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

Abstract

We have reported a murine model of autoimmune cholangitis, generated by altering the AU rich element by deletion of the IFN-γ 3'UTR region (coined ARE-Del^-/-), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the gender 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 gender 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. In conclusion, our data implicate type I IFN signaling as a necessary component of the gender 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. This article is protected by copyright. All rights reserved.

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