A Novel Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis.

We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 (). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated transcript. A novel NOD congenic mouse expressing aberrant , but lacking the c3 and c4 chromosomal regions (NOD.), reproduces the immunopathological features of NOD ABD. RNA sequencing of NOD. common bile duct early in disease demonstrates upregulation of genes involved in cholangiocyte injury/morphology and downregulation of immunoregulatory genes. Consistent with this, bone marrow chimera studies show that aberrant must be expressed in the target tissue (cholangiocytes) and the immune system (bone marrow). Mutations of produce biliary abnormalities in mice but have not been previously associated with autoimmunity. In this study, we eliminate clinical biliary disease by backcrossing this mutation onto the C57BL/6 genetic background; thus, the NOD genetic background (which promotes autoimmunity) is essential for disease. We propose that loss of functional on the NOD background produces early bile duct abnormalities, initiating a break in tolerance that leads to autoimmune cholangitis in NOD. congenic mice. This model is important for understanding loss of tolerance to cholangiocytes and is relevant to the pathogenesis of several human cholangiopathies.