title: Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance.
abstract: 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.
  
  
  
  Changes in IFNγ expression are critical for the pathogenesis of PBC. (Hepatology 2016;64:1189-1201).
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD.
authors.forename: Heekyong R
authors.initials: HR
authors.lastname: Bae
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, CA.
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Valencia
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Hodge
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD.
authors.forename: Seohyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD.
authors.forename: Tim
authors.initials: T
authors.lastname: Back
authors.affiliation: Laboratory of Animal Science, National Cancer Institute-Frederick, Frederick, MD.
authors.forename: Megan
authors.initials: M
authors.lastname: Karwan
authors.affiliation: CCR Collaborative Bioinformatics Core, National Cancer Institute, Bethesda, MD.
authors.forename: Anand S
authors.initials: AS
authors.lastname: Merchant
authors.affiliation: Central Laboratory Kagawa Prefectural Central Hospital, Takamatsu, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Baba
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD.
authors.forename: Dechun
authors.initials: D
authors.lastname: Feng
authors.affiliation: The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, CA.
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis School of Medicine, Davis, CA. megershwin@ucdavis.edu.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD. YoungHow@mail.nih.gov.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology* / Q000378:metabolism; D002761:Cholangitis / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D012737:Sex Factors
chemical_list: D007371:Interferon-gamma