Insights into Pathogenesis of Chronic Spontaneous Urticaria

Torsten Zuberbier, Hanna Bonnekoh, Emek Kocatürk, et al.  British Journal of Dermatology, 2026, ljag277, https://doi.org/10.1093/bjd/ljag277

Abstract

Molecular mechanisms of CSU

Chronic spontaneous urticaria (CSU) is a mast cell–mediated inflammatory disease marked by recurrent wheals and/or angioedema in the absence of identifiable external triggers. Once considered idiopathic, CSU is now recognized as a heterogeneous immunological disorder that results in mast cell activation. Two major endotypes have been described: autoallergic (type I) CSU, mediated by IgE autoantibodies directed against self-antigens, and autoimmune (type IIb) CSU, mediated by IgG autoantibodies targeting IgE or FcεRI on mast cells and basophils. Type IIb CSU is associated with higher disease severity, autoimmune comorbidities, low total IgE levels, and reduced responsiveness to antihistamines and omalizumab.

Beyond classical autoantibody-mediated mechanisms, increasing evidence supports the contribution of non–IgE-dependent pathways in CSU pathogenesis. These include Mas-related G protein–coupled receptor X2 (MRGPRX2) – mediated mast cell activation, neuroimmune interactions, activation of coagulation and complement cascades, and persistent low-grade inflammation. Alterations of the gut microbiome and impaired barrier function have also been implicated in sustaining systemic immune activation and lowering mast cell activation thresholds in subsets of patients.

Recent therapeutic advances, including biologics targeting type 2 inflammation and small-molecule inhibitors of intracellular signaling pathways such as Bruton's tyrosine kinase, highlight the clinical relevance of these mechanistic insights. However, a substantial proportion of patients remain inadequately controlled, underscoring the need for improved biomarkers, refined endotype stratification, and disease-modifying treatment strategies.

This review summarizes current insights into the multifactorial pathophysiology of CSU, highlights remaining knowledge gaps, and discusses how emerging concepts may inform more precise, personalized, and potentially disease-modifying therapeutic approaches.

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