Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Mar 6, 2021; 9(7): 1619-1630
Published online Mar 6, 2021. doi: 10.12998/wjcc.v9.i7.1619
Elevated soluble 4-1BB is associated with serum markers of hepatitis B virus in patients with chronic hepatitis B
Meng-Ru Zhan, Xiu-Zhu Gao, Chang Wang, Fei Peng, Xiao-Mei Wang, Hong-Qin Xu, Jun-Qi Niu
Meng-Ru Zhan, Xiu-Zhu Gao, Chang Wang, Fei Peng, Xiao-Mei Wang, Hong-Qin Xu, Jun-Qi Niu, Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
Xiu-Zhu Gao, Phase I Clinical Research Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
Author contributions: Niu JQ was the guarantor and designed the study; Zhan MR, Gao XZ and Peng F participated in the acquisition, analysis and interpretation of the data; Zhan MR drafted the initial manuscript; Wang C and Xu HQ revised the article critically for important intellectual content; All authors issued final approval for the version to be submitted.
Supported by Chinese Foundation for Hepatitis Prevention and Control—Tian-Qing Liver Disease Research Fund Subject, No. TQGB20200118.
Institutional review board statement: The study was reviewed and approved by the local medical ethics committee of the First Hospital of Jilin University.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All authors declare no conflict of interest related to this article.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement— checklist of items, and the manuscript was prepared and revised according to the STROBE Statement— checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: Jun-Qi Niu, MD, PhD, Professor, Department of Hepatology, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun 130021, Jilin Province, China. junqiniu@jlu.edu.cn
Received: November 10, 2020
Peer-review started: November 10, 2020
First decision: December 8, 2020
Revised: December 13, 2020
Accepted: December 22, 2020
Article in press: December 22, 2020
Published online: March 6, 2021
Research background

Chronic hepatitis B infection is a global health burden. However, current therapies cannot achieve a functional cure, and the development of immunological therapeutic strategies is urgently needed. Previous studies have suggested that the costimulatory molecule 4-1BB, a member of the tumor necrosis factor superfamily, plays pivotal roles in regulating immunity during chronic viral infection.

Research motivation

Recently there was a study suggesting that 4-1BB signal enhancement inhibits hepatitis B virus replication in a noncytolytic manner, which indicates that 4-1BB may be a promising target to control hepatitis B virus (HBV) infection. However, there are no studies about 4-1BB in chronic hepatitis B (CHB) up to now.

Research objectives

Our main purpose was to analyze the soluble form and mRNA level of 4-1BB in peripheral blood to determine whether the costimulatory molecule is aberrantly produced in this disease and to provide more evidence for 4-1BB-targeted therapies for curing HBV.

Research methods

Peripheral blood samples were collected from a total of 64 patients with CHB and 37 healthy controls in this study. The method of ELISA was used to measure the levels of soluble 4-1BB (s4-1BB). 4-1BB mRNA expression in peripheral blood mononuclear cells was detected by real-time quantitative PCR. The cytokines in plasma were assayed using the MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel - Immunology Multiplex Assay.

Research results

We found a higher level of s4-1BB in the plasma of patients with CHB compared with healthy adults. The s4-1BB level in plasma was significantly increased in patients with a higher viral load and a disease flare up. However, the level of s4-1BB in treatment-naïve patients was not significantly different from that in entecavir-treated patients. Interestingly, among treatment-naïve patients with CHB, the levels of s4-1BB in plasma had a significant positive correlation with hepatitis B surface antigen, HBV DNA, hepatitis B e antigen, and triglyceride levels (r = 0.748, P < 0.001; r = 0.406, P = 0.004; r = 0.356, P = 0.019; and r = -0.469, P = 0.007, respectively). The 4-1BB mRNA expression was higher in the peripheral blood mononuclear cells of patients with CHB than in the peripheral blood mononuclear cells of healthy adults, but the difference was not statistically significant. The number of subjects limited the ability of this study to clarify causality between 4-1BB and CHB.

Research conclusions

The levels of s4-1BB may be associated with pathogenesis of HBV and therefore may be a promising biomarker for disease progression and a target for curing CHB.

Research perspectives

The mechanism of aberrantly produced 4-1BB needs to be investigated in the future, and whether agitating the target of 4-1BB can cure hepatitis B needs to be also further studied.