Increased tryptase expression in HαT is associated with upregulation of epithelia-derived MRGPRX2 agonists and MRGPRX2+ MCs in the GI mucosa

Abstract Hereditary α-tryptasemia (HαT) is a genetic trait characterized by elevated serum tryptase and increased copy number of the TPSAB1 gene. It is associated with flushing, itching, GI symptoms and anaphylaxis. HαT gut epithelia undergo increased rates of pyroptosis, and HαT gut mast cells (MCs) are increased in number with highly expressed FCER1 and CD203C. Gut MCs express Mas-related G protein–coupled receptor-X2 (MRGPRX2). Studies have clearly shown that this receptor contributes to host defense, mediates pseudo-allergy, and is involved in a number of atopic skin conditions. Herein, we sought to evaluate the impact of MRGPRX2 in individuals with HαT and GI symptoms. We observed increased numbers of MRGPRX2+ mast cells in HαT versus non-HαT gastrointestinal (GI) biopsies (colon->duodenum->stomach->Ileum). mRNA expression of tryptase and MRGPRX2 in intestine of HαT increased ~6-fold and 3-fold respectively over non-HαT biopsies. Epithelial derived agonists of MGPRX2 including human beta defensin (HBD) 2 and adrenomedullin (PAMP12) mRNA expression were also found to be upregulated ~2-fold and ~3-folds in HαT over non-HαT biopsies. MC protease carboxydeptidase-3 was also increased. Taken together, this data suggests that in addition to upregulation of MRGPRX2 in MCs, increased tryptase expression in HαT leads to upregulation of MRGPRX2 agonists and modifiers in gut epithelial cells, nociceptors and MCs, and results in GI symptoms. This work was supported by National Institutes of Health grants R01-AI124182, R01-AI143185 and R01-AI149487 to Hydar Ali.