Liza Konnikova1, Tanya O Robinson2, Anna H Owings2, James F Shirley3, Elisabeth Davis4, Ying Tang5, Sarah Wall6, Jian Li3, Mohammad H Hasan2, Raad Z Gharaibeh3, Lybil B Mendoza Alvarez7, Lisa K Ryan8, Andria Doty9, Jack F Chovanec10, Michael P O'Connell10, Dianne E Grunes11, William P Daley11, Emeran Mayer12, Lin Chang12, Julia Liu13, Scott B Snapper6, Joshua D Milner14, Sarah C Glover15, Jonathan J Lyons16. 1. Division of Newborn Medicine, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Children's Hospital of UPMC, Pittsburgh, Pa; Department of Pediatrics, Yale University School of Medicine, New Haven, Conn. 2. Division of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, Miss. 3. Division of Gastroenterology, Department of Medicine, University of Florida, Gainesville, Fla. 4. Division of Gastroenterology, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Ark. 5. Division of Gastroenterology, Department of Medicine, University of Florida, Gainesville, Fla; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Mass. 6. Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, Mass. 7. Division of Pediatric Gastroenterology, Department of Pediatrics, University of Florida, Gainesville, Fla. 8. Division of Infectious Disease, Department of Medicine, University of Florida, Gainesville, Fla. 9. Interdisciplinary Center for Biotechnology Research Cytometry Core, University of Florida, Gainesville, Fla. 10. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 11. Department of Pathology, University of Mississippi Medical Center, Jackson, Miss. 12. Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, UCLA, Los Angeles, Calif. 13. Morehouse School of Medicine, Atlanta, Ga. 14. Division of Allergy, Immunology and Rheumatology, Columbia University Medical Center, New York, NY. 15. Division of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, Miss; Division of Gastroenterology, Department of Medicine, University of Florida, Gainesville, Fla. Electronic address: scglover@umc.edu. 16. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: jonathan.lyons@nih.gov.
Abstract
BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase 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: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT 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 FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. 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 HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.
BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase 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: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT 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 FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. 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 HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.
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