Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis [bulk RNASeq]
Primary sclerosing cholangitis (PSC) is an autoimmune-like 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 both 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 PSC, IBD, and healthy controls we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia specifically in patients with PSC. This inflammatory signature is characterized by antigen-driven IL-17A+ Foxp3+ CD4 T-cell and an expansion of IgG-secreting B-cell responses. These data results suggest that the mechanisms that drive the emergence of dysplasia in of PSC and IBD dysplasia are distinct and provide molecular insights to guide prevention of colorectal cancer in PSC. Overall design: Colon biopsy  gene expression profiles from PSC, IBD and healthy controls