Dupilumab is approved for severe uncontrolled asthma. It blocks the shared receptor component of IL-4 and IL-13 signalling. Which receptor subunit does it specifically target and what is the downstream consequence?

• A IL-4 receptor alpha chain (IL-4Rα) — shared by both the type I (IL-4Rα/γc) and type II (IL-4Rα/IL-13Rα1) receptor complexes, blocking both IL-4 and IL-13 signalling and reducing Th2-driven IgE production, TSLP, and airway remodelling ✓
• B IL-13 receptor alpha-2 (IL-13Rα2) decoy receptor, preventing IL-13 from binding the signalling IL-13Rα1 complex
• C Common gamma chain (γc/CD132) shared by IL-4, IL-7, and IL-21 receptors, providing broad immunosuppression beyond type 2 cytokines
• D JAK1 kinase intracellularly downstream of both IL-4 and IL-13 receptors, blocking STAT6 phosphorylation

Explanation

Dupilumab is a fully human monoclonal antibody that binds to IL-4Rα (the alpha subunit of the IL-4 receptor), which is shared by two distinct receptor complexes: the type I complex (IL-4Rα + common gamma chain/γc, which responds to IL-4 on lymphocytes) and the type II complex (IL-4Rα + IL-13Rα1, which responds to both IL-4 and IL-13 on non-hematopoietic cells including airway epithelium, fibroblasts, and smooth muscle). By binding IL-4Rα, dupilumab simultaneously blocks both IL-4 and IL-13 downstream signalling (STAT6 phosphorylation). This inhibits IL-4-driven Th2 differentiation, B-cell class switching to IgE, and goblet cell hyperplasia, while blocking IL-13-mediated airway smooth muscle hyperresponsiveness, mucus production, subepithelial fibrosis, and increased periostin expression. The result is reduction in eosinophilic inflammation, IgE levels, and exacerbation rates.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.