Immunobiology of primary sclerosing cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.

Keywords: autoimmunity; cholestatic liver diseases; fibrosis; liver immunology; single-cell methods.

FIGURE 1

Overview of PSC immunobiology. Summary of the immune features from PSC livers is presented in extended circles depending on the techniques used. These mainly arise from studies on parenchyma of advanced PSC livers, whereas less is known regarding extrahepatic bile duct, intrahepatic and extrahepatic strictures, gallbladder, or intrahepatic small duct areas as indicated by the areas of interest box. Immune cells and specific features/findings are depicted by colored circles, symbols, and letters. Analysis of cell suspensions shows the immune composition of the biliary tree (cytobrushing) and the global modifications of the immune system in the liver parenchyma. Spatial analysis highlights differences within the liver based on a central to portal (PV) axis, bile-duct interacting (BD) cells, as well as in fibrotic versus nonfibrotic areas. Abbreviations: BD, bile duct; PSC, primary sclerosing cholangitis; PV, portal vein.

FIGURE 2

PSC pathogenesis through time, space, comorbidities, and clinical heterogeneity. Locations (space) of the immune studies are indicated in the left part of the figure. The extent of immunological knowledge in relation to disease stage (time) is thereafter depicted (preclinical, postdiagnosis/advanced disease, and posttransplant recurrent PSC). Most of the current immunobiological knowledge originates from a narrow spatiotemporal window, mostly from liver tissue postdiagnosis or in end-stage disease. The main immune features per location are detailed in bullet points. On the right side, related comorbidities and clinical heterogeneity–related aspects for each location are brought up. In most instances, it remains unclear how these aspects affect immunology. Abbreviation: PSC, primary sclerosing cholangitis.