MRGPRX2-expressing mast cells are increased in the GI tract of individuals with active inflammatory bowel disease and hereditary α-tryptasemia

Hereditary α-tryptasemia (HαT), defined by increased <i>TPSAB1</i> copy number and elevated basal serum tryptase, is associated with mast cell (MC)-mediated symptoms, yet its role in gastrointestinal disease remains unclear. Because intestinal MCs express the non-IgE-dependent activation receptor MRGPRX2, we investigated whether MRGPRX2 expression is altered in individuals with HαT and inflammatory bowel disease (IBD). We genotyped 854 biobanked IBD samples, performed spatial transcriptomics on descending colon tissue (n = 4 HαT; n = 4 non-HαT), and analyzed small-intestinal biopsies by mass cytometry (CyTOF; n = 5 HαT; n = 9 controls). Across these complementary platforms, HαT was associated with increased gastrointestinal MC abundance and higher expression of activation markers including CD203c, LAMP-1, and SIGLEC8. Both spatial transcriptomics and ddPCR demonstrated significantly increased MRGPRX2 and SIGLEC8 transcripts in IBD samples from individuals with HαT compared with matched non-HαT IBD cases. These findings suggest that enhanced MRGPRX2 expression and associated MC activation may contribute to gastrointestinal symptoms in HαT, particularly in the context of IBD. As interest in precision immunogenetics grows, defining MC phenotypes linked to α-tryptase copy number may help refine diagnostic evaluation and identify patients who could benefit from emerging mast cell-targeted therapeutic strategies in the context of IBD.