Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

ABSTRACT Background Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase (BST) due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. Objective To determine the prevalence of HaT in an IBS cohort and associated immunological characteristics that may distinguish HaT from non-HaT patients. Methods Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight (CyTOF), Immunohistochemistry, and other molecular biology techniques were employed. Results HaT prevalence in an large IBS cohort was 5% (N=X/158). Immunophenotyping of HαT peripheral blood mononuclear cells (N≥27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells (MC) with expression of CD203c, HLA-DR and FceRI, higher intestinal epithelial cell (IEC) pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N=21) significantly differed from quiescent Crohn’s (N=20) and non-HαT controls (N=19), with increased antibodies directed against GI-associated proteins identified in individuals with HaT. Conclusions Increased MC number and IEC pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins distinguish HaT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.