Innate immune cells in the pathogenesis of PSC

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Background / Preliminary findings: The causes of chronic immune activation in PSC are not known, but bile toxicity and microbial recognition are believed to be important triggers. As cell death and microbes are primarily sensed by innate immune cells, these cells might be activated in PSC and might represent critical drivers of the pathogenic immune response. Indeed, using mouse models of PSC, we found that the immediate response to biliary injury is the expansion and activation of dendritic cells in the portal field, which subsequently triggers the recruitment of monocyte-derived cells and neutrophils to the portal tract. Notably dendritic cells and monocyte-derived cells seem to organise the subsequent innate and adaptive immune response in the inflamed portal field. We furthermore observed that NK cells are also activated and expanded in patients with PSC, and express chemokine receptors, suggesting migration of NK cells into the inflamed liver where they contribute to the chronic progressive inflammation of portal tracts.Hypothesis: Innate immune cells sensing biliary cell death and microbial traits are essential pathogenic drivers in PSC. Innate immune cell populations adopt a phenotype that sustains both chronic biliary injury and remodelling.Work programme: 1. We will analyse the functional relevance of dendritic cell and monocyte-derived cell populations in murine cholangitis by transcriptional profiling, multi-colour flow cytometry, and cell depletion studies. 2. We will analyse the effect of dendritic cell and monocyte-derived cell populations in murine cholangitis on T cell responses by multi-colour flow cytometry, and cell depletion studies. 3. We will characterize antigen-presenting cell populations in the liver of PSC patients, and their chemokine secretion patterns resulting in NK cell recruitment by transcriptional profiling, and multi-colour flow cytometry. 4. We will study the role of HLA class II in the interaction between NK cells and APCs in human PSC by co-culture studies and multi-colour flow cytometry.