Primary sclerosing cholangitis (PSC) is an immune-mediated, cholestatic liver disease characterized by progressive fibrosis of the liver bile ducts. PSC patients have significantly greater rates of liver failure, portal hypertension, and cholangiocarcinoma (CCA) than the general population, and the median survival time from diagnosis is only 12 years without a liver transplant. Aside from transplant, there are no therapies that can prevent or cure the liver pathology. Nearly all PSC patients have a secondary diagnosis of inflammatory bowel disease (IBD), however the presentation of PSC colitis differs from that which is observed in IBD alone. Additionally, PSC patients have significantly increased risk for colorectal cancer (CRC) that is far greater than the already increased risk of CRC in IBD. Some hypothesize that PSC colitis is distinct from IBD though no differences have been formally identified. Others believe that PSC is antigen driven, due to the strong association with the human leukocyte antigen (HLA) locus by genome-wide association studies (GWAS). In this thesis we provide formal evidence that PSC colitis is distinct from IBD, and is characterized by the presence of lamina propria immunoglobulin G (IgG)-producing plasma cells and interleukin (IL)-17A+ forkhead box P3 (Foxp3)+ CD4 T-cells. We demonstrate that both cell types show signs of selection, consistent with the antigen drive hypothesis. 16S sequencing identified a handful of bacterial taxa enriched specifically in PSC colitis, suggesting that a driving antigen could be bacterial in origin. Finally, we show that PSC patients with this unique colitis are at greater risk for dysplasia than PSC patients without it. Our data suggests that an antigen in PSC drives inflammation and subsequently CRC, representing a hypothetical therapeutic target for the prevention of colonic inflammation and CRC, and potentially liver inflammation as well.