Primary biliary cholangitis (PBC) is an incurable autoimmune biliary disease (“ABD”) in which the immune system destroys bile ducts by targeting cholangiocytes. Many immune based therapies have been applied to PBC, but none have been successful and the disease is currently incurable. Progress in finding new therapies for PBC has been blocked because the clinical symptoms of disease often arise many years after initiation of disease; thus data derived from human patients has not permitted fundamental insights into the immunopathogenesis of the disease. Fundamental new insights that can generate new therapeutic targets require information about the earliest pathogenesis of PBC, which must come from animal models of disease. We developed the first spontaneous animal model of PBC: NOD.ABD mice that develop autoimmune biliary disease remarkably similar to human including 1) anti-mitochondrial antibodies highly specific for human PBC; 2) disease transferable by autoreactive T cells; and 3) immunohistopathology highly characteristic of PBC with granuloma formation, T cell infiltrates in the biliary lining, and destructive cholangitis. Recently we discovered a novel genetic mutation in NOD ABD. Understanding how this novel genetic system controls the aberrant cholangiocyte: immune system interaction which drives ABD is the goal of the current grant. Here we have constructed a novel congenic mouse (NOD.Abd3) that allows us to mechanistically analyze the very earliest basis of disease. We also show that a genetic background which enhances autoimmunity (the NOD genetic background, which predisposes to many autoimmune conditions including T1D, Sjogren’s syndrome, and thyroiditis) must be present. This complex genetic etiology is similar to human disease. Therefore our unique model offers new insights into basic immunopathology relevant to human PBC and other cholangiopathies. We propose 3 aims: Aim 1: Determine the genetic basis of NOD autoimmune biliary disease. We show that disease in congenic NOD.Abd3 mice requires a region on chromosome 1, “Abd3”, which includes a 1.0 Mb B6 interval (“B6-Abd3”) as well as mutated Pkhd1del36-67 upstream of it. Our hypothesis is that early expression of aberrant Pkhd1 in cholangiocytes breaks immune tolerance to cholangiocytes. We can prove/disprove this hypothesis by sophisticated genetic approaches. Aim 2: Determine the role of early cholangiocyte “ductular reaction” in NOD.Abd3 pathogenesis. By 4 weeks of age, NOD.Abd3 bile ducts show massive immune infiltration which then ascends into intrahepatic bile ducts. Our hypothesis is that the aberrant immune response is due to an early “ductular reaction” of NOD.Abd3 cholangiocytes, which stimulates the innate immune system. Aim 3: Mechanistic role of myeloid derived suppressor cells (MDSCs) and activated macrophages in NOD.Abd3 and human PBC pathogenesis. The immune system is required for clinical ABD in our model. We hypothesize that the Abd3 genetic region alters macrophag...