Heekyong R Bae1, Patrick S C Leung2, Koichi Tsuneyama3, Julio C Valencia1, Deborah L Hodge1, Seohyun Kim1, Tim Back1, Megan Karwan4, Anand S Merchant5, Nobuyuki Baba6, Dechun Feng7, Ogyi Park8, Bin Gao7, Guo-Xiang Yang2, M Eric Gershwin9, Howard A Young10. 1. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD. 2. Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, CA. 3. Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan. 4. Laboratory of Animal Science, National Cancer Institute-Frederick, Frederick, MD. 5. CCR Collaborative Bioinformatics Core, National Cancer Institute, Bethesda, MD. 6. Central Laboratory Kagawa Prefectural Central Hospital, Takamatsu, Japan. 7. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD. 8. The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD. 9. Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, CA. megershwin@ucdavis.edu. 10. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD. YoungHow@mail.nih.gov.
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 (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 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 IFNγ 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 IFNγ expression are critical for the pathogenesis of PBC. (Hepatology 2016;64:1189-1201).
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 (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 3'-untranslated region adenylate uridylate-rich element (ARE). The ARE-Del(-/-) mice develop primary biliary cholangitis (PBC) with a female predominance that mimics humanPBC 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 IFNγ 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 IFNγ expression are critical for the pathogenesis of PBC. (Hepatology 2016;64:1189-1201).
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