Mechanism of NOD.IDD3/10/17/18/9(LD) Liver Disease

描述（由申请人提供）：本申请的目的是确定NOD中发现的一种新型自身免疫性和胆道疾病的机制。ldd3/10/17/18/9 (LD)鼠标。非肥胖糖尿病（NOD）小鼠是一种自发的、遗传复杂的自身免疫性糖尿病的动物模型。NOD小鼠的胰岛淋巴细胞浸润（胰岛素炎）发展为糖尿病。的点头。ldd3/1 0/17/1 8/9（LD）基因小鼠，具有95% NOD遗传背景和5%“保护性”B6/B10遗传背景。ldd3/10/17/18和NOD。ld9基因小鼠，并且完全免受自身免疫性糖尿病的侵害。然而，我们发现它发展为一种完全独立的疾病，其特征是淋巴细胞浸润到门静脉，抗丙酮酸脱氢酶复合物（PDC）和其他自身抗体，进行性多囊肝导致致命的胆道梗阻。在这项资助中，我们将剖析这种新型疾病的免疫学、细胞和遗传机制。这项拨款的中心假设是NOD患者的胆道疾病。ldd3/10/17/18/9（LD）小鼠是一种自身免疫性疾病，通过NOD背景基因与B6/B10位点之间的相互作用而引起，而B6/B10位点对自身免疫性糖尿病具有“保护性”。该模型提供了一个独特的机会来解剖遗传和免疫机制，导致遗传相关谱系中的2种不同器官特异性自身免疫性疾病。在具体的目的一，我们将确定肝脏疾病的细胞和免疫遗传学机制在NOD。ldd3/10/17/18/9（LD）基因小鼠及相关NOD基因菌株的转移研究。在具体目标二，我们将解剖免疫亚表型NOD的细胞和免疫遗传学机制。ldd3/10/17/18/9（LD）和相关NOD基因小鼠，包括自身抗体的产生，T和B细胞对PDC（丙酮酸脱氢酶，特别是E2成分）的反应，以及NOD中淋巴细胞肝浸润的机制。ldd3/10/17/18/9（LD）及相关基因小鼠。这些研究对于了解自身免疫性胆道疾病、自身免疫性糖尿病的发病机制以及家族自身免疫的遗传具有重要意义。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine mechanisms of a novel autoimmune and biliary tract disease discovered in the NOD.ldd3/10/17/18/9(LD) mouse. The Nonobese diabetic (NOD) mouse is an animal model of spontaneous, genetically complex autoimmune diabetes. NOD mice develop lymphocytic infiltrates into the pancreatic islets (insulitis) progressing to diabetes. The NOD.ldd3/1 0/17/1 8/9(LD) congenic mouse, which has a 95% NOD genetic background and 5% "protective" B6/B10 genetic background, was bred from the NOD.ldd3/10/17/18 and NOD.ldd9 congenic mice, and is completely protected from autoimmune diabetes. However, we have discovered that it develops an entirely separate disease characterized by lymphocytic infiltrates into the portal tract, anti-pyruvate dehydrogenase complex (PDC) and other autoantibodies, and progressive polycystic liver leading to fatal biliary obstruction. In this grant, we will dissect the immunological, cellular, and genetic mechanisms of this novel disease. The central hypothesis of this grant is that the biliary disease in NOD.ldd3/10/17/18/9(LD) mice is an autoimmune disease arising via an interaction between the NOD background genes and B6/B10 loci, which are "protective" for autoimmune diabetes. This model provides a unique opportunity to dissect genetic and immunologic mechanisms resulting in 2 different organ specific autoimmune diseases in a genetically related pedigree. In specific aim one, we will define cellular and immunogenetic mechanisms of the liver disease in NOD.ldd3/10/17/18/9(LD) congenic mice by using transfer studies and related NOD congenic strains. In specific aim two, we will dissect cellular and immunogenetic mechanisms of immune subphenotypes in NOD.ldd3/10/17/18/9(LD) and related NOD congenic mice, including autoantibody production, T and B cell responses to PDC (Pyruvate dehydrogenase, specifically the E2 component), and mechanisms of lymphocytic liver infiltration in NOD.ldd3/10/17/18/9(LD) and related congenic mice. These studies are important for understanding the pathogenesis of autoimmune biliary diseases, autoimmune diabetes, and the genetics of autoimmunity in families.