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

描述(由申请人提供)：这项建议的目标是确定在NOD.ldd3/10/17/18/9(LD)小鼠中发现的一种新的自身免疫和胆道疾病的机制。非肥胖糖尿病(NOD)小鼠是自发的、基因复杂的自身免疫性糖尿病的动物模型。NOD小鼠出现淋巴细胞渗入胰岛(胰岛炎症)，进展为糖尿病。NOD.ldd3/1 0/17/1 8/9(LD)同源小鼠由NOD.ldd3/10/17/18和NOD.ldd9同源小鼠杂交而成，具有95%的NOD遗传背景和5%的B6/B10“保护性”遗传背景，对自身免疫性糖尿病具有完全保护作用。然而，我们发现它会发展成一种完全独立的疾病，其特征是淋巴细胞渗入门静脉，抗丙酮酸脱氢酶复合体(PDC)和其他自身抗体，以及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、细胞学和遗传学机制。这项资助的中心假设是，NOD.ldd3/10/17/18/9(LD)小鼠的胆道疾病是一种自身免疫性疾病，通过NOD背景基因和B6/B10基因座之间的相互作用而产生，B6/B10基因座对自身免疫性糖尿病具有保护作用。这个模型提供了一个独特的机会来剖析遗传和免疫机制，导致两种不同的器官特异性自身免疫性疾病在遗传相关的家系中。在特定的目标一，我们将通过转移研究和相关的nod同源株来确定NOD.ldd3/10/17/18/9(LD)同源小鼠肝脏疾病的细胞和免疫遗传机制。在特定的目的二中，我们将剖析NOD.ldd3/10/17/18/9(LD)及相关NOD同源基因小鼠免疫亚型的细胞和免疫遗传机制，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组分)的反应，以及NOD.ldd3/10/17/18/9(LD)及相关同源基因小鼠淋巴细胞性肝脏浸润的机制。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自身免疫性家系的遗传学具有重要意义。

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.