Chronic Expression of Interferon-Gamma Leads to Murine Autoimmune Cholangitis With a Female Predominance

In most autoimmune diseases the serologic hallmarks of disease precede clinical pathology by years. Therefore, the use of animal models in defining early disease events becomes critical. We took advantage of a designer mouse with dysregulation of interferon gamma (IFN gamma) characterized by prolonged and chronic expression of IFN through deletion of the IFN gamma 3-untranslated region adenylate uridylate-rich element (ARE). The ARE-Del(-/-) mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human PBC that is characterized by up-regulation of total bile acids, spontaneous production of anti-mitochondrial antibodies, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del(-/-) to B6/Rag1(-/-) mice induced moderate portal inflammation and parenchymal inflammation, and RNA sequencing of liver gene expression revealed that up-regulated genes potentially define early stages of cholangitis. Interestingly, up-regulated genes specifically overlap with the gene expression signature of biliary epithelial cells in PBC, implying that IFN gamma may play a pathogenic role in biliary epithelial cells in the initiation stage of PBC. Moreover, differentially expressed genes in female mice have stronger type 1 and type 2 IFN gamma signaling and lymphocyte-mediated immune responses and thus may drive the female bias of the disease. Conclusion: Changes in IFN expression are critical for the pathogenesis of PBC.