Figure 2A. Physiology of mast cell activation (left panel) and clinical images of an 8-year-old girl with PLCγ2-associated antibody deficiency and immune dysregulation (right panel; PLCG2 variant c.313G>A p.(Val10Ile), Department of Human Genetics, University of Göttingen) and urticaria on the right wrist after exposure to cooling (swimming pool) (above) and vesiculobullous eruptions on colder areas, knees (below). SCF is the primary growth factor for mast cells, KIT, the cognate receptor for SCF. EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2) is encoded by ADGRE2. Attachment to the membrane is mediated by a noncovalently bound subunit of the receptor, which activates EMR2/ADGRE2 in mast cells, when forcefully dissociated by physical shearing forces/mechanical stress (vibration), leading to degranulation. Phosphoinositide-specific phospholipase Cγ2 (PLCγ2) is important for B-cell differentiation and function. In mast cells, PLCγ2 is downstream of the IgE receptor and catalyzes the hydrolysis of phosphatidylinositol 4, 5-bisphosphate to the secondary messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of Ca2+ from the ER. PLCγ2 can be activated by cold temperature, which leads to spontaneous calcium flux and degranulation. Tryptase (TPSAB1) is present in mast cell secretory granules. α- and β-tryptases form tetramers stabilized by heparin and are released after degranulation, where they contribute to allergic inflammation, inducing pruritus (adapted from Carlberg and Velleuer. Molecular Immunology: How Science Works, Publisher, Springer International Publishing, 2022 and [6, 7, 8]).