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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)
Bae et al. (Mon,) studied this question.