Mechanisms of B Cell Pathogenicity in Non-Alcoholic Fatty Liver Disease

项目总结 肥胖及其并发症，包括非酒精性脂肪性肝病(NAFLD)已经流行起来 世界范围内的比例。据估计，非酒精性脂肪肝影响了30%的人口，是导致 西方国家的肝功能异常。非酒精性脂肪肝涵盖了广泛的肝脏病理，从 简单的脂肪堆积会导致更严重的情况，称为非酒精性脂肪性肝炎(NASH)。 肝脏炎症是NAFLD发生、维持和发展的关键过程。然而， 引发这一炎症过程的机制尚不清楚。B淋巴细胞是一种中枢调节因子。 自身免疫性和炎症性疾病，因为它们能够分泌有害物质。我们有证据 在饮食诱导的NAFLD模型中，促炎症B细胞在小鼠的肝脏中积聚，这与 人类的状况。肝脏是一个独特的器官，免疫细胞在这里与来自 含有源自肠道微生物区系的细菌产物的胃肠道。在NAFLD期间， 肠道微生物群的数量和组成的变化会导致细菌产品的泄漏，这些细菌产品 促进炎症。然而，B细胞在NAFLD进展中的作用及其影响因素 激活情况仍有待调查。我们的长期目标是揭示细胞的创新机制 免疫系统促进NAFLD的发生。因为我们的初步数据显示，肝脏中聚集了致病的B细胞 作为NAFLD的小鼠模型，我们计划研究它们在NAFLD发病机制中的作用。中心假说 肝内B细胞刺激局部炎症和纤维化，导致NAFLD的进展。我们预计 NAFLD期间肝脏B细胞致病性受到细菌进入等关键因素的支持 来自肠道的产品。我们的具体目标是确定肝B细胞促进 NAFLD(目标1)，确定促进肝脏B细胞致病的肠源性微生物因素(目标2)， 并揭示了B细胞介导的肝星状细胞活化的机制(目标3)。它由来已久。 B淋巴细胞在经典的自身免疫性疾病中扮演着重要的角色，这一点越来越明显 在代谢性疾病期间，它们会导致组织炎症。因为NAFLD还没有批准的治疗方法 它的治疗，B细胞效应器和调节功能的研究将提供机械洞察力，可以导致 新的疾病标记物和治疗方法。

PROJECT SUMMARY Obesity and its complications including non-alcoholic fatty liver disease (NAFLD) have reached epidemic proportions worldwide. NAFLD is estimated to affect 30% of the population and is one of the leading causes of abnormal liver function in Western countries. NAFLD covers a wide spectrum of liver pathology ranging from a simple accumulation of fat to a more serious condition known as non-alcoholic steatohepatitis (NASH). Inflammation in the liver is a key process in the initiation, maintenance, and progression of NAFLD. However, the mechanisms triggering this inflammatory process remains unclear. B lymphocytes are central mediators of autoimmune and inflammatory disease because of their ability to secrete harmful substances. We have evidence that pro-inflammatory B cells accumulate in the liver of mice in a model of diet-induced NAFLD that is relevant to the human condition. The liver is a unique organ where immune cells interact with blood from the gastrointestinal tract that contains bacterial products that originate from the gut microbiota. During NAFLD, changes in the amounts and composition of the gut microbiota can lead to the leakage of bacterial products that promote inflammation. However, the role of B cells in the progression of NAFLD and the factors influencing their activation remain to be investigated. Our long-term goal is to reveal innovative mechanisms by which cells of the immune system promote NAFLD. As our preliminary data show that the liver accumulates pathogenic B cells in a mouse model of NAFLD, we plan to investigate their role in the pathogenesis of NAFLD. The central hypothesis is that intrahepatic B cells fuel local inflammation and fibrosis, resulting in the progression of NAFLD. We expect that hepatic B cell pathogenicity during NAFLD is supported by critical factors such as the entry of bacterial products from the intestines. Our specific aims are to identify the mechanisms by which hepatic B cells promote NAFLD (Aim 1), determine the intestinal-derived microbial factors fueling hepatic B cell pathogenicity (Aim 2), and reveal the mechanisms of B cell-mediated activation of hepatic stellate cells (Aim 3). It is well established that B lymphocytes play important roles in classical autoimmune disorders, and it is becoming increasingly clear that they contribute to tissue inflammation during metabolic disease. As NAFLD has no approved therapies for its treatment, the study of B cell effector and regulatory functions will provide mechanistic insights that can lead to new disease markers and therapeutics.