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

描述（由申请人提供）：原发性胆汁性肝硬化（PBC）是一种神秘的肝脏特异性自身免疫性疾病，其特征为抗线粒体抗体和肝内胆管的进行性破坏。目前还没有PBC的动物模型，研究依赖于人类临床标本，这一问题因疾病发作的神秘性而变得更加复杂，这阻碍了早期阶段患者的识别。在其他自身免疫性疾病中，信息丰富的动物模型促进了免疫过程的解剖。我们提出了一个财团的方法，利用3个校区的优势，研究2种新的小鼠模型的自身免疫性胆道疾病，NOD.c3c4同源小鼠与B6/B10衍生区域的染色体3和4，以及一个新的菌株，称为2445。与NOD.c3c4相比，品系2445在3号和4号染色体上具有显著减少的B6/B10间隔，这将促进与疾病相关的基因的定位克隆。两种品系的小鼠均出现进行性门静脉淋巴细胞浸润、肉芽肿、抗线粒体抗体和终末胆道疾病。我们的目标是进行一个详细的个体发育分析的免疫系统，以确定动力学的特定谱系有助于疾病的过程中使用NOD.c3c4，菌株2445，和控制。要进行的研究是那些反映人类PBC，包括先天，体液和细胞免疫系统的分析，包括肝淋巴细胞亚群和免疫组织化学，以确定每个组成部分有助于疾病发病机制的发育阶段。我们还将使用目前可用的同源菌株以及将产生的新同源菌株定位克隆引起肝病的关键基因。基于这些数据，使用NOD.c3c4-和2445-scid受体的过继转移策略将确定肝脏疾病发展所需的致病效应细胞。我们认为，这种模式提供了显着的潜力，不仅提高我们的理解PBC，但也自身免疫一般。PBC是具有组织特异性影响的原型自身免疫性疾病，但具有恒定的非组织特异性自身反应性，这些特征在该模型中密切再现。最后，由于PBC的小鼠模型在病理学和免疫学上与人类PBC相似，因此它开启了对起始事件进行区分性分析并最终研究治疗干预的可能性。

DESCRIPTION (provided by applicant): Primary biliary cirrhosis (PBC) is an enigmatic, liver specific, autoimmune disease characterized by antimitochondrial 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 3 campuses to study 2 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 intervals on chromosome 3 and 4 compared to NOD.c3c4, which will facilitate positional cloning of genes integral 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 this 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 immunologically similar to human PBC, it opens the possibility of discriminative analysis of initiating events and eventually study of therapeutic interventions.