Mast Cell Biology and Its Role in Chronic Spontaneous Urticaria, Angioedema, and Mastocytosis

Conclusions

• Chronic spontaneous urticaria appears to arise from mast cell activation through multiple overlapping pathways rather than a single mechanism.
• The most important drivers are IgE-mediated autoallergy and IgG-mediated autoimmune pathways, which together explain much of CSU degranulation biology.
• BTK functions as a key downstream signaling node in CSU and may be an important therapeutic target because it integrates signals from both IgE and IgG pathways.
• MRGPRX2 provides an additional mast cell activation route and may help explain severe disease, pseudoallergic triggers, and drug-induced flares.
• Complement activation and PAR receptor signaling are independent amplifiers of mast cell degranulation and may contribute to CSU activity.
• Type 2 inflammation, especially IL-4 and IL-13 signaling, likely sustains and amplifies CSU by shaping mast cell behavior and vascular sensitivity.
• B cells and other immune cells participate in CSU by producing autoantibodies and interacting with mast cells, basophils, eosinophils, and T cells.
• KIT signaling is essential for mast cell survival and proliferation, and KIT mutations such as D816V point to systemic mastocytosis rather than ordinary CSU.
• Joint swelling can occur in CSU as periarticular angioedema and is typically short-lived, helping distinguish it from lupus arthritis and hereditary angioedema.
• CSU can produce lupus-like laboratory abnormalities, including ANA positivity, anti-dsDNA, and low complement, which can complicate diagnosis but do not necessarily indicate systemic lupus.