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

Authors

• Heekyong R. Bae, National Cancer Institute at Frederick
• Deborah L. Hodge, National Cancer Institute at Frederick
• Guo Xiang Yang, University of California, Davis
• Patrick S.C. Leung, University of California, Davis
• Sathi Babu Chodisetti, Penn State College of Medicine
• Julio C. Valencia, National Cancer Institute at Frederick
• Michael Sanford, National Cancer Institute at Frederick
• John M. Fenimore, National Cancer Institute at Frederick
• Ziaur S.M. Rahman, Universität Bonn
• Koichi Tsuneyama, Tokushima University
• Gary L. Norman, Werfen
• M E. Gershwin, University of California Davis School of MedicineFollow
• Howard A. Young, National Cancer Institute at FrederickFollow

Date of this Version

4-1-2018

Citation

HEPATOLOGY, VOL. 67, NO. 4, 2018

DOI 10.1002/hep.29524

Comments

U.S. government work

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).