Pathogenesis of Chronic Spontaneous Urticaria With or Without Angioedema

Abstract

Chronic spontaneous urticaria (CSU) is a complex, immune-mediated skin disorder characterized by the appearance of wheals and/or angioedema. Histopathologic analysis reveals skin mast cell degranulation and a perivascular infiltrate composed of lymphocytes, eosinophils, neutrophils, and basophils. Mast cells and basophils are key effector cells in the pathogenesis and severity of CSU, and both cells can be activated by IgE-dependent and independent mechanisms. The pathogenesis of CSU remains incompletely understood, though recent studies have highlighted autoimmune mechanisms involving both IgG and IgE autoantibodies. Two major autoimmune endotypes have emerged: type I (autoallergic), involving IgE autoantibodies to autoantigens like thyroid peroxidase, and type IIb (autoimmune), characterized by IgG autoantibodies targeting IgE or its high-affinity receptor (FcεRI). Recently, it has been found that patients can co-express both endotypes and the disease implications are unclear. Diagnostic tools such as the autologous serum skin test, basophil histamine release assay, and detection of circulating autoantibodies aid in identifying these endotypes but lack standardized assays. In addition to IgE-dependent pathways, recent evidence implicates complement and mas-related G protein–coupled receptor X2 in non–IgE-mediated mast cell activation. Notably, endotype classification has been shown to predict therapeutic response, with type IIb patients often exhibiting lower responsiveness to antihistamines and omalizumab treatments.