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    Increased type-I interferon level is associated with liver damage and fibrosis in primary sclerosing cholangitis
    (2024)
    Salzmann, Rebekka J.S. 
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    Krötz, Christina 
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    Mocan, Tudor 
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    Mocan, Lavinia P. 
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    Grapa, Cristiana 
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    Rottmann, Sophia 
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    Reichelt, Ramona 
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    Keller, Cindy M. 
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    Langhans, Bettina 
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    ; ; ; ;
    Krawczyk, Marcin 
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    Milkiewicz, Piotr 
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    Sparchez, Zeno 
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    Lammert, Frank 
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    Gonzalez-Carmona, Maria A. 
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    Willms, Arnulf 
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    Strassburg, Christian P. 
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    Kornek, Miroslaw T. 
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    Dold, Leona 
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    Lukacs-Kornek, Veronika 
    Background: The level of type-I interferons (IFNs) in primary sclerosing cholangitis (PSC) was investigated to evaluate its association with disease activity and progression. Methods: Bioactive type-I IFNs were evaluated in a murine model of PSC and human patients’ sera using a cell-based reporter assay and ELISA techniques. In total, 57 healthy participants, 71 PSC, and 38 patients with primary biliary cholangitis were enrolled in this study. Results: Bioactive type-I IFNs were elevated in the liver and serum of multidrug resistance protein 2–deficient animals and showed a correlation with the presence of CD45+ immune cells and serum alanine transaminase levels. Concordantly, bioactive type-I IFNs were elevated in the sera of patients with PSC as compared to healthy controls (sensitivity of 84.51%, specificity of 63.16%, and AUROC value of 0.8267). Bioactive IFNs highly correlated with alkaline phosphatase (r=0.4179, p<0.001), alanine transaminase (r=0.4704, p<0.0001), and gamma-glutamyl transpeptidase activities (r=0.6629, p<0.0001) but not with serum bilirubin. In addition, patients with PSC with advanced fibrosis demonstrated significantly higher type-I IFN values. Among the type-I IFN subtypes IFNα, β and IFNω could be detected in patients with PSC with IFNω showing the highest concentration among the subtypes and being the most abundant among patients with PSC. Conclusions: The selectively elevated bioactive type-I IFNs specifically the dominating IFNω could suggest a novel inflammatory pathway that might also have a hitherto unrecognized role in the pathomechanism of PSC.
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