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

TitleAntigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis.
Publication TypeJournal Article
Year of Publication2023
AuthorsShaw DG, Aguirre-Gamboa R, Vieira MC, Gona S, DiNardi N, Wang A, Dumaine A, Gelderloos-Arends J, Earley ZM, Meckel KR, Ciszewski C, Castillo A, Monroe K, Torres J, Shah SC, Colombel J-F, Itzkowitz S, Newberry R, Cohen RD, Rubin DT, Quince C, Cobey S, Jonkers IH, Weber CR, Pekow J, Wilson PC, Barreiro LB, Jabri B
JournalNat Med
Date Published2023 Jun
KeywordsCholangitis, Sclerosing, Colorectal Neoplasms, Humans, Inflammation, Inflammatory Bowel Diseases

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.

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Alternate JournalNat Med
PubMed ID37322120
PubMed Central IDPMC10287559
Grant ListP30 DK042086 / DK / NIDDK NIH HHS / United States
P30 DK120515 / DK / NIDDK NIH HHS / United States
F99 NS124187 / NS / NINDS NIH HHS / United States
F30 DK121470 / DK / NIDDK NIH HHS / United States
IK2 CX002027 / CX / CSRD VA / United States

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