Primary sclerosing cholangitis (PSC) is a class II human leukocyte antigen (HLA-II) associated autoimmune disease of the liver, characterized by the progressive fibrosis of the bile ducts, for which there is no cure. Upwards of 80% of individuals with PSC also have inflammatory bowel disease (IBD), and are at five times greater risk for colorectal cancer (CRC) than individuals with IBD alone. PSC is a major health concern, as 50% of individuals with PSC-IBD develop CRC within 25 years of diagnosis. The mechanisms causing the high risk of CRC in PSC-IBD, however, are unknown. Our group took an unbiased transcriptional approach to analyzing human colonic tissue in order to investigate the mechanisms of the increased risk of CRC and other pathologies in PSC. Our analysis revealed that expression of immunoglobulin G1 (IgG1) and genes downstream of interleukin-17 (IL-17) signaling accurately predicted all cases of dysplasia (the precursor to CRC) in patients with PSC-IBD. Further investigation suggests that these transcriptional signals may originate from an increase in adaptive immune cells, namely IgG plasma cells and IL-17+ CD4 T-cells, in the colon of PSC subjects that develop dysplasia. The objective of this study is to use primary human tissue samples to better understand the relationship between these cell types and the development of dysplasia in PSC-IBD patients. Previous work demonstrates that in HLA-II associated autoimmunity, a pathogenic antigen causes clonal expansion of plasma cells and T-cells which leads to tissue destruction. We hypothesize that in PSC, IgG plasma cells and IL-17+ CD4 T-cells are clonally expanded in response to a pathogenic antigen. Moreover, we hypothesize that these cells induce dysplasia in PSC subjects. To address this hypothesis, we propose to 1) dissect the relationship between plasma cells, T-cells, and dysplasia in PSC-IBD as compared to IBD alone; and 2) further characterize the nature and clonality of these cellular responses, and use this to identify the causative antigen. We will take a multidisciplinary approach, including single cell transcriptional analysis, to complete this investigation. As this study will be done on human tissue, the results will be directly applicable to understanding of the development of CRC in PSC-IBD. Additionally, this work may help identify a causative antigen driving dysplasia in PSC-IBD. Ultimately, this will allow for the development of therapeutics specific for individuals with PSC. This work will also contribute to our understanding of how adaptive immunity can induce cancer.
This study uses human tissue to understand the mechanisms by which colorectal cancer develops in individuals with primary sclerosing cholangitis and inflammatory bowel disease. As our approaches are human- based, all of our findings will be directly applicable to understanding these diseases. The outcomes of this work could provide diagnostic predictors for colorectal cancer, identify targets for therapeutic intervention, and ultimately reduce the rates of colorectal cancer in this at-risk population.
