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Viral Hepatitis
Re-evaluation of HBV clinical phases by system biology identifies unappreciated roles for the innate immune response and B cells
Thomas Vanwolleghem1,
Jun Hou1,
Gertine van Oord1,
Arno C. Andeweg2,
A.D.M.E. Osterhaus2,
Suzan D. Pas2,
Harry L.A. Janssen1,3,† and
Andre Boonstra1,†,*
DOI: 10.1002/hep.27805
© 2015 by the American Association for the Study of Liver Diseases
Issue
Cover image for Vol. 61 Issue 4
Hepatology
Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)
Article has an altmetric score of 7
Author Information
1 Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
2 Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
3 Liver Clinic, University Health Network, Toronto, Canada
† these authors contributed equally
*Address for correspondence: Andre Boonstra, PhD, [email protected], Phone: +31-10-7035944, Associate Professor - Immunology of Viral Hepatitis, Dept. of Gastroenterology and Hepatology, Na10-11, Erasmus MC, University Hospital Rotterdam, The Netherlands
Abstract
Objective: To identify immunological mechanisms that govern distinct clinical phases of a chronic HBV infection, -immune tolerant (IT), immune active (IA), inactive carrier (IC) and HBeAg negative (ENEG) hepatitis phases- we performed a systems biology study.
Design: Serum samples from untreated chronic HBV patients (n=71) were used for multiplex cytokine measurements, quantitative HBsAg, HBeAg levels, HBV genotype and mutant analysis. Leukocytes were phenotyped using multicolour flowcytometry and whole blood transcriptome profiles were generated. The latter were compared with liver biopsy transcriptomes from IA (n=16) and IT (n=3) patients.
Results: HBV viral load, HBeAg and HBsAg levels (P<0.001), but not leukocyte composition differed significantly between distinct phases. Serum MCP-1, IL-12p40, IP-10, MIP-1β levels were different between two or more clinical phases (P<0.05). Comparison of blood transcriptomes identified 64 differentially expressed genes. The gene signature distinguishing IA from IT and IC patients was predominantly composed of highly upregulated immunoglobulin encoding genes. Modular repertoire analysis using gene sets clustered according to similar expression patterns, corroborated the abundant expression of B cell function-related genes in IA patients, and pointed towards increased ISG transcript levels in IT patients compared to subsequent phases. NK cell activities were clustered in clinical phases with biochemical liver damage (IA and ENEG phases), while T cell activities were higher in all phases compared to IT patients. B cell related transcripts proved to be higher in biopsies from IA vs IT patients.
Conclusion: HBV clinical phases are characterised by distinct blood gene signatures. Innate interferon and B cell responses are highly active during the IT and IA phases, respectively. This suggests that the presumed immune tolerance in chronic HBV infections needs to be redefined. This article is protected by copyright. All rights reserved.
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发表于 2015-3-30 17:29
