Dupilumab, used in severe eosinophilic asthma, targets the shared IL-4Ralpha subunit. Which signalling cascade is blocked by this mechanism?

• A Dupilumab blocks the IL-4Ralpha common gamma chain (gamma-c), preventing IL-4, IL-7, IL-15, and IL-21 signalling in T cells
• B Dupilumab blocks the shared gp130 receptor subunit used by IL-6 family cytokines, reducing Jak2/STAT3 signalling
• C Dupilumab blocks IL-4Ralpha, preventing signalling of both IL-4 (IL-4R type I heterodimer) and IL-13 (IL-4R type II heterodimer with IL-13Ralpha1), inhibiting Jak1/TYK2-mediated STAT6 phosphorylation and downstream Th2 inflammatory gene transcription ✓
• D Dupilumab is an IL-4 direct neutralising antibody that prevents IL-4 from binding its receptor without blocking IL-13 signalling

Explanation

IL-4 signals through a Type I receptor (IL-4Ralpha + gamma-c, primarily on haematopoietic cells) and a Type II receptor (IL-4Ralpha + IL-13Ralpha1, on epithelial and smooth muscle cells). IL-13 signals only through the Type II receptor. Dupilumab binds IL-4Ralpha, blocking assembly of both receptor types. Downstream, JAK1 (associated with IL-4Ralpha) and TYK2 (Type I) or JAK2 (Type II) are prevented from transphosphorylating STAT6. STAT6 phosphorylation drives IgE class switching, goblet cell metaplasia, mucus hypersecretion, and airway smooth muscle contraction. This dual IL-4/IL-13 blockade explains dupilumab's efficacy across asthma, atopic dermatitis, chronic rhinosinusitis, and eosinophilic oesophagitis.

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

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Written and medically reviewed by the StethoPrep medical team.