Primary biliary cirrhosis: molecular genetics and microbial pathogenesis

描述(申请人提供)：原发性胆汁性肝病(PBC)是一种慢性炎症性肝病，除非进行肝移植，否则通常会进展为肝功能衰竭和死亡。虽然PBC的病因还不是很清楚，但遗传和环境因素都是已知的因素。最近的临床研究强烈表明，芳香新环菌(N.aro)的感染与易患PBC的个体的发展具有特异性的相关性。利用小鼠模型，我们最近发现小鼠感染N.aro可导致PBC样肝损害，这依赖于通过激活NKT和传统T细胞而产生的干扰素-3和IL-17。根据我们的初步数据，表达B6 CD101等位基因的NOD小鼠或CD101表达缺陷的小鼠表现出比它们的同源或野生型小鼠更严重的PBC，我们认为CD101基因位于编码负共刺激分子表达的Idd10糖尿病基因座上，是一种新的PBC易感基因。因此，这项建议的总体目标是确定CD101在严重PBC易感性/耐药性中的作用。虽然CD101易感等位基因调节T细胞活化和PBC的确切机制尚不清楚，但我们的初步发现支持这样的假设，即在NOD背景下，B6 CD101等位基因信号的减弱/改变通过Vav3激活和/或PTPN22诱导的缺失介导了T细胞信号的增强，从而破坏了调节性T细胞和效应性T细胞之间的平衡，导致炎症和肝脏疾病的加剧。为了验证这一假说，我们的目标是：1)进一步探讨CD101在N.aro诱导的PBC急性期和慢性期的作用；2)确定CD101的遗传差异是否增加了DC介导的NKT和/或常规T细胞的激活，从而对疾病的慢性期易感性；以及3)确定B6 CD101同系小鼠T细胞功能的差异调节是否源于CD101介导的Vav3和/或PTPN22调节的变化。将CD101确定为PBC的易感基因将为开发治疗这种危及生命的疾病的新疗法提供有价值的见解，同时也可能为未来的临床干预识别自身免疫性疾病的共同靶点。公共卫生相关性：环境因素和遗传倾向决定了个人对自身免疫性疾病的易感性。在这方面，我们已经确定CD101是一种无法治愈的人类肝病的“危险因素”，这种疾病是由于感染了一种普遍存在的甲型蛋白杆菌而导致的。使用CD101作为不同免疫细胞反应的读出系统，这一建议将探索遗传背景和细菌感染影响小鼠对慢性肝脏炎症易感性的细胞机制。

DESCRIPTION (provided by applicant): Primary Biliary Cirrhosis (PBC) is a chronic inflammatory liver disease that usually progresses to liver failure and death unless liver transplantation is performed. Although the etiology of PBC is not well understood, both genetic and environmental factors are known to contribute. Recent clinical studies strongly suggest that infection with Novosphingobium aromaticivorans (N. aro) is specifically associated with development of PBC in predisposed individuals. Utilizing a mouse model, we have recently shown that N. aro infection of mice results in the development of PBC-like liver lesions, which are dependent upon the production of IFN-3 and IL-17 through activation of NKT and conventional T cells. Based on our preliminary data that NOD mice expressing the B6 CD101 allele or mice deficient in CD101 expression exhibit more severe PBC than their congenic or wildtype littermates, we propose that the CD101 gene, which lies within the Idd10 diabetes locus that encodes the expression of the negative co-stimulatory molecule, is a novel PBC susceptibility gene. Thus the overall goal of this proposal is to determine the role of CD101 in susceptibility/resistance to severe PBC. Although the exact mechanisms by which CD101 susceptibility alleles regulate T cell activation and PBC are unknown, our preliminary findings support the hypothesis that diminished/altered signaling by the B6 CD101 allele on the NOD background mediates enhanced T cell signals through Vav3 activation and/or lack of PTPN22 induction that impair the balance between regulatory and effector T cells and leads to enhanced inflammation and liver disease. To test this hypothesis, we aim to: 1) further explore the role of CD101 in the acute and chronic phases of N. aro-induced PBC; 2) determine whether genetic differences in CD101 increase DC-mediated activation of NKT and/or conventional T cells, and, thereby susceptibility to the chronic phase of disease; and 3) determine whether the differential regulation of T cell function in B6 CD101 congenic mice results from alterations in CD101-mediated regulation of Vav3 and/or PTPN22. Identification of CD101 as a susceptibility gene for PBC should provide valuable insight into the development of novel therapeutics to treat this life-threatening disease, but may also allow the identification of common targets in autoimmune disease for clinical intervention in the future. PUBLIC HEALTH RELEVANCE: Environmental factors and genetic predisposition determine the susceptibility of an individual to autoimmune disease. In this regard, we have identified a single molecule, CD101 as "risk factor" for an incurable human liver disease, Primary Biliary Cirrhosis in response to infection with a ubiquitous alphaproteobacterium. Using CD101 as readout system for different immune cell responses, this proposal will explore the cellular mechanisms by which the genetic background and bacterial infection influence the susceptibility of a mouse to chronic liver inflammation.