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

Heekyong R. Bae, Deborah L. Hodge, Guo Xiang Yang, Patrick S Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M. Eric Gershwin, Howard A. Young

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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).

Original languageEnglish (US)
Pages (from-to)1408-1419
Number of pages12
JournalHepatology
Volume67
Issue number4
DOIs
StatePublished - Apr 1 2018

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AU Rich Elements
Interferon Type I
Cholangitis
Autoimmunity
Interferon-gamma
Sexism
Germinal Center
3' Untranslated Regions
Gastroenterology
Knockout Mice
B-Lymphocytes
Pathology
Inflammation
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hepatology

Cite this

Bae, H. R., Hodge, D. L., Yang, G. X., Leung, P. S., Chodisetti, S. B., Valencia, J. C., ... Young, H. A. (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. https://doi.org/10.1002/hep.29524

The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. / Bae, Heekyong R.; Hodge, Deborah L.; Yang, Guo Xiang; Leung, Patrick S; 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.

In: Hepatology, Vol. 67, No. 4, 01.04.2018, p. 1408-1419.

Research output: Contribution to journalArticle

Bae, HR, Hodge, DL, Yang, GX, Leung, PS, Chodisetti, SB, Valencia, JC, Sanford, M, Fenimore, JM, Rahman, ZSM, Tsuneyama, K, Norman, GL, Gershwin, ME & Young, HA 2018, 'The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity', Hepatology, vol. 67, no. 4, pp. 1408-1419. https://doi.org/10.1002/hep.29524
Bae, Heekyong R. ; Hodge, Deborah L. ; Yang, Guo Xiang ; Leung, Patrick S ; 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. / The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity. In: Hepatology. 2018 ; Vol. 67, No. 4. pp. 1408-1419.
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AU - Chodisetti, Sathi Babu

AU - Valencia, Julio C.

AU - Sanford, Michael

AU - Fenimore, John M.

AU - Rahman, Ziaur S.M.

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AU - Norman, Gary L.

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AB - 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).

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