Multi-parametric analysis of human livers reveals variation in intrahepatic inflammation across phases of chronic hepatitis B infection

Noe A Rico Montanari, Ricardo Ramírez, Abhishek Aggarwal, Nick van Buuren, Michael Doukas, Christina Moon, Scott Turner, Lauri Diehl, Li Li, Jose D. Debes, Becket Feierbach, Andre Boonstra

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Background & Aims: Chronic HBV is clinically categorized into 4 phases by a combination of serum HBV DNA levels, HBeAg status and alanine aminotransferase (ALT): immunotolerant (IT), immune-active (IA), inactive carrier (IC) and HBeAg-negative hepatitis (ENEG). Immune and virological measurements in the blood have proven useful but are insufficient to explain the interrelation between the immune system and the virus since immune dynamics differ in the blood and liver. Furthermore, the inflammatory response in the liver and parenchymal cells cannot be fully captured in blood. Methods: Immunological composition and transcriptional profiles of core needle liver-biopsies in chronic HBV phases were compared to those of healthy controls by multiplex immunofluorescence and RNA-sequencing (n = 37 and 78, respectively) analyses. Results: Irrespective of the phase-specific serological profiles, increased immune-gene expression and frequency was observed in chronic HBV compared to healthy livers. Greater transcriptomic deregulation was seen in IA and ENEG (172 vs. 243 DEGs) than in IT and IC (13 vs. 35 DEGs) livers. Interferon-stimulated genes, immune-activation and exhaustion genes (ICOS, CTLA4, PDCD1) together with chemokine genes (CXCL10, CXCL9) were significantly induced in IA and ENEG livers. Moreover, distinct immune profiles associated with ALT elevation and a more accentuated immune-exhaustion profile (CTLA4, TOX, SLAMF6, FOXP3) were observed in ENEG, which set it apart from the IA phase (LGALS9, PDCD1). Interestingly, all HBV phases showed downregulation of metabolic pathways vs. healthy livers (fatty and bile acid metabolism). Finally, increased leukocyte infiltrate correlated with serum ALT, but not with HBV DNA or viral proteins. Conclusion: Our comprehensive multi-parametric analysis of human livers revealed distinct inflammatory profiles and pronounced differences in intrahepatic gene profiles across all chronic HBV phases in comparison to healthy liver. Lay summary: Immunological studies on chronic HBV remain largely restricted to assessment of peripheral responses due to the limited access to the site of infection, the liver. In this study, we comprehensively analyzed livers from a well-defined cohort of patients with chronic HBV and uninfected controls with state-of-the-art techniques, and evaluated the differences in gene expression profiles and inflammation characteristics across distinct disease phases in patients with chronic HBV.

Original languageEnglish (US)
Pages (from-to)332-343
Number of pages12
JournalJournal of Hepatology
Volume77
Issue number2
DOIs
StatePublished - Aug 2022

Bibliographical note

Funding Information:
This work was funded by Foundation for Liver and Gastrointestinal Research (AB) and Robert Wood Johnson Foundation , Harold Amos Medical Faculty Development Program and University of Minnesota AIRP grant (JDD).

Publisher Copyright:
© 2022 The Authors

Keywords

  • HBV
  • RNA-Seq
  • immunology
  • inflammation
  • liver
  • liver biopsy
  • tissue

Fingerprint

Dive into the research topics of 'Multi-parametric analysis of human livers reveals variation in intrahepatic inflammation across phases of chronic hepatitis B infection'. Together they form a unique fingerprint.

Cite this