ID: 62. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Bae, Heekyong; Valencia, Julio C.; Hodge, Deborah L.; Sanford, Michael E.; Hanson, Charlotte A.; Back, Tim; Karwan, Megan; Feng, Dechun; Gao, Bin; Park, Ogyi; Tsuneyama, Koichi; Leung, Patrick S.; Gershwin, M. Eric; Young, Howard A.
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 76
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.092
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">Primary biliary cirrhosis (PBC, now called autoimmune cholangitis) is an autoimmune liver disease and occurs primarily in women (<inline-formula><alternatives><inline-graphic xlink:href="ark:/27927/pgj2n6x7nzr" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /><mml:math altimg="si1.gif" display="inline" overflow="scroll" id="d13e237" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>></mml:mo></mml:mrow></mml:math></alternatives></inline-formula>90%), eventually leads to liver failure. IFN-gamma is elevated in patients with PBC, but the functional role of IFN-gamma on PBC is not known. Here, we characterized the distinctive pathological phenotype of PBC in a mouse model of chronic IFN-gamma expression generated by deletion of the IFN-gamma 3′ UTR AU-rich element (ARE-Del). Consistent with clinical features seen in PBC, female ARE-Del mice have moderate immune cell infiltration and bile duct destruction near hepatic portal tracts with dramatically upregulated bile acids and spontaneous production of anti-mitochondria antibodies in serum. In contrast, male ARE-Del have relatively mild histological and serological evidences of PBC compared to female ARE-Del. By focusing on genes whose expression is highly specific to female ARE-Del, type I interferon receptor and dendritic maturation are top upstream pathways for this female specific disease progression. Remarkably, deletion of the interferon a/b receptor in ARE-Del mice significantly suppressed the female-specific pathological phenotypes, specifically eliminating the sex-different phenotypes in PBC. Furthermore, female ARE-Del have notably increased plasmacytoid dendritic cells (pDC), specialized in massive secretion of type I interferon (IFN alpha and beta), suggesting that increased type I interferon via pDC is critical for the sex-difference in this disease progression. Taken together, the ARE-Del is the first mice model to present the sex differences seen in PBC and startlingly demonstrates how type II interferon coordinates with type I interferon in this disease progression.</p> </sec> </abstract>