IgE

**Structure & production** - Heavy chain: epsilon (ε); monomer with 4 constant domains (Cε1–Cε4). Does NOT fix complement, does not cross the placenta, is heat-labile, and has the shortest serum half-life (~2 days free in serum) but persists for weeks to months when bound to mast cells. - Class switching to IgE in B cells requires: IL-4 and IL-13 from Th2 cells (signaling via STAT6) plus CD40–CD40L interaction. IL-5 (Th2) recruits and activates eosinophils (and promotes IgA production). - Th2 differentiation is driven by IL-4; Th1 cytokine IFN-γ inhibits IgE class switching.

**Mechanism: Type I hypersensitivity** 1. Sensitization: allergen is presented to naive T cells → Th2 → IL-4/IL-13 → B cell class switch to IgE → IgE binds FcεRI on mast cells and basophils. 2. Re-exposure: allergen cross-links two or more IgE molecules on mast cells/basophils → degranulation. - Early phase (minutes): preformed mediators (histamine, tryptase, heparin, chemotactic factors) → vasodilation, increased vascular permeability, bronchoconstriction, urticaria, pruritus. - Late phase (2–24 hr): newly synthesized leukotrienes (LTC4, D4, E4), prostaglandin D2, PAF, and cytokines recruit eosinophils and neutrophils → sustained inflammation (basis for biphasic anaphylaxis and chronic asthma).

**Clinical significance** - Atopic diseases: allergic rhinitis, atopic dermatitis (eczema), allergic asthma, food allergies. Atopic triad = asthma, eczema, allergic rhinitis. - Anaphylaxis: systemic type I reaction (e.g., penicillin, bee stings, peanuts, latex). Treat with IM epinephrine (first line) via α1 (vasoconstriction), β1 (inotropy), and β2 (bronchodilation, and inhibition of mast cell mediator release). Adjuncts: H1/H2 blockers, steroids, fluids. - Helminth defense: IgE + eosinophils → antibody-dependent cellular cytotoxicity (ADCC); eosinophils release major basic protein. Elevated IgE and eosinophilia suggest parasitic (helminth) infection or allergy. - Elevated IgE: atopy, parasitic infection, hyper-IgE syndrome (Job syndrome), allergic bronchopulmonary aspergillosis (ABPA), eosinophilic granulomatosis with polyangiitis (EGPA), Wiskott-Aldrich syndrome, and Netherton syndrome. - Hyper-IgE (Job) syndrome: STAT3 mutation (AD-HSS) → defective Th17 differentiation → low IFN-γ/IL-17 → impaired neutrophil recruitment. Features: coarse facies, cold (noninflamed) staphylococcal abscesses, retained primary teeth, eczema, increased IgE, eosinophilia, and bone fractures. - Celiac/IgA considerations: IgA deficiency patients can develop anaphylaxis to IgA-containing blood products (anti-IgA antibodies).

**Diagnostics and therapy** - Allergy testing: skin prick test (wheal-and-flare), serum allergen-specific IgE (RAST/ImmunoCAP). Total IgE is nonspecific. - Omalizumab: anti-IgE monoclonal antibody that binds the Fc portion of free IgE, preventing binding to FcεRI. Used for moderate–severe allergic asthma, chronic urticaria, and nasal polyps/food allergy. Related biologics: dupilumab (anti-IL-4Rα; blocks IL-4/IL-13), mepolizumab/reslizumab (anti-IL-5), benralizumab (anti-IL-5R). - Other mast cell–targeted therapy: cromolyn (stabilizes mast cells), antihistamines, leukotriene receptor antagonists (montelukast), allergen immunotherapy (shifts toward Th1/Treg, increases IgG4 "blocking" antibodies).

**High-yield pearls** - Type I hypersensitivity is the only classic hypersensitivity type that is IgE-mediated; Types II and III are IgG/IgM-mediated and Type IV is T cell–mediated. - Serum tryptase is elevated after anaphylaxis/mast cell activation (useful for diagnosis; also elevated in systemic mastocytosis). - Some food allergies (e.g., alpha-gal from tick bites, red meat allergy) are IgE-mediated and delayed 3–6 hr. - Eosinophils and mast cells both express FcεRI (eosinophil expression is low), and Th2 cytokine profile (IL-4, IL-5, IL-13) is central.