Innate immune cells in the pathogenesis of PSC

背景/初步发现：PSC慢性免疫激活的原因尚不清楚，但胆汁毒性和微生物识别被认为是重要的触发因素。由于细胞死亡和微生物主要由先天免疫细胞感知，这些细胞可能在PSC中被激活，并可能代表致病性免疫反应的关键驱动因素。事实上，通过小鼠PSC模型，我们发现对胆道损伤的直接反应是门静脉野树突状细胞的扩张和激活，随后触发单核细胞来源的细胞和中性粒细胞向门静脉募集。值得注意的是，树突状细胞和单核细胞来源的细胞似乎组织了随后的先天性和适应性免疫反应。我们进一步观察到，NK细胞在PSC患者中也被激活和扩增，并表达趋化因子受体，这表明NK细胞迁移到发炎的肝脏，在那里它们有助于门静脉的慢性进行性炎症。假设：感知胆道细胞死亡和微生物特性的先天免疫细胞是PSC的重要致病驱动因素。先天免疫细胞群采用一种维持慢性胆道损伤和重塑的表型。工作方案：1。我们将通过转录谱分析、多色流式细胞术和细胞耗尽研究来分析小鼠胆管炎中树突状细胞和单核细胞来源细胞群的功能相关性。2. 我们将通过多色流式细胞术和细胞耗竭研究分析小鼠胆管炎中树突状细胞和单核细胞来源细胞群对T细胞反应的影响。3. 我们将通过转录谱分析和多色流式细胞术表征PSC患者肝脏中的抗原呈递细胞群，以及它们的趋化因子分泌模式导致NK细胞募集。4. 我们将通过共培养研究和多色流式细胞术研究HLA II类在人类PSC中NK细胞和APCs相互作用中的作用。

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.