Heekyong R Bae1, Deborah L Hodge1, Guo-Xiang Yang2, Patrick S C Leung2, Sathi Babu Chodisetti3, Julio C Valencia1, Michael Sanford1, John M Fenimore1, Ziaur S M Rahman4, Koichi Tsuneyama5, Gary L Norman6, M Eric Gershwin2, Howard A Young1. 1. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, and Leidos Frederick, Frederick, MD. 2. Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA. 3. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA. 4. Cellular Interactions and Immunimaging Institutes of Molecular Medicine and Experimental Immunology (IMMEI), University of Bonn, Bonn, Germany. 5. Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. 6. Inova Diagnostics, San Diego, CA.
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).
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 humanprimary 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).
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