Asthma

Category: disease_cascade

Overview

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).

Organ Systems

Pathway Steps

  1. inhaled allergen / virus / irritant → airway epithelial damage + alarmin release — via TSLP + IL-33 + IL-25 secretion from compromised epithelium. Allergic (type 2) asthma starts at the airway epithelium: allergens (often with intrinsic protease activity), viruses, or irritants damage the barrier and trigger alarmin release. The epithelium is thus an active initiating sensor, not a passive barrier — the target of newer epithelial-directed biologics (anti-TSLP).
  2. alarmins (TSLP, IL-33, IL-25) → ILC2 + Th2 cell activation — via group-2 innate lymphoid cells + naive CD4+ → Th2 polarization (GATA3 transcription factor). The alarmins TSLP, IL-33, and IL-25 activate group 2 innate lymphoid cells (ILC2s) and prime dendritic cells to drive Th2 responses. ILC2s provide a rapid, antigen-independent source of type-2 cytokines, explaining type-2 inflammation even in non-allergic asthma.
  3. Th2 / ILC2 cytokines → IL-4, IL-5, IL-13 secretion — via IL-4 → B-cell IgE class switching; IL-5 → eosinophil mobilization; IL-13 → mucus + AHR. Activated Th2 cells and ILC2s secrete the signature type-2 cytokines IL-4, IL-5, and IL-13, which orchestrate the allergic response. Each has a distinct job — making them precise biologic targets (dupilumab blocks IL-4/IL-13 signaling; mepolizumab blocks IL-5).
  4. IL-4 + IL-13 (B cells) → IgE class switching → high-affinity binding to mast-cell FcεRI — via allergen-IgE bridging on FcεRI triggers degranulation. IL-4 and IL-13 drive B-cell class switching to IgE, which binds the high-affinity receptor FcεRI on mast cells and basophils, arming them against the allergen. This IgE sensitization defines the allergic phenotype and is the target of anti-IgE therapy (omalizumab).
  5. mast cell degranulation → histamine + leukotrienes (LTC4/D4/E4) + PGD2 release — via bronchoconstriction + vascular leak + mucus + neural reflex (cross-link arachidonic_acid_cascade). Re-exposure cross-links mast-cell IgE, triggering degranulation: preformed histamine plus newly made cysteinyl leukotrienes (LTC4/D4/E4) and prostaglandin D2 cause the immediate bronchoconstriction, edema, and mucus of the early response. The leukotriene arm is blocked by montelukast.
  6. IL-5 axis → eosinophil bone-marrow release → eotaxin-driven airway homing — via CCL11/24/26 chemokines; eosinophil survival + maturation. IL-5 is the master eosinophil cytokine: it drives eosinophil production and release from marrow, while eotaxins guide their homing to the airway. Eosinophils drive the late-phase response and tissue damage — and blood/sputum eosinophilia defines the type-2-high asthma that responds to anti-IL-5 biologics.
  7. chronic Th2-eosinophil inflammation → airway remodeling (hypertrophy + fibrosis + goblet hyperplasia) — via irreversible FEV1 loss; remodeling is the late-stage target. Sustained type-2 inflammation remodels the airway: smooth-muscle hypertrophy, subepithelial fibrosis, goblet-cell (mucus) hyperplasia, and angiogenesis. Remodeling causes the fixed, partly irreversible airflow obstruction of chronic asthma — a structural change bronchodilators cannot reverse, motivating early anti-inflammatory control.

Known Modulators

References