| First Author | Bae HR | Year | 2018 |
| Journal | Hepatology | Volume | 67 |
| Issue | 4 | Pages | 1408-1419 |
| PubMed ID | 28921595 | Mgi Jnum | J:313159 |
| Mgi Id | MGI:6791275 | Doi | 10.1002/hep.29524 |
| Citation | Bae HR, et al. (2018) The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. Hepatology 67(4):1408-1419 |
| abstractText | 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-gamma) 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). |
