Chronic expression of interferon‐gamma leads to murine autoimmune cholangitis with a female predominance

Abstract

In most autoimmune diseases the serologic hallmarks of disease precede clinical pathology by years. Therefore the use of animal models in defining early disease events becomes critical. Herein we have taken advantage of a “designer” mouse with dysregulation of interferon gamma (IFNγ) characterized by prolonged and chronic expression of IFNγ through deletion of the IFNγ 3′ UTR AU-rich element. These mice develop primary biliary cholangitis (PBC) with a female predominance that mimics human disease and is characterized by upregulation of total bile acids, spontaneous production of AMA, and portal duct inflammation. Transfer of CD4 T cells from ARE-Del−/− to B6/Rag1−/− mice induced moderate portal inflammation, and parenchymal inflammation, RNA-sequencing of liver gene expression revealed that upregulated genes potentially define early stages of cholangitis. Interestingly, upregulated genes specifically overlap with the gene expression signature of biliary epithelial cells in PBC, implying that IFNγ may play a pathogenic role in biliary epithelial cells (BEC) in the initiation stage of PBC. Moreover, differentially expressed genes in female mice have stronger Type I and II interferon signaling and lymphocyte-mediated immune responses and thus may drive the female bias of the disease. In conclusion, changes in IFNγ expression are critical for the pathogenesis of PBC.

Current prospects of type II interferon γ signaling and autoimmunity

“…The persistent serum levels of IFN␥, due to increased stability of mRNA, result in gradual establishment of SLE-like autoimmunity (80). More importantly, we have provided evidence that heterozygous ARE-del mice share similar levels of autoantibodies and demonstrate a histological score of tissue damage in target organs like that seen in homozygous ARE-del mice that express twice the systemic IFN␥ levels (80,81). This evidence suggests the existence of a threshold level of IFN␥ that, when crossed, results in a more severe pathology.…”

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

“…ARE‐Del −/− mice were generated and maintained as reported . Ifnar1 −/− mice were initially obtained from The Jackson Laboratory and back‐crossed onto the C57BL/6 background by speed congenic analysis.…”

“…In particular, we have taken advantage of a “designer” mouse with posttranscriptional dysregulation of IFN‐γ through deletion of the IFN 3' untranslated region (3'‐UTR) AU‐rich element (ARE −/− ). These animals, coined ARE −/− mice, exhibit prolonged and chronic overexpression of IFN‐γ and, more important, develop a female predominant autoimmune cholangitis, with portal inflammation, liver granulomas, elevation of bile salts, elevation of sera immunoglobulin (Ig) M, and the presence of both antimitochondrial antibodies (AMAs) and antibodies to gp210 …”

“…Previous analysis of differentially expressed genes in female ARE‐Del −/− mice revealed stronger type I and II IFN signaling and lymphocyte‐mediated immune responses, especially CD4 T‐cell‐mediated responses. Type I IFN receptors were detected as one of the top upstream regulators next to IFN‐γ in liver gene expression analysis . Therefore, to extend these pilot observations and define a translational application to human PBC, we developed IFNα/β receptor alpha‐chain–deficient ARE‐Del −/− animals, coined ARE‐Del −/− Ifnar1 −/− mice.…”

Geoepidemiology and changing mortality in primary biliary cholangitis

“…An enormous effort has been made to define the genetics and immuobiology of human autoimmue liver diseases in both human and mouse models [59][60][61][62][63][64][65][66][67][68][69][70][71][72]. Yet there remains an enormous gap between these investigative efforts and clinical translation.…”