Chronic Interferon-gamma expression triggers a female bias in the development of primary biliary cholangitis

Abstract

Abstract An important issue in autoimmunity research has been the ability to identify the mechanisms that link genetic susceptibility to environmental influences. In most autoimmune diseases, including primary biliary cholangitis (PBC), the serologic hallmarks of disease precede clinical pathology by years, thus making early diagnosis and potential treatment difficult if not unlikely. Thus identifying animal models that present early events becomes essential to understanding disease initiation and progression. Although murine models of PBC have been identified, there are none that fully recapitulate the human disease. Herein we have utilized a novel mouse model exhibiting dysregulation of interferon-gamma (IFNg) expression, characterized by prolonged and chronic expression of IFNg as a result of the replacement of the IFNg 3′ UTR AU-rich element with random nucleotides (designated ARE-Del−/−). These C57 BL/6 ARE-Del−/− mice develop autoimmune cholangitis with a female predominance characterized by upregulation of total serum bile acids, portal duct inflammation, spontaneous production of AMA and increased skin pigmentation. RNA seq data has revealed that female ARE-Del−/− mice have >1000 genes deferentially expressed in hepatocytes compared to control mice, including genes that represent early responses in disease progression. Furthermore, the data indicates that the Type 1 IFN pathway is also involved, implying that Type II interferon interplays with Type I IFNs in the initiation of PBC. Thus persistent IFNg expression, along with Type I and Type II IFN pathway interactions, is critical for the pathogenesis of PBC and recapitulates the sex bias observed in patients.