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

## TL;DR

This study finds that people with hereditary α-tryptasemia and inflammatory bowel disease have more mast cells and signs of mast cell activation in their gut.

## Contribution

The study links elevated MRGPRX2 expression and mast cell activation to gastrointestinal symptoms in hereditary α-tryptasemia within the context of IBD.

## Key findings

- HαT is associated with increased gastrointestinal mast cell abundance and activation markers like CD203c and LAMP-1.
- MRGPRX2 and SIGLEC8 transcript levels are significantly higher in HαT IBD samples compared to non-HαT IBD controls.
- Findings suggest enhanced mast cell activation may contribute to gut symptoms in HαT individuals with IBD.

## Abstract

Hereditary α-tryptasemia (HαT), defined by increased TPSAB1 copy number and elevated basal serum tryptase, is associated with mast cell (MC)–mediated symptoms. However, its role in gastrointestinal disease remains unclear. Because intestinal MCs express the non–IgE-dependent activation receptor MRGPRX2, we investigated whether MRGPRX2 expression and MC phenotypes are altered in individuals with HαT in the context of inflammatory bowel disease (IBD).

We genotyped 854 biobanked IBD samples to identify individuals with HαT. Spatial transcriptomic analysis was performed on descending colon tissue from individuals with HαT (n = 4) as well as tissue and severity matched non-HαT controls (n = 4). Small intestinal biopsies were additionally analyzed using mass cytometry (CyTOF) from HαT individuals (n = 5) and non-HαT controls (n = 9). Droplet digital PCR (ddPCR) was used to establish TPSAB1 copy number variant for HαT detection. Comparisons across groups were performed using Welch's t-test with effect sizes and 95% CI.

Across complementary platforms, HαT was associated with increased gastrointestinal mast cell abundance and elevated expression of mast cell activation markers, including CD203c, LAMP-1, and SIGLEC8. Both spatial transcriptomics and ddPCR demonstrated significantly increased MRGPRX2 and SIGLEC8 transcript levels in IBD samples from individuals with HαT compared with matched non-HαT IBD controls.

These findings suggest that enhanced MRGPRX2 expression and mast cell activation may contribute to gastrointestinal symptoms in individuals with HαT, particularly in the setting of IBD. As interest in precision immunogenetics grows, defining mast cell 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.