Copyright
©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Immune response pattern varies with the natural history of chronic hepatitis B
Wen-Tao Wang, Xue-Qi Zhao, Gui-Ping Li, Yi-Zhi Chen, Lin Wang, Mei-Fang Han, Wei-Na Li, Tao Chen, Guang Chen, Dong Xu, Qin Ning, Xi-Ping Zhao
Wen-Tao Wang, Lin Wang, Mei-Fang Han, Wei-Na Li, Tao Chen, Guang Chen, Dong Xu, Qin Ning, Xi-Ping Zhao, Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Xue-Qi Zhao, Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Gui-Ping Li, Department of Heart Function Examination, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Yi-Zhi Chen, Department of Pathophysiology, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
Author contributions: Wang WT performed the majority of experiments and analyzed the data; Wang WT and Zhao XP wrote the manuscript; Zhao XP designed the study; Zhao XQ, Li GP, Chen YZ and Wang L performed a part of experiments; Li WN, Chen T, Chen G and Xu D coordinated the research and provided ideas; Han MF and Ning Q revised the manuscript for important intellectual content.
Supported by National Science Fund of China (NSFC) No. 30771911; National Science and Technology Major Project No. 2012ZX10002007-003.
Institutional review board statement: This study was approved by the ethics committee of Tongji Medical College, Huazhong University of Science and Technology. All participants provided written informed consent prior to the study.
Institutional animal care and use committee statement: No animals were involved in this study.
Conflict-of-interest statement: All authors declare that there is no financial or conflict of interest that may inappropriately influence our work.
Data sharing statement: No additional data is available.
ARRIVE guidelines statement: No animals were involved in this study, and thus the ARRIVE Guidelines were not available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Xi-Ping Zhao, MD, Professor, Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, Hubei Province, China. xpzhao@tjh.tjmu.edu.cn
Telephone: +86-13100672752 Fax: +86-027-83663604
Received: February 14, 2019
Peer-review started: February 17, 2019
First decision: March 5, 2019
Revised: March 12, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: April 28, 2019
BACKGROUND
Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG).
AIM
To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B.
METHODS
The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.
RESULTS
The ability of NK cells to produce IFN-γ was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56bright NK cells and CD69 in CD56dim NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-α expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.
CONCLUSION
Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.
Core tip: Chronic hepatitis B is a highly heterogeneous disease, which can be divided into four phases: immune tolerant, immune active (IA), inactive carrier and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG). Natural killer (NK) and virus-specific T cells are two key effector cells of cellular immunity. Our study demonstrates the conversion of the immune response pattern along the natural history of chronic hepatitis B virus infection. NK cells were phenotypically activated in the clinical phases (IA and ENEG) with biochemical liver damage. NK, non-specific and virus-specific T cells were functionally impaired in immune tolerant and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T cell responses were partially restored in the inactive carrier phase, and the ENEG phase was primarily dominated by nonantigen-specific T cell responses.
