Primary biliary cirrhosis: molecular genetics and microbial pathogenesis

描述（由申请人提供）：原发性胆汁性肝硬化（PBC）是一种慢性炎症性肝病，除非进行肝移植，否则通常进展为肝功能衰竭和死亡。虽然PBC的病因还不清楚，但已知遗传和环境因素都有影响。最近的临床研究强烈表明，感染新鞘氨醇菌aromaticivorans（N。aro）与易感个体中PBC的发展特异性相关。利用小鼠模型，我们最近表明，N。小鼠的aro感染导致PBC样肝损伤的发展，其依赖于通过NKT和常规T细胞的活化产生IFN-3和IL-17。基于我们的初步数据，NOD小鼠表达的B6 CD 101等位基因或小鼠缺乏CD 101表达表现出更严重的PBC比他们的同类或野生型同窝，我们建议，CD 101基因，这是一个新的PBC易感基因，位于Idd 10糖尿病基因座编码的负共刺激分子的表达。因此，本提案的总体目标是确定CD 101在对严重PBC的易感性/耐药性中的作用。虽然CD 101易感性等位基因调节T细胞活化和PBC的确切机制尚不清楚，我们的初步发现支持了这样的假设，即在NOD背景下，B6 CD 101等位基因的信号减弱/改变通过Vav 3激活介导了增强的T细胞信号，或缺乏PTPN 22诱导，这损害了调节性T细胞和效应T细胞之间的平衡，并导致炎症和肝脏疾病的增强。为了验证这一假设，我们的目标是：1）进一步探讨CD 101在N. aro诱导的PBC; 2）确定CD 101的遗传差异是否增加DC介导的NKT和/或常规T细胞的活化，从而增加对疾病慢性期的易感性;和3）确定B6 CD 101同源小鼠中T细胞功能的差异调节是否由CD 101介导的Vav 3和/或PTPN 22调节的改变引起。鉴定CD 101作为PBC的易感基因应该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，但也可能允许鉴定自身免疫性疾病的共同靶点，以供将来进行临床干预。公共卫生相关性：环境因素和遗传易感性决定了个体对自身免疫性疾病的易感性。在这方面，我们已经确定了一个单一的分子，CD 101作为一个不可治愈的人类肝脏疾病，原发性胆汁性肝硬化的“风险因素”，在感染普遍存在的α-变形杆菌。使用CD 101作为不同免疫细胞反应的读出系统，该提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.