Increased Type-I Interferon Level is Associated with Liver Damage and Fibrosis in Primary Sclerosing Cholangitis

Overview

Journal Hepatol Commun

Specialty Gastroenterology

Date 2024 Feb 15

PMID 38358371

Authors

Rebekka J S Salzmann

Christina Krotz

Tudor Mocan

Lavinia P Mocan

Cristiana Grapa

Sophia Rottmann

Ramona Reichelt

Cindy M Keller

Bettina Langhans

Frederik Schunemann

Alexander Pohl

Thomas Bohler

Kathe Bersiner

Marcin Krawczyk

Piotr Milkiewicz

Zeno Sparchez

Frank Lammert

Sebastian Gehlert

Maria A Gonzalez-Carmona

Arnulf Willms

Christian P Strassburg

Miroslaw T Kornek

Leona Dold

Veronika Lukacs-Kornek

Affiliations

Soon will be listed here.

Abstract

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.

References

Chapman R, Fevery J, Kalloo A, Nagorney D, Boberg K, Shneider B . Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51(2):660-78. DOI: 10.1002/hep.23294. View

Colonna M . TLR pathways and IFN-regulatory factors: to each its own. Eur J Immunol. 2007; 37(2):306-9. DOI: 10.1002/eji.200637009. View

. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009; 51(2):237-67. DOI: 10.1016/j.jhep.2009.04.009. View

Ravichandran G, Neumann K, Berkhout L, Weidemann S, Langeneckert A, Schwinge D . Interferon-γ-dependent immune responses contribute to the pathogenesis of sclerosing cholangitis in mice. J Hepatol. 2019; 71(4):773-782. DOI: 10.1016/j.jhep.2019.05.023. View

Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H . Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004; 127(1):261-74. DOI: 10.1053/j.gastro.2004.04.009. View

Giles E, Sanders T, McCarthy N, Lung J, Pathak M, MacDonald T . Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease. Mucosal Immunol. 2016; 10(1):184-193. DOI: 10.1038/mi.2016.44. View

Lazaridis K, LaRusso N . Primary Sclerosing Cholangitis. N Engl J Med. 2016; 375(25):2501-2502. DOI: 10.1056/NEJMc1613273. View

Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, Paschos E . Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis. 2007; 14(2):204-12. DOI: 10.1002/ibd.20315. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

10.

Maroni L, Haibo B, Ray D, Zhou T, Wan Y, Meng F . Functional and structural features of cholangiocytes in health and disease. Cell Mol Gastroenterol Hepatol. 2015; 1(4):368-380. PMC: 4530547. DOI: 10.1016/j.jcmgh.2015.05.005. View

11.

Halaoui A, Hajj Ali A, Habib S, Kanso M, Daniel F, Mukherji D . Gender differences in liver fibrosis among patients younger than 50 years: A retrospective cohort study. Clin Res Hepatol Gastroenterol. 2020; 44(5):733-738. DOI: 10.1016/j.clinre.2020.01.001. View

12.

de Vries E, Wang J, Leeflang M, Boonstra K, Weersma R, Beuers U . Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value. Liver Int. 2016; 36(12):1867-1875. DOI: 10.1111/liv.13110. View

13.

Palmela C, Peerani F, Castaneda D, Torres J, Itzkowitz S . Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Review of the Phenotype and Associated Specific Features. Gut Liver. 2017; 12(1):17-29. PMC: 5753680. DOI: 10.5009/gnl16510. View

14.

Sterling R, Lissen E, Clumeck N, Sola R, Correa M, Montaner J . Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006; 43(6):1317-25. DOI: 10.1002/hep.21178. View

15.

Coulstock E, Sosabowski J, Ovecka M, Prince R, Goodall L, Mudd C . Liver-targeting of interferon-alpha with tissue-specific domain antibodies. PLoS One. 2013; 8(2):e57263. PMC: 3581439. DOI: 10.1371/journal.pone.0057263. View

16.

Karlsen T, Folseraas T, Thorburn D, Vesterhus M . Primary sclerosing cholangitis - a comprehensive review. J Hepatol. 2017; 67(6):1298-1323. DOI: 10.1016/j.jhep.2017.07.022. View

17.

Singh S, Fujii L, Murad M, Wang Z, Asrani S, Ehman R . Liver stiffness is associated with risk of decompensation, liver cancer, and death in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2013; 11(12):1573-84.e1-2. PMC: 3900882. DOI: 10.1016/j.cgh.2013.07.034. View

18.

Vesterhus M, Holm A, Hov J, Nygard S, Schrumpf E, Melum E . Novel serum and bile protein markers predict primary sclerosing cholangitis disease severity and prognosis. J Hepatol. 2017; 66(6):1214-1222. DOI: 10.1016/j.jhep.2017.01.019. View

19.

Jones D . Pathogenesis of primary biliary cirrhosis. J Hepatol. 2003; 39(4):639-48. DOI: 10.1016/s0168-8278(03)00270-8. View

20.

Sorensen J, Nielsen O, Andersson M, Ainsworth M, Ytting H, Belard E . Inflammatory bowel disease with primary sclerosing cholangitis: A Danish population-based cohort study 1977-2011. Liver Int. 2017; 38(3):532-541. DOI: 10.1111/liv.13548. View