Pathogenesis of chronic spontaneous urticaria beyond autoantibodies

Purpose of Review: Autoimmunity and autoallergy are recognized as the main determinants of chronic spontaneous urticaria (CSU) pathogenesis, but other mechanisms are also involved. Here, we review the ancillary mechanisms that contribute to CSU pathogenesis beyond histamine-releasing IgG autoantibodies and autoreactive IgE. Recent Findings: Approximately 50% of CSU patients show activation of coagulation, mainly via the extrinsic pathway, correlating with symptom severity. Thrombin, the final enzyme in the coagulation cascade, increases vascular permeability and induces mast cell degranulation by binding to protease-activated receptors and promoting complement anaphylatoxin C5a production. Another pathway involves mast cell activation via Mas-related G protein-coupled receptor X2 (MRGPRX2), whose gene is upregulated in the skin of patients with severe CSU. Neuropeptides and eosinophil-derived proteins can trigger mast cell activation through MRGPRX2. Additionally, mast cells could be activated by platelet-activating factor through indirect neurogenic mechanisms or direct contact with activated T cells. Summary: Experimental and clinical findings support the role of mechanisms other than autoimmunity and autoallergy in the pathogenesis of CSU. Understanding the interplay among the various biological systems, including coagulation, complement and neurogenic inflammation, may lead to the development of novel targeted treatments, particularly for patients with CSU refractory to H1-antihistamines and omalizumab.