Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance

Heekyong R. Bae, Patrick S C Leung, Koichi Tsuneyama, Julio C. Valencia, Deborah L. Hodge, Seohyun Kim, Tim Back, Megan Karwan, Anand S. Merchant, Nobuyuki Baba, Dechun Feng, Ogyi Park, Bin Gao, Guo Xiang Yang, M. Eric Gershwin, Howard A. Young

Research output: Contribution to journalArticle

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. Conclusion: Changes in IFNγ expression are critical for the pathogenesis of PBC. (Hepatology 2016;64:1189-1201).

Original languageEnglish (US)
Pages (from-to)1189-1201
Number of pages13
JournalHepatology
Volume64
Issue number4
DOIs
StatePublished - Oct 1 2016

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Cholangitis
Interferon-gamma
Inflammation
Epithelial Cells
Genes
RNA Sequence Analysis
Interferon Type I
Clinical Pathology
3' Untranslated Regions
Gastroenterology
Bile Acids and Salts
Transcriptome
Autoimmune Diseases
Anti-Idiotypic Antibodies
Up-Regulation
Animal Models
Lymphocytes
T-Lymphocytes
Gene Expression
Liver

ASJC Scopus subject areas

  • Hepatology

Cite this

Bae, H. R., Leung, P. S. C., Tsuneyama, K., Valencia, J. C., Hodge, D. L., Kim, S., ... Young, H. A. (2016). Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology, 64(4), 1189-1201. https://doi.org/10.1002/hep.28641

Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. / 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.

In: Hepatology, Vol. 64, No. 4, 01.10.2016, p. 1189-1201.

Research output: Contribution to journalArticle

Bae, HR, Leung, PSC, Tsuneyama, K, Valencia, JC, Hodge, DL, Kim, S, Back, T, Karwan, M, Merchant, AS, Baba, N, Feng, D, Park, O, Gao, B, Yang, GX, Gershwin, ME & Young, HA 2016, 'Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance', Hepatology, vol. 64, no. 4, pp. 1189-1201. https://doi.org/10.1002/hep.28641
Bae HR, Leung PSC, Tsuneyama K, Valencia JC, Hodge DL, Kim S et al. Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. Hepatology. 2016 Oct 1;64(4):1189-1201. https://doi.org/10.1002/hep.28641
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. / Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. In: Hepatology. 2016 ; Vol. 64, No. 4. pp. 1189-1201.
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AU - Hodge, Deborah L.

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AB - 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).

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