Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance.
Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance.
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DOI：
10.1002/hep.28641
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发表时间：
2016-10
期刊：
影响因子：
13.5
通讯作者：
Young, Howard A.
中科院分区：
文献类型：
--
作者：
Bae, Heekyong R.;Leung, Patrick S. C.;Tsuneyama, Koichi;Valencia, Julio C.;Hodge, Deborah L.;Kim, Seohyun;Back, Tim;Karwan, Megan;Merchant, Anand S.;Baba, Nobuyuki;Feng, Dechun;Park, Ogyi;Gao, Bin;Yang, Guo-Xiang;Gershwin, M. Eric;Young, Howard A.
在大多数自身免疫性疾病中，疾病的血清学标志先于临床病理学多年。因此，使用动物模型来定义早期疾病事件变得至关重要。在此，我们利用了干扰素γ（IFNγ）失调的“设计者”小鼠，其特征在于通过缺失IFNγ 3′ UTR AU富集元件而延长和慢性表达IFNγ。这些小鼠发生原发性胆汁性胆管炎（PBC），女性占优势，模拟人类疾病，其特征为总胆汁酸上调、自发产生AMA和门静脉导管炎症。将CD 4 T细胞从ARE-Del−/−转移到B6/Rag 1 −/−小鼠诱导中度门静脉炎症和实质炎症，肝脏基因表达的RNA测序显示上调的基因可能定义胆管炎的早期阶段。有趣的是，上调的基因特异性地与PBC中胆管上皮细胞的基因表达特征重叠，这意味着IFNγ可能在PBC起始阶段的胆管上皮细胞（BEC）中发挥致病作用。此外，雌性小鼠中差异表达的基因具有更强的I型和II型干扰素信号传导和淋巴细胞介导的免疫应答，因此可能导致疾病的雌性偏好。总之，IFNγ表达的变化是PBC发病的关键。
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. Herein we have taken 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′ UTR AU-rich element. These mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human disease and is characterized by upregulation of total bile acids, spontaneous production of AMA, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del−/− to B6/Rag1−/− mice induced moderate portal inflammation, and parenchymal inflammation, RNA-sequencing of liver gene expression revealed that upregulated genes potentially define early stages of cholangitis. Interestingly, upregulated 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 (BEC) in the initiation stage of PBC. Moreover, differentially expressed genes in female mice have stronger Type I and II interferon signaling and lymphocyte-mediated immune responses and thus may drive the female bias of the disease. In conclusion, changes in IFNγ expression are critical for the pathogenesis of PBC.
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DOI：
10.1016/j.clinre.2015.08.001
发表时间：
2015-10-01
影响因子：
2.7
作者：
Beuers, Ulrich;Gershwin, M. Eric;Poupon, Raoul
通讯作者：
Poupon, Raoul
影响因子：
13.5
作者：
Dhirapong, Amy;Yang, Guo-Xiang;Nadler, Steven;Zhang, Weici;Tsuneyama, Koichi;Leung, Patrick;Knechtle, Stuart;Ansari, Aftab A.;Coppel, Ross L.;Liu, Fu-Tong;He, Xiao-Song;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric
影响因子：
12.8
作者：
Hodge DL;Berthet C;Coppola V;Kastenmüller W;Buschman MD;Schaughency PM;Shirota H;Scarzello AJ;Subleski JJ;Anver MR;Ortaldo JR;Lin F;Reynolds DA;Sanford ME;Kaldis P;Tessarollo L;Klinman DM;Young HA
通讯作者：
Young HA
影响因子：
5
作者：
Kar, S. P.;Seldin, M. F.;Chen, W.;Lu, E.;Hirschfield, G. M.;Invernizzi, P.;Heathcote, J.;Cusi, D.;Gershwin, M. E.;Siminovitch, K. A.;Amos, C. I.
通讯作者：
Amos, C. I.
影响因子：
29.4
作者：
Salas, January T.;Banales, Jesus M.;Medina, Juan F.
通讯作者：
Medina, Juan F.