PBMC transcriptomics identifies immune-metabolism disorder during the development of HBV-ACLF.

Abstract

OBJECTIVE:

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics.

METHODS:

Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs).

RESULTS:

The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis.

CONCLUSIONS:

This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

• Authors: Jiang Li, Xi Liang, Jing Jiang, Lingling Yang, Jiaojiao Xin, Dongyan Shi, Yingyan Lu, Jun Li, Keke Ren, Hozeifa Mohamed Hassan, Jianing Zhang, Pengcheng Chen, Heng Yao, Jiaqi Li, Tianzhou Wu, Linfeng Jin, Ping Ye, Tan Li, Huafen Zhang, Suwan Sun, Beibei Guo, Xingping Zhou, Qun Cai, Jiaxian Chen, Xiaowei Xu, Jianrong Huang, Shaorui Hao, Jinqiu He, Shaojie Xin, Di Wang, Jonel Trebicka, Xin Chen, Jun Li, Chinese Group on the Study of Severe Hepatitis B (COSSH)
• Journal: Gut (Gut) Vol. 71 Issue 1 Pg. 163-175 (01 2022) ISSN: 1468-3288 [Electronic] England
• PMID: 33431576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• DNA, Viral

Topics

• Acute-On-Chronic Liver Failure (pathology, virology)
• Adaptive Immunity
• Adult
• Animals
• Case-Control Studies
• DNA, Viral (blood)
• Female
• Hepatitis B virus
• Hepatitis B, Chronic (complications)
• Humans
• Immunity, Innate
• Leukocytes, Mononuclear (immunology)
• Male
• Metabolome
• Middle Aged
• Prospective Studies
• Rats
• Transcriptome