On this basis, we speculate that in the presence of a longstanding GERD, the slightly elevated serum levels of SP as well as low levels of IgE initially produced in the gut could progressively activate gut MCs and the small subset of MCTC in the submucosa, as well as MCTC in the skin, where SP would act initially via MRGPRX2 present on intravascular processes of these cells [21, 61]. Here, MRGPRX2 is linked to gastroesophageal reflux disease.