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

Background: Hereditary alpha-tryptasemia (H alpha T) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with H alpha T frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. Objective: We sought to determine the prevalence of H alpha T in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HaT from patients without H alpha T. Methods: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. Results: H alpha T prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of H alpha T PBMCs (N >= 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and Fc epsilon RI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HaT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-H alpha T controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with H alpha T. Conclusions: Increased mast cell number and intestinal epithelial cell 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 H alpha T from functional GI disease. These innate and adaptive immunologic findings identified in association with H alpha T are suggestive of subclinical intestinal inflammation in symptomatic individuals.