Innate immune cells in the pathogenesis of PSC

PSC发病机制中的先天免疫细胞

• 批准号: 290523246
• 负责人: Professor Dr. Marcus Altfeld
• 金额: --
• 依托单位: Leibniz-Institut für Virologie (LIV)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290523246?language=en
• 关键词: Innate; immune; cells; pathogenesis; PSC

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.

背景/初步研究结果：原发性硬化症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应答的关键驱动因素。事实上，使用PSC小鼠模型，我们发现对胆道损伤的直接反应是门脉野树突状细胞的扩增和活化，其随后触发单核细胞衍生的细胞和中性粒细胞向门脉道的募集。值得注意的是，树突状细胞和单核细胞衍生的细胞似乎组织随后的先天性和适应性免疫反应在发炎的门静脉领域。我们还观察到，NK细胞也被激活和扩大在PSC患者，并表达趋化因子受体，表明NK细胞迁移到发炎的肝脏，在那里他们有助于慢性进行性炎症的门脉tractes.Hypothesis：先天免疫细胞的胆管细胞死亡和微生物的特性是必不可少的致病驱动程序在PSC。先天性免疫细胞群体采用维持慢性胆道损伤和重塑的表型。我们将通过转录谱分析、多色流式细胞术和细胞耗竭研究来分析树突状细胞和单核细胞来源的细胞群在小鼠胆管炎中的功能相关性。2.我们将分析树突状细胞和单核细胞衍生的细胞群体在小鼠胆管炎T细胞反应的多色流式细胞术，和细胞耗竭的研究。3.我们将表征PSC患者肝脏中的抗原呈递细胞群体，以及通过转录谱分析和多色流式细胞术导致NK细胞募集的趋化因子分泌模式。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PSC中NK细胞和APC之间相互作用中的作用。