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The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex‐biased autoimmunity
Author(s) -
Bae Heekyong R.,
Hodge Deborah L.,
Yang GuoXiang,
Leung Patrick S.C.,
Chodisetti Sathi Babu,
Valencia Julio C.,
Sanford Michael,
Fenimore John M.,
Rahman Ziaur S.M.,
Tsuneyama Koichi,
Norman Gary L.,
Gershwin M. Eric,
Young Howard A.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29524
Subject(s) - autoimmunity , autoimmune hepatitis , immunology , biology , interferon type i , autoimmune disease , interferon , receptor , germinal center , knockout mouse , inflammation , hepatitis , antibody , genetics , b cell
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. (H epatology 2018;67:1408‐1419)