While allergic mast cell (MC) degranulation occurs by FcεRI aggregation and varies in strength among subjects, the analogous pseudo-allergic route was recently uncovered to proceed via MRGPRX2. Here, we examine interindividual variability in skin MC responses to FcεRI triggering vs those evoked by MRGPRX2. While population-based variability is comparable between the routes, FcεRI- and MRGPRX2-stimulated pathways are completely independent from each other, and responsiveness to one has therefore no predictive value for the other. Conversely, degranulation triggered by compound 48/80 is highly correlated to the process elicited by substance P. MRGPRX2 mRNA shows pronounced population-based variability (coefficient of variation 102.9%). Surprisingly, stem cell factor (SCF) as the MC-supportive mediator par excellence potently inhibits pseudo-allergic degranulation, while it simultaneously promotes allergic stimulation via FcεRI. We conclude that SCF can have selective MC-dampening functions. Clinically, the data imply that subjects highly reactive in one pathway are not automatically hyper-responsive in terms of the alternative route.
Keywords: MRGPRX2; mast cell; pseudo-allergy; stem cell factor; substance P.
© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.