IGHE and allergic disease: Other than IgE or IgG, a plethora of stimuli such as toll-like receptor (TLR) ligands, cytokines, and chemokines can also directly activate mast cells to produce inflammatory mediators without degranulation; however, this way may exert a synergic or antagonistic effect on IgE/IgG-mediated mast cell degranulation, indicating the potential importance of non-IgE/IgG-mediated mast cell activation in the aggravation or mitigation of inflammation in allergic diseases including CSU (Yu et al., 2016; Varricchi et al., 2019).