Mast Cells, Eosinophils & Allergic (Type I) Inflammation

Sensitization and the IgE-FcεRI axis

Sensitization. On first exposure, dendritic cells present allergen to naive CD4 T cells, which become Th2 cells. Their IL-4 and IL-13 switch allergen-specific B cells to IgE. The IgE loads onto the high-affinity receptor FcεRI on mast cells and basophils. No symptoms occur yet; they appear only on re-exposure.

Armed cells. FcεRI grips the Fc of IgE so tightly that most IgE is cell-bound: free IgE survives only a few days in serum, whereas mast cells stay armed for weeks to months. Mast cells reside in skin, airways and gut, clustered near blood vessels; basophils are their circulating counterparts. Omalizumab binds free IgE and prevents its loading onto FcεRI (allergic asthma, chronic urticaria).

The early phase: mast-cell mediators

Trigger. A multivalent allergen bridges adjacent IgE-FcεRI complexes; the cross-linking signal releases granules within minutes. Some drugs activate mast cells directly without IgE (see below).

Clinical effects. Within minutes the mediators cause vasodilation (flushing, hypotension), capillary leak (urticaria, angioedema), bronchospasm with mucus, itch and GI cramping. Confined to one organ this is allergic rhinitis, conjunctivitis or hives; when systemic it is anaphylaxis.

The late phase and eosinophils

Late-phase reaction. Cytokines released by mast cells and Th2 cells (IL-4, IL-5, IL-13, TNF) and the chemokine eotaxin recruit eosinophils, basophils and more Th2 cells, producing a second wave 4-12 hours after exposure. IL-5 drives eosinophil production in the marrow and their activation and survival in tissue. The resulting swelling and airway hyperreactivity respond to corticosteroids but not to antihistamines. Neutrophil recruitment, by contrast, is driven by IL-17 and IL-8.

Eosinophils. These bilobed cells carry red-orange granules with a crystalloid core of major basic protein. They release major basic protein, eosinophil cationic protein, eosinophil peroxidase and eosinophil-derived neurotoxin, which kill helminths but also strip airway epithelium in chronic asthma. Charcot-Leyden crystals in asthmatic sputum are crystallized eosinophil protein. Eosinophils also carry histaminase, which can blunt the reaction.

Anaphylaxis: confirmation, triggers and treatment

Serum tryptase. Tryptase peaks about 1-2 hours after the onset of anaphylaxis and normalizes within about a day. A sample drawn early and compared with a later baseline confirms mast-cell activation; histamine clears within an hour and is impractical to measure. A normal level does not exclude anaphylaxis, especially food-induced.

IgE-independent triggers. Opioids (morphine, codeine), vancomycin and radiocontrast media can degranulate mast cells directly. Because no sensitization is needed, reactions occur on first exposure and allergy testing is negative. Vancomycin's rate-related flushing and itching of the face and neck improves when the infusion is slowed.

Epinephrine. Intramuscular epinephrine into the anterolateral thigh is first-line for anaphylaxis (0.01 mg/kg of the 1 mg/mL solution, maximum 0.5 mg in adults, repeated every 5-15 minutes as needed). Each receptor contributes: α1 constricts vessels, raising blood pressure and shrinking mucosal edema; β1 increases contractility and heart rate; β2 dilates bronchi and raises cAMP in mast cells, curbing further mediator release.

Antihistamines and corticosteroids never replace epinephrine. Patients taking β-blockers may respond poorly; glucagon raises cAMP independent of β receptors.

Systemic mastocytosis

Mechanism. An activating KIT D816V mutation lets mast cells proliferate clonally without stem cell factor and accumulate in skin, marrow, liver, spleen and gut.

Features. Urticaria pigmentosa (reddish-brown macules that wheal and redden when stroked, the Darier sign), episodic flushing, pruritus, diarrhea and hypotensive or syncopal spells. Excess histamine drives acid secretion through parietal-cell H2 receptors, causing peptic ulcers. Baseline serum tryptase is persistently elevated, unlike the transient spike of anaphylaxis. Symptoms are controlled with H1 and H2 blockers and oral cromolyn; patients carry epinephrine.

Do not confuse the mutations: KIT D816V (mastocytosis), JAK2 V617F (polycythemia vera), FIP1L1-PDGFRA (a hypereosinophilic syndrome).

Causes of eosinophilia

Eosinophilia is a count above 500/μL; hypereosinophilia is above 1500/μL.

Cortisol excess (Cushing syndrome, steroid therapy) causes eosinopenia, so a normal or high eosinophil count in a critically ill, hypotensive patient should raise suspicion of adrenal insufficiency. DRESS lacks the mucosal erosions and epidermal detachment of Stevens-Johnson syndrome.