Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis

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Shaw, Dustin G., Aguirre-Gamboa, Raúl, Vieira, Marcos C., Gona, Saideep, DiNardi, Nicholas, Wang, Anni, Dumaine, Anne, Gelderloos-Arends, Jody, Earley, Zachary M., Meckel, Katherine R., Ciszewski, Cezary, Castillo, Anabella, Monroe, Kelly, Torres, Joana, Shah, Shailja C., Colombel, Jean-Frédéric, Itzkowitz, Steven, Newberry, Rodney, Cohen, Russell D., Rubin, David T., Quince, Christopher, Cobey, Sarah, Jonkers, Iris H., Weber, Christopher R., Pekow, Joel, Wilson, Patrick C., Barreiro, Luis B. and Jabri, Bana (2023) Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis. Nature Medicine, 29 (6). pp. 1520-1529. ISSN 1078-8956

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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.

Item Type:	Article
Additional Information:	Data availability statement: Raw expression data from both bulk (gut biopsies) and single cells from purified CD4+ T cells and plasma cells are deposited in the Gene Expression Omnibus (accession no. GSE230524 for gut biopsy RNA-seq and accession no. GSE230569 for CD4 T cell and plasma cell single-cell gene expression sequencing and repertoire sequencing). Process flow cytometry, ELISpot and clinical meta-data can be accessed at the Zenodo repository (https://doi.org/10.5281/zenodo.7857026). Individual-level data are available from these repositories without time limitation: GRCh38 can be accessed at https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.26/; GRCh37/hg19 can be accessed at https://www.ncbi.nlm.nih.gov/assembly/GCF_000001405.13/. Code availability: Alongside processed data, the code relevant to the analysis and figures in the manuscript was deposited in the Zenodo repository (https://doi.org/10.5281/zenodo.7857026). Code related to the Ig analysis can be accessed at https://github.com/cobeylab/psc_repertoire. 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: © 2023, The Author(s).
Uncontrolled Keywords:	biochemistry, genetics and molecular biology(all),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300
Faculty \ School:	Faculty of Science > School of Biological Sciences
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	31 Oct 2024 16:30
Last Modified:	12 Nov 2024 14:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/97398
DOI:	10.1038/s41591-023-02372-x

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