granzyme/FasL → cell death. IVd – Th17 → IL‑17/IL‑8 → neutrophil recruitment. Complement deficiency (classical pathway) → ↑ risk of SLE because immune complexes linger. IgA deficiency → markedly increased risk of celiac disease (a Type IV reaction). --- 🔄 Key Processes Type I Sensitization & Activation Sensitization – Naïve B cell class‑switches → IgE specific for allergen. IgE loading – IgE binds high‑affinity FcεRI on mast cells/basophils (weeks‑long residence). Re‑exposure – Allergen cross‑links ≥2 IgE‑FcεRI complexes. Signal transduction – Calcium influx via ORAI1 → degranulation. Mediator release – Histamine, heparin, tryptase (pre‑formed) + PGD₂, LTC₄/D₄, PAF (synthesized). Late phase (hrs) – Eosinophil recruitment, cytokine production. Type II Cytotoxic Reaction Antibody binding – IgG/IgM recognizes surface antigen (cell or matrix). Complement activation – Classical pathway → C5b‑9 (MAC) → lysis. Opsonic phagocytosis – C3b tags cells for macrophage clearance. ADCC – FcγR on NK cells/macrophages bind antibody Fc → cellular killing. Type III Immune‑Complex Reaction Complex formation – Antigen + antibody → lattice; size dictated by Ag:Ab ratio. Deposition – Small/medium complexes settle in vessel walls, glomeruli, synovium. Complement cascade – C3a/C5a (anaphylatoxins) recruit neutrophils. Effector damage – Neutrophil ROS, enzymes, NETs → vasculitis, tissue injury. Type IV Delayed‑Type Reaction Sensitization – Antigen presented on MHC II → CD4⁺ Th priming (or cross‑presentation → CD8⁺). Memory T‑cell generation – Th1, Th2, Th17, or CTL subsets. Re‑exposure (48–72 h) – Rapid T‑cell activation → cytokine burst. Effector recruitment – IVa: IFN‑γ/TNF‑α → macrophage activation → granuloma. IVb: IL‑4/5/13 → eosinophils. IVc: Perforin/granzyme/FasL → target cell apoptosis. IVd: IL‑17/IL‑8 → neutrophils. --- 🔍 Key Comparisons Type I vs. Type II – IgE‑mediated mast‑cell degranulation vs. IgG/IgM‑mediated complement/ADCC. Immediate (≤ minutes) vs. Delayed (48–72 h) – Mast‑cell histamine release vs. T‑cell cytokine–driven inflammation. Antibody‑dependent (I–III) vs. Antibody‑independent (IV) – Presence of circulating immunoglobulin vs. reliance on memory T cells. Small immune complexes (pathogenic) vs. Large complexes (cleared) – Size determines tissue deposition. IgE‑binding allergen vs. Allergen (any antigen that can trigger a hypersensitivity) – Not all allergens require IgE. --- ⚠️ Common Misunderstandings “All allergies are IgE‑mediated.” – Only Type I reactions involve IgE; other types can be called allergies by modern societies. Positive skin prick = clinical allergy. – It shows sensitization; disease requires compatible symptoms. All drug reactions are Type I. – Many are Type II–IV; drugs often act as haptens (Pichler classification). Low complement always points to Type II. – Complement consumption is characteristic of Type III immune‑complex diseases. Coombs test positivity equals hemolysis severity. – It indicates bound antibodies, not the amount of hemolysis. --- 🧠 Mental Models / Intuition “Loaded gun” model (Type I): IgE‑coated mast cell = loaded gun; allergen = trigger that fires all bullets at once. “Size‑filter” model (Type III): Think of a sieve – large complexes are caught and cleared; the medium‑sized ones slip through and lodge in vessels. “T‑cell subtype toolbox” – each Th subset carries a signature “tool” (IFN‑γ for macrophages, IL‑5 for eosinophils, IL‑17 for neutrophils, perforin for killing). “Overlap radar” – many diseases sit on the border of two types (e.g., allergic asthma = Type I upper airway + Type IV lower airway). --- 🚩 Exceptions & Edge Cases Mixed‑type diseases – Acute hypersensitivity pneumonitis can start as immune‑complex (III) and evolve to delayed‑type (IV). Galactosylation of IgG – Increases IgG oligomer formation → boosts classical complement activation, augmenting Type II/III effects. Complement deficiency – Paradoxically increases autoimmune disease risk (SLE) because immune complexes persist. IgA deficiency – Masks serologic screening for celiac disease; the disease is still a Type IV reaction. --- 📍 When to Use Which | Clinical Question | Preferred Test / Tool | Reason | |-------------------|-----------------------|--------| | Suspected immediate allergic reaction | Skin prick test + serum specific IgE | Detects IgE sensitization; combine with history. | | Confirm food allergy | Double‑blind placebo‑controlled food challenge | Gold‑standard; rules out false‑positive IgE. | | Drug‑induced hemolysis | Direct Coombs test | Detects antibodies bound to patient RBCs. | | Unexplained vasculitis with low C3/C4 | Complement panel + immune‑complex assays | Suggests Type III (classical pathway activation). | | Contact dermatitis or tuberculin reaction | Patch test (48–72 h read) | Demonstrates Type IV delayed hypersensitivity. | | Severe systemic reaction (anaphylaxis) | IM epinephrine (0.3 mg adult) | Immediate reversal of bronchoconstriction & vasodilation. | | Chronic eosinophilic airway disease | Anti‑IL‑5 or anti‑IL‑4/13 biologics | Target underlying Type 2 (IVb) inflammation. | | Persistent IgE‑mediated disease despite avoidance | Anti‑IgE monoclonal antibody (omalizumab) | Lowers free IgE, down‑regulates FcεRI. | --- 👀 Patterns to Recognize Rapid onset (seconds–minutes) + urticaria/angioedema → Type I. Hemolysis, thrombocytopenia, or myasthenic symptoms after drug/auto‑antibody exposure → Type II. Arthritis, glomerulonephritis, low complement, “lumpy‑bumpy” deposits → Type III. Granulomas, chronic induration, or contact dermatitis after 48‑72 h → Type IV (subtype clues from cell infiltrate). Eosinophil‑rich infiltrate → think IVb; neutrophil‑rich → IVd; granulomatous → IVa; keratinocyte apoptosis → IVc. --- 🗂️ Exam Traps Distractor: “A positive serum IgE test confirms food allergy.” – Wrong: Requires clinical correlation and challenge confirmation. Distractor: “All drug hypersensitivity reactions are mediated by IgE.” – Wrong: Many are Type II–IV (hapten‑mediated). Distractor: “Low C3 level points to a Type II reaction.” – Wrong: Low C3 is classic for Type III immune‑complex activation (e.g., SLE). Distractor: “The direct Coombs test is used for diagnosing drug‑induced rash.” – Wrong: Direct Coombs detects RBC‑bound antibodies, not skin reactions. Distractor: “Epinephrine should be given after antihistamines in anaphylaxis.” – Wrong: Epinephrine is first‑line; antihistamines are adjuncts. Distractor: “Allergy = only IgE‑mediated.” – Wrong: Modern definition includes any immunologic hypersensitivity. ---