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 language | English (US) |
|---|---|
| Pages (from-to) | 1408-1419 |
| Number of pages | 12 |
| Journal | Hepatology |
| Volume | 67 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2018 |
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ASJC Scopus subject areas
- Hepatology
Cite this
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 journal › Article
}
TY - JOUR
T1 - The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex-biased autoimmunity
AU - Bae, Heekyong R.
AU - Hodge, Deborah L.
AU - Yang, Guo Xiang
AU - Leung, Patrick S
AU - Chodisetti, Sathi Babu
AU - Valencia, Julio C.
AU - Sanford, Michael
AU - Fenimore, John M.
AU - Rahman, Ziaur S.M.
AU - Tsuneyama, Koichi
AU - Norman, Gary L.
AU - Gershwin, M. Eric
AU - Young, Howard A.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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).
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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U2 - 10.1002/hep.29524
DO - 10.1002/hep.29524
M3 - Article
C2 - 28921595
AN - SCOPUS:85044289308
VL - 67
SP - 1408
EP - 1419
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 4
ER -