@article{22f1446d50554fac8f82e0c7d18a2ce6,
title = "Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis",
abstract = "Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A)+ forkhead box P3 (FOXP3)+ CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC.",
author = "Shaw, {Dustin G.} and Ra{\'u}l Aguirre-Gamboa and Vieira, {Marcos C.} and Saideep Gona and Nicholas DiNardi and Anni Wang and Anne Dumaine and Jody Gelderloos-Arends and Earley, {Zachary M.} and Meckel, {Katherine R.} and Cezary Ciszewski and Anabella Castillo and Kelly Monroe and Joana Torres and Shah, {Shailja C.} and Colombel, {Jean Fr{\'e}d{\'e}ric} and Steven Itzkowitz and Rodney Newberry and Cohen, {Russell D.} and Rubin, {David T.} and Christopher Quince and Sarah Cobey and Jonkers, {Iris H.} and Weber, {Christopher R.} and Joel Pekow and Wilson, {Patrick C.} and Barreiro, {Luis B.} and Bana Jabri",
note = "Funding Information: We thank the patients, and the clinicians from the University of Chicago Inflammatory Bowel Disease Center, for supporting our research. We thank the Human Disease and Immunology Discovery Core, the Genomics Facility and the Cytometry and Antibody Technology Core at the University of Chicago for assistance with flow cytometry, cell sorting and sequencing. We thank A. Halper Stromberg, B. McDonald and V. Abadie for critically reading the manuscript. This work was supported by the Leona M. and Harry B. Helmsley Charitable trust (SHARE), the Digestive Diseases Research Core Center C-IID P30 DK42086 at the University of Chicago, the PSC Partners Seeking a Cure Canada and the Sczholtz Family Foundation. K.R.M. is supported by grant no. NS124187. S.C.S. is supported by an American Gastroenterological Association Research Scholar Award, Veterans Affairs Career Development Award (no. ICX002027A01) and the San Diego Digestive Diseases Research Center (no. P30 DK120515). C.Q. is supported by the BBSRC Core Strategic Programme Grant (BB/CSP1720/1, BBS/E/T/000PR9818 and BBS/E/T/000PR9817). I.H.J. is supported by a Rosalind Franklin Fellowship from the University of Groningen and a Netherlands Organization for Scientific Research VIDI grant no. 016.171.047. D.G.S. is supported by grant no. F30DK121470. Funding Information: We thank the patients, and the clinicians from the University of Chicago Inflammatory Bowel Disease Center, for supporting our research. We thank the Human Disease and Immunology Discovery Core, the Genomics Facility and the Cytometry and Antibody Technology Core at the University of Chicago for assistance with flow cytometry, cell sorting and sequencing. We thank A. Halper Stromberg, B. McDonald and V. Abadie for critically reading the manuscript. This work was supported by the Leona M. and Harry B. Helmsley Charitable trust (SHARE), the Digestive Diseases Research Core Center C-IID P30 DK42086 at the University of Chicago, the PSC Partners Seeking a Cure Canada and the Sczholtz Family Foundation. K.R.M. is supported by grant no. NS124187. S.C.S. is supported by an American Gastroenterological Association Research Scholar Award, Veterans Affairs Career Development Award (no. ICX002027A01) and the San Diego Digestive Diseases Research Center (no. P30 DK120515). C.Q. is supported by the BBSRC Core Strategic Programme Grant (BB/CSP1720/1, BBS/E/T/000PR9818 and BBS/E/T/000PR9817). I.H.J. is supported by a Rosalind Franklin Fellowship from the University of Groningen and a Netherlands Organization for Scientific Research VIDI grant no. 016.171.047. D.G.S. is supported by grant no. F30DK121470. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = jun,
doi = "10.1038/s41591-023-02372-x",
language = "English",
volume = "29",
pages = "1520--1529",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Research",
number = "6",
}
