Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance.

ABSTRACT: UNLABELLED: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?) characterized by prolonged and chronic expression of IFN? through deletion of the IFN? 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? 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 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. (Hepatology 2016;64:1189-1201).

SUBMITTER: Bae HR 

PROVIDER: S-EPMC5033675 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature