The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity

Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M. Eric Gershwin, Howard A. Young

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13 Scopus citations

Abstract

We have reported on a murine model of autoimmune cholangitis, generated by altering the AU-rich element (ARE) by deletion of the interferon gamma (IFN-γ) 3' untranslated region (coined ARE-Del−/−), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the sex bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE-Del−/− mice with IFN type I receptor alpha chain (Ifnar1) knockout mice. We report herein that loss of type I IFN receptor signaling in the double construct of ARE-Del−/− Ifnar1−/− mice dramatically reduces liver pathology and abrogated sex bias. More importantly, female ARE-Del−/− mice have an increased number of germinal center (GC) B cells as well as abnormal follicular formation, sites which have been implicated in loss of tolerance. Deletion of type I IFN signaling in ARE-Del−/− Ifnar1−/− mice corrects these GC abnormalities, including abnormal follicular structure. Conclusion: Our data implicate type I IFN signaling as a necessary component of the sex bias of this murine model of autoimmune cholangitis. Importantly these data suggest that drugs that target the type I IFN signaling pathway would have potential benefit in the earlier stages of PBC. (Hepatology 2018;67:1408-1419).

Original languageEnglish (US)
Pages (from-to)1408-1419
Number of pages12
JournalHepatology
Volume67
Issue number4
DOIs
StatePublished - Apr 1 2018

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ASJC Scopus subject areas

  • Hepatology

Cite this

Bae, H. R., Hodge, D. L., Yang, G. X., Leung, P. S., Chodisetti, S. B., Valencia, J. C., Sanford, M., Fenimore, J. M., Rahman, Z. S. M., Tsuneyama, K., Norman, G. L., Gershwin, M. E., & Young, H. A. (2018). The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. Hepatology, 67(4), 1408-1419. https://doi.org/10.1002/hep.29524