TNFSF13 insufficiency disrupts human colonic epithelial cell-mediated B cell differentiation.

Autor:	Ma X; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Dawany N; Department of Biomedical and Health Informatics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Kondo A; Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, PA, 19104, USA., Maurer K; Division of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Karakasheva T; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Shraim R; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA.; Department of Biomedical and Health Informatics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Williams PA; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Parham LR; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Simon LA; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Danan CH; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Conrad MA; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Piccoli DA; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Devoto M; Institute for Research in Genetics and Biomedicine, CNR, Cagliari, Italy, and Department of Translational and Precision Medicine, University Sapienza, Rome, Italy., Sullivan KE; Division of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Kaestner KH; Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, Philadelphia, PA, 19104, USA., Kelsen JR; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA., Hamilton KE; Division of Gastroenterology, Hepatology, and Nutrition; Department of Pediatrics; Children's Hospital of Philadelphia; Philadelphia, PA, 19104, USA.; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 23. Date of Electronic Publication: 2024 Sep 23.
DOI:	10.1101/2024.09.23.614260
Abstrakt:	Cytokines mediating epithelial and immune cell interactions modulate mucosal healing- a process that goes awry with chronic inflammation as in inflammatory bowel disease. TNFSF13 is a cytokine important for B cell maturation and function, but roles for epithelial TNFSF13 and putative contribution to inflammatory bowel disease are poorly understood. We evaluated functional consequences of a novel monoallelic TNFSF13 variant using biopsies, tissue-derived colonoids and induced pluripotent stem cell (iPSC)-derived colon organoids. TNFSF13 variant colonoids exhibited a >50% reduction in secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis, which was confirmed in iPSC-derived colon organoids. Single cell RNA-sequencing, flow cytometry, and co-immunoprecipitation identified FAS as the predominant colonic epithelial receptor for TNFSF13. Imaging mass cytometry revealed an increase in epithelial-associated B cells in TNFSF13 variant colon tissue sections. Finally, TNFSF13 variant colonoids co-cultured with memory B cells demonstrated a reduction in the production of IgA+ plasma cells compared to control colonoid co-cultures. Our findings support a role for epithelial TNFSF13 as a regulator of colonic epithelial growth and epithelial crosstalk with B cells. Competing Interests: CONFLICTS OF INTEREST The authors disclose no conflicts.
Databáze:	MEDLINE
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