Chronic spontaneous urticaria (CSU) is a complex dermatological disorder that affects both adults and children, with a higher prevalence among women, significantly impacting quality of life. Characterized by persistent itchy wheals and angioedema lasting over six weeks without a clear trigger, CSU is driven by a multifaceted interplay of immune dysfunction, neuroimmune interactions, and gut microbiome imbalances. While mast cells and basophils play a central role, recent insights highlight autoantibodies, nerve-mediated inflammation, and microbiome dysbiosis as critical factors influencing disease progression. This review explored emerging autoimmune mechanisms, including IgG autoantibodies targeting IgE receptors, non-IgE-dependent mast cell activation via MRGPRX2, and increased Spleen tyrosine kinase (SYK) expression, alongside the gut-skin connection and neuropeptide-driven inflammation. We examined how microbiome alterations affect immune homeostasis and how neuropeptides, like substance P (SP) and calcitonin gene-related peptide (CGRP), contribute to CSU severity. By integrating established immunological principles with recent neurobiological discoveries, this review provides fresh insights into CSU pathogenesis, paving the way for personalized therapeutic strategies that target immune modulation, microbiome restoration, and neuroimmune regulation.
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