Chronic expression of interferon‐gamma leads to murine autoimmune cholangitis with a female predominance
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- Heekyong R. Bae
- Cancer and Inflammation Program, Center for Cancer Research,National Cancer Institute‐Frederick,Frederick,MD
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- Patrick S.C. Leung
- Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis School of Medicine,Davis,CA
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- Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences,Tokushima University Graduate School,Japan
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- Julio C. Valencia
- Cancer and Inflammation Program, Center for Cancer Research,National Cancer Institute‐Frederick,Frederick,MD
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- Deborah L. Hodge
- Cancer and Inflammation Program, Center for Cancer Research,National Cancer Institute‐Frederick,Frederick,MD
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- Seohyun Kim
- Cancer and Inflammation Program, Center for Cancer Research,National Cancer Institute‐Frederick,Frederick,MD
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- Tim Back
- Cancer and Inflammation Program, Center for Cancer Research,National Cancer Institute‐Frederick,Frederick,MD
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- Megan Karwan
- Laboratory of Animal Science,National Cancer Institute‐Frederick,Frederick,MD
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- Anand S. Merchant
- CCR Collaborative Bioinformatics Core,National Cancer Institute,Bethesda,MD
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- Nobuyuki Baba
- Central Laboratory Kagawa Prefectural Central Hospital,Takamatsu,Japan
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- Dechun Feng
- Laboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism,Rockville,MD
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- Ogyi Park
- The Russell H. Morgan Department of Radiology and Radiological Science,Johns Hopkins University School of Medicine,Baltimore,MD
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- Bin Gao
- Laboratory of Liver Diseases,National Institute on Alcohol Abuse and Alcoholism,Rockville,MD
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- Guo‐Xiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis School of Medicine,Davis,CA
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- M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis School of Medicine,Davis,CA
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- Howard A. Young
- Cancer and Inflammation Program, Center for Cancer Research,National Cancer Institute‐Frederick,Frederick,MD
説明
<jats:p>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<jats:sup>‐/‐</jats:sup> 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<jats:sup>‐/‐</jats:sup> to B6/Rag1<jats:sup>‐/‐</jats:sup> 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. <jats:italic toggle="yes">Conclusion:</jats:italic> Changes in IFNγ expression are critical for the pathogenesis of PBC. (H<jats:sc>epatology</jats:sc> 2016;64:1189‐1201)</jats:p>
収録刊行物
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- Hepatology
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Hepatology 64 (4), 1189-1201, 2016-06-15
Ovid Technologies (Wolters Kluwer Health)
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詳細情報 詳細情報について
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- CRID
- 1360567180080829312
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- ISSN
- 15273350
- 02709139
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- データソース種別
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- Crossref
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