Immunological and fibrotic profiling in the NOD.c3c4 murine model of autoimmune cholangitis

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by intrahepatic bile duct destruction, progressive cholestasis, and fibrosis, accompanied by elevated anti-mitochondrial antibodies (AMAs) and IgM. While multiple mouse models have been developed to study PBC pathogenesis, no single model fully recapitulates all aspects of human disease. Among these, the NOD.c3c4 mouse model, generated by incorporating B10 and B6 insulin-dependent diabetes (Idd) loci into NOD mice, uniquely develops PBC-like features without progressing to type-1 diabetes. NOD.c3c4 exhibit PDC-E2-reactive AMAs, elevated autoantibodies, biliary leukocyte infiltration, and progressive liver dysfunction. However, key pathogenic mechanisms, particularly the role of fibrosis, remain poorly understood. Here, we provide a comprehensive characterization of PBC development and progression in NOD.c3c4 mice, focusing on adaptive and innate immune contributions to disease pathology. Our study confirms that both T and B cells are central drivers, as their depletion significantly mitigates PBC pathology. Additionally, our findings highlight a previously underappreciated role of innate immunity in disease progression. Notably, NOD.c3c4 mice develop fibrosis, which advances with age, making them a valuable model for studying fibrotic events in PBC. Given their resemblance to human disease, NOD.c3c4 mice represent a powerful platform for investigating PBC pathogenesis and evaluating new immunotherapeutics.