| First Author | Bae HR | Year | 2016 |
| Journal | Hepatology | Volume | 64 |
| Issue | 4 | Pages | 1189-201 |
| PubMed ID | 27178326 | Mgi Jnum | J:312456 |
| Mgi Id | MGI:6790289 | Doi | 10.1002/hep.28641 |
| Citation | Bae HR, et al. (2016) Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology 64(4):1189-201 |
| abstractText | 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 (IFNgamma) characterized by prolonged and chronic expression of IFNgamma through deletion of the IFNgamma 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 IFNgamma 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 IFNgamma expression are critical for the pathogenesis of PBC. (Hepatology 2016;64:1189-1201). |
