THE PATHOGENESIS OF AUTOIMMUNITY IN A MURINE MODEL OF PRIMARY BILIARY CIRRHOSIS

原发性胆汁性肝硬化（PBC）是一种神秘的、肝脏特异性的自身免疫性疾病，其特征在于抗线粒体抗体， 血清抗体与肝内胆管的进行性破坏。从没有一种动物 PBC模型和研究依赖于人类临床标本，这一问题因 疾病发作的隐蔽性，使患者无法在早期阶段识别。在其他自身免疫 疾病，解剖的免疫过程已经促进了信息丰富的动物模型。我们 提出一个联盟的方法，利用三个校区的优势，研究两个新的小鼠模型 自身免疫性胆道疾病，NOD.c3c4同源小鼠与B6/B10衍生区域， 3号和4号染色体以及一个新的菌株，称为2445。第2445行显著降低了B6/B10 与NOD.c3c4相比，染色体3和4上的间隔，这将有助于基因的定位克隆 与疾病相适应。两种品系的小鼠都发生了进行性门静脉淋巴细胞浸润、肉芽肿， 抗线粒体抗体和晚期胆道疾病。我们的目标是进行详细的 免疫系统的个体发生分析，以确定特定谱系有助于免疫系统的动力学。 利用NOD.c3c4，菌株2445和对照的疾病过程。要进行的研究是那些 反映人类PBC，包括先天性，体液和细胞免疫系统的分析，包括肝脏 淋巴细胞亚群和免疫组化，以确定发育阶段的每个组成部分 有助于疾病的发病机制。我们还将定位克隆导致肝硬化的关键基因， 使用目前可用的同类菌株以及将产生的新同类菌株来治疗疾病。 基于这些数据，使用NOD.c3c4-和2445-scid受体的过继转移策略将定义 肝脏疾病发展所需的致病效应细胞。我们认为，这种模式提供了 这不仅对增强我们对PBC的理解，而且对一般的自身免疫性也有重大的潜力。PBC 是具有组织特异性影响的原型自身免疫性疾病，但恒定的非组织特异性 自体反应性，在该模型中密切再现的特征。最后，因为PBC的小鼠模型是 在病理学和免疫学上与人类PBC相似，它开启了区分分析PBC的可能性。 启动事件并最终研究治疗干预。

rimary biliary cirrhosis (PBC) is an enigmatic, liver specific, autoimmune disease characterized by antimito- chondrial antibodies and progressive destruction of intrahepatic bile ducts. There has not been an animal model of PBC and studies are dependent on human clinical specimens, a problem compounded by the cryptic nature of disease onset that prevents identification of patients in early stages. In other autoimmune diseases, the dissection of the immune process has been facilitated by informative animal models. We propose a consortium approach utilizing the strengths of three campuses to study two novel murine models of autoimmune biliary disease, the NOD.c3c4 congenic mouse with B6/B10 derived regions on chromosomes 3 and 4 as well as a new strain, called 2445. Line 2445 has significantly reduced B6/B10 ntervals on chromosome 3 and 4 compared to NOD.c3c4, which will facilitate positional cloning of genes ntegral to disease. Both strains of mice develop progressive portal tract lymphocytic infiltrates, granulomas, anti-mitochondrial antibodies and terminal biliary disease. Our objectives are to perform a detailed ontogenetic analysis of the immune system to define the kinetics by which specific lineages contribute to disease process utilizing NOD.c3c4, strain 2445, and controls. The studies to be performed are those which mirror human PBC, including analysis of the innate, humoral and cellular immune systems, including liver lymphoid subpopulations and immunohistochemistry to identify the developmental stage each component contributes to disease pathogenesis. We will also positionally clone the genes critical for causing liver disease using currently available congenic strains as well as novel congenic strains that will be generated. Based upon these data, adoptive transfer strategies using NOD.c3c4- and 2445-scid recipients will define the pathogenic effector cells required for the development of liver disease. We submit that this model offers significant potential for not only enhancing our understanding of PBC, but also autoimmunity in general. PBC is the prototypic autoimmune disease with a tissue specific impact, but a constant non-tissue specific autoreactivity, features closely reproduced in this model. Finally, because this murine model of PBC is pathologically and immunologieally similar to human PBC, it opens the possibility of discriminative analysis of initiating events and eventually study of therapeutic interventions.