Hereditary α-tryptasemia; a review of mechanisms linking α-tryptase gene dosage to intestinal homeostasis and immunopathology

copy number. Identified in 2015, the HαT trait impacts approximately 4%-6% of individuals of European ancestry and manifests with core clinical features in one-third of individuals who test positive for the genetic trait. HαT represents a natural human model of α-tryptase overexpression which can be leveraged to better and more comprehensively understand tryptase and mast cell (MC) biology at the tissue level. In this review, we synthesize emerging evidence demonstrating that HαT is a clinically significant modifier of disease in the gastrointestinal (GI) tract. We summarize findings demonstrating that HαT impacts small intestinal immunopathology even in the absence of overt GI pathology. In celiac disease, coexisting HαT is associated with increased duodenal MCs and persistent GI symptoms (diarrhea, bloating, abdominal pain) despite a gluten-free diet. We also review emerging data indicating that HαT may act as a disease modifier in inflammatory bowel disease (IBD); increased α-tryptase gene dosage is associated with intestinal MC activation and increased expression of MRGPRX2. These changes may amplify MC-mediated inflammatory pathways within the intestinal mucosa and contribute to the complexity of immune signaling traditionally attributed to T-cell-driven inflammation in IBD. Taken together, emerging modern cellular and molecular biology evidence suggests that the natural overexpression of α-tryptase in HαT alters MC behavior and GI intestinal immunopathology, thereby modifying disease outcomes across a spectrum of GI illnesses.