Category: disease_cascade
Asthma is a heterogeneous chronic airway disease. The dominant phenotype is Type-2 (T2-high) inflammation driven by eosinophils + Th2 cytokines. Step 1: trigger — inhaled allergen, virus, irritant. Step 2: epithelial alarmins — damaged airway epithelium releases TSLP (thymic stromal lymphopoietin), IL-25, IL-33 — the "alarmin axis." Step 3: ILC2 + Th2 activation — TSLP + IL-33 + IL-25 activate group 2 innate lymphoid cells (ILC2) + naive CD4+ T cells differentiating to Th2 → IL-4, IL-5, IL-13 production. Step 4: IgE class switching — IL-4 + IL-13 drive B-cell IgE class switching; IgE binds high-affinity FcεRI on mast cells + basophils. Step 5: mast-cell degranulation — allergen-IgE-FcεRI cross-linking → histamine, tryptase, leukotrienes (LTC4/D4/E4), prostaglandins (PGD2) → bronchoconstriction + vascular leak + mucus + neural reflex. Step 6: eosinophil recruitment — IL-5 → bone marrow eosinophil release + survival; eotaxins (CCL11/24/26) → airway homing; eosinophilic infiltrate releases major basic protein, ECP, EDN → epithelial damage + remodeling. Step 7: airway remodeling — chronic Th2-eosinophil inflammation → goblet cell hyperplasia + mucus, smooth-muscle hypertrophy, subepithelial fibrosis, irreversible loss of FEV1. Therapeutics by mechanism: ICS (fluticasone, budesonide, beclomethasone, ciclesonide, mometasone) — anti-inflammatory mainstay; LABA (salmeterol, formoterol) + LAMA (tiotropium, umeclidinium); leukotriene modifiers (montelukast, zafirlukast, zileuton); anti-IgE (omalizumab); anti-IL-5 (mepolizumab, reslizumab, benralizumab — not in registry); anti-IL-4Rα (dupilumab — blocks IL-4 + IL-13); anti-TSLP (tezepelumab — pan-T2). Cross-links: [[mast_cell_leukotriene_axis]], [[arachidonic_acid_cascade]] (LT + PG), [[jak_stat_signaling]] (cytokine signaling), [[tlr_innate_signaling]] (alarmin upstream).