From acute mast cell activation to a structured immunothrombotic and autoimmune niche in chronic spontaneous urticaria.

Abstract

Background: Chronic spontaneous urticaria (CSU) presents recurrent wheals and/or angioedema for more than six weeks without an identifiable trigger. Although mast cell activation and histamine release are well-established effector mechanisms, this model does not explain disease persistence, immune dysregulation, or treatment refractoriness. A deeper mechanistic framework is required to explain progression to chronic disease.

Purpose: To propose a stage-wise CSU chronification model, reframing the disease as a structured dermal immunothrombotic and autoimmune niche rather than an episodic mast cell-effector event, and to derive therapeutic implications.

Methods: A narrative synthesis of ultrastructural, immunohistochemical, transcriptomic, and clinical evidence from the published clinical literature, including original studies from our group on acute drug-induced urticaria and antihistamine-refractory CSU was performed.

Results: Five sequential stages drive chronification: (1) FcεRI/BTK-dependent mast cell degranulation; (2) eosinophil tissue-factor activation of the coagulation-complement loop; (3) FXIIIa⁺ dendrocyte phagocytosis and T-cell priming via OX40/OX40L; (4) Th2-driven M2 macrophage polarization with autoantibody-mediated mast cell reactivation; and (5) JAK/STAT and IFN-λ1 signaling sustaining dermal immune niche. Transcriptomic hub genes and cytokine profiling further support this model.

Conclusion: CSU reflects a structured immune architecture rather than isolated mast cell activation. This explains treatment refractoriness and supports targeting upstream checkpoints, including BTK, JAK, and OX40/OX40L for sustained control.