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.
