Abstract

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. 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. 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. 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. 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.

Highlights

  • Immune genes and inflammatory pathways are enriched in HBV livers with chronic inflammation (IA and ENEG), whereas metabolic pathways are suppressed

  • We performed RNA sequencing (RNA-seq) on liver biopsies from 69 chronic HBV patients at the different phases (15 IT, 15 IA, 23 inactive carrier (IC) and 16 ENEG) and compared them to biopsies obtained from individuals who volunteered as altruistic liver donors (Table 1)

  • We identified 30 and 32 candidate genes in the IA and ENEG group, respectively associated with associated with the inflammation level (ALT) (Rho>0.5), where only CXCL9, GBP5 and APOL3 correlated in both phases (Figure 2D)

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Summary

Introduction

4 Figures and 1 Table na ur Jo. Chronic HBV is clinically defined in 4 phases by a combination of serum. HBV DNA levels, HBeAg status and ALT: immunotolerant (IT), immune-active (IA), inactive carrier (IC) and HBeAg-negative hepatitis (ENEG). Immune and virological differences between phases as detected in blood have proven useful but are insufficient to appreciate the interrelation between the immune system and the virus since immune dynamics in blood and liver differ. The inflammatory response in the liver and parenchymal cells cannot be fully captured in blood

Methods
Results
Conclusion

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