NIH Research Festival
FARE Award Winner
Primary biliary cirrhosis (PBC) is an autoimmune liver disease and occurs primarily in women (> 90%). PBC is characterized by lymphocytic infiltrates near portal tracts, destruction of small bile ducts and presence of anti-mitochondrial Abs (AMAs), and eventually leads to liver failure. IFN gamma is elevated in patients with PBC, but the functional role of IFN gamma on PBC is not known. Here, we characterized the distinctive pathological phenotype of PBC in a mouse model of chronic IFN gamma expression generated by deletion of the IFN-gamma 3’ UTR AU-rich element. Histological assessment of the liver shows that female ARE-Del mice have moderate immune cell infiltration and bile duct destruction near portal tracts. Consistent with clinical features seen in PBC, female ARE-Del have over 30 fold upregulated total bile acids and spontaneous production of AMAs in serum. In contrast, male ARE-Del have mild histological and serological evidence of PBC. To investigate the mechanisms involved in PBC development, we analyzed liver gene expression in ARE-Del mice using RNA-sequencing. By focusing on genes whose expression is highly specific to female ARE-Del, we determined that IFN gamma and interferon alpha receptor are top upstream regulators for this female specific disease progression based on pathway analysis. Remarkably, deletion of the interferon alpha receptor in ARE-Del mice significantly reversed the pathological phenotypes of PBC. Taken together, the ARE-Del mice model mimics the features presented in human PBC and demonstrates that the IFN signature is critical in PBC progression.
Scientific Focus Area: Immunology
This page was last updated on Friday, March 26, 2021