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1
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Singer M, Elsayed AM, Husseiny MI. Regulatory T-cells: The Face-off of the Immune Balance. FRONT BIOSCI-LANDMRK 2024; 29:377. [PMID: 39614434 DOI: 10.31083/j.fbl2911377] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/29/2024] [Accepted: 08/13/2024] [Indexed: 12/01/2024]
Abstract
Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, ensuring a balanced immune response. Tregs primarily operate in an antigen-specific fashion, facilitated by their distinct distribution within discrete niches. Tregs have been studied extensively, from their point of origin in the thymus origin to their fate in the periphery or organs. Signals received from antigen-presenting cells (APCs) stimulate Tregs to dampen inflammation. Almost all tumors are characterized by a pathological abundance of immune suppression in their microenvironment. Conversely, the lack thereof proves detrimental to immunological disorders. Achieving a balanced expression of Tregs in relation to other immune compartments is important in establishing an effective and adaptable immune tolerance towards cancer cells and autoantigens. In the context of cancer, it is essential to decrease the frequency of Tregs to overcome tumor suppression. A lower survival rate is associated with the presence of excessive exhausted effector immune cells and an increased frequency of regulatory cells. However, when it comes to treating graft rejection and autoimmune diseases, the focus lies on immune tolerance and the transfer of Tregs. Here, we explore the complex mechanisms that Tregs use in human disease to balance effector immune cells.
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Affiliation(s)
- Mahmoud Singer
- School of Medicine, University of California Irvine, Irvine, CA 92617, USA
| | - Ahmed M Elsayed
- Division of Infectious Diseases, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA
| | - Mohamed I Husseiny
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
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2
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Zheng Q, Sun Q, Yao H, Shi R, Wang C, Ma Z, Xu H, Zhou G, Cheng Z, Xia H. Single-cell landscape identifies the immunophenotypes and microenvironments of HBV-positive and HBV-negative liver cancer. Hepatol Commun 2024; 8:e0364. [PMID: 38251896 PMCID: PMC10805423 DOI: 10.1097/hc9.0000000000000364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 12/04/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND HBV infection leads to HCC and affects immunotherapy. We are exploring the tumor ecosystem in HCC to help gain a deeper understanding and design more effective immunotherapy strategies for patients with HCC with or without HBV infection. METHODS Single-cell RNA sequencing series were integrated as a discovery cohort to interrogate the tumor microenvironment of HBV-positive (HBV+) HCC and HBV-negative (HBV-) HCC. We further dissect the intratumoral immune status of HBV+ HCC and HBV- HCC. An independent cohort, including samples treated with immune checkpoint blockade therapy, was used to validate the major finding and investigate the effect of HBV infection on response to immunotherapy. RESULTS The interrogation of tumor microenvironment indicated that regulatory T cells, exhausted CD8+ T cells, and M1-like Macrophage_MMP9 were enriched in HBV+ HCC, while mucosa-associated invariant T cells were enriched in HBV- HCC. All subclusters of T cells showed high expression of immune checkpoint genes in HBV+ HCC. Regulatory T cells enriched in HBV+ HCC also showed more robust immunosuppressive properties, which was confirmed by cross talk between immune cell subsets. The ability of antigen presentation with major histocompatibility complex-II was downregulated in HBV+ HCC and this phenomenon can be reversed by immunotherapy. Two types of HCC also present different responses to immunotherapy. CONCLUSIONS There is a more immunosuppressive and exhausted tumor microenvironment in HBV+ HCC than in HBV- HCC. This in-depth immunophenotyping strategy is critical to understanding the impact of HBV and the HCC immune microenvironment and helping develop more effective treatments in patients with HCC.
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Affiliation(s)
- Qian Zheng
- Zhongda Hospital, School of Medicine & Advanced Institute for Life and Health, Southeast University, Nanjing, China
- Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Qi Sun
- Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Hong Yao
- Department of Cancer Biotherapy Center & Cancer Research Institute of Yunnan, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Ruoyu Shi
- Department of Anatomical Pathology, Singapore General Hospital, Singapore
| | - Cheng Wang
- School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Zhijie Ma
- School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Haojun Xu
- School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Guoren Zhou
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Zhangjun Cheng
- Zhongda Hospital, School of Medicine & Advanced Institute for Life and Health, Southeast University, Nanjing, China
| | - Hongping Xia
- Zhongda Hospital, School of Medicine & Advanced Institute for Life and Health, Southeast University, Nanjing, China
- Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
- School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
- Department of Cancer Biotherapy Center & Cancer Research Institute of Yunnan, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
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3
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Chen X, Liu X, Jiang Y, Xia N, Liu C, Luo W. Abnormally primed CD8 T cells: The Achilles' heel of CHB. Front Immunol 2023; 14:1106700. [PMID: 36936922 PMCID: PMC10014547 DOI: 10.3389/fimmu.2023.1106700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/20/2023] [Indexed: 03/05/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a significant public health challenge, and more than 250 million people around world are infected with HBV. The clearance of HBV with virus-specific CD8 T cells is critical for a functional cure. However, naïve HBV-specific CD8 T cells are heavily hindered during the priming process, and this phenomenon is closely related to abnormal cell and signal interactions in the complex immune microenvironment. Here, we briefly summarize the recent progress in understanding the abnormal priming of HBV-specific CD8 T cells and some corresponding immunotherapies to facilitate their functional recovery, which provides a novel perspective for the design and development of immunotherapy for chronic HBV infection (CHB). Finally, we also highlight the balance between viral clearance and pathological liver injury induced by CD8 T-cell activation that should be carefully considered during drug development.
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Affiliation(s)
- Xiaoqing Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Yichao Jiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- The Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen, Fujian, China
| | - Chao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
| | - Wenxin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China
- Xiang An Biomedicine Laboratory, Xiamen, Fujian, China
- *Correspondence: Wenxin Luo, ; Chao Liu,
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4
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Sato K, Imamura H, Watahiki Y, Hazama H, Hashimoto T, Mukae S, Ohhira H. A Hepatitis B Virus Reactivation Case Potentially Triggered by the Onset of Diffuse Large B Cell Lymphoma. Intern Med 2022. [PMID: 36261374 DOI: 10.2169/internalmedicine.0420-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
Abstract
An 81-year-old man underwent rituximab-containing chemotherapy for chronic lymphocytic leukemia (CLL). Thirteen years after his last chemotherapy, he was diagnosed with hepatitis B virus (HBV) reactivation. He was then treated with entecavir, and improvement was seen in his liver injury. He developed diffuse large B cell lymphoma (DLBCL) after improvement in his hepatitis. Despite chemotherapy, he contracted the coronavirus disease 2019 (COVID-19) and died of COVID-19. We suspect that HBV reactivation was triggered by DLBCL. When HBV reactivation occurs a long time after chemotherapy has concluded, the onset of DLBCL should be considered.
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Affiliation(s)
- Kentaro Sato
- Department of Gastroenterology, Aizu medical center, Japan
| | | | - Yu Watahiki
- Department of Gastroenterology, Ohta Nishinouchi Hospital, Japan
| | - Hiromasa Hazama
- Department of Gastroenterology, Ohta Nishinouchi Hospital, Japan
| | | | - Shinji Mukae
- Department of Gastroenterology, Ohta Nishinouchi Hospital, Japan
| | - Hiromasa Ohhira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
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ceRNA network development and tumor-infiltrating immune cell analysis in hepatocellular carcinoma. Med Oncol 2021; 38:85. [PMID: 34148185 DOI: 10.1007/s12032-021-01534-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/10/2021] [Indexed: 01/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is among the primary causes of cancer deaths globally. Despite efforts to understand liver cancer, its high morbidity and mortality remain high. Herein, we constructed two nomograms based on competing endogenous RNA (ceRNA) networks and invading immune cells to describe the molecular mechanisms along with the clinical prognosis of HCC patients. RNA maps of tumors and normal samples were downloaded from The Cancer Genome Atlas database. HTseq counts and fragments per megapons per thousand bases were read from 421 samples, including 371 tumor samples and 50 normal samples. We established a ceRNA network based on differential gene expression in normal versus tumor subjects. CIBERSORT was employed to differentiate 22 immune cell types according to tumor transcriptomes. Kaplan-Meier along with Cox proportional hazard analyses were employed to determine the prognosis-linked factors. Nomograms were constructed based on prognostic immune cells and ceRNAs. We employed Receiver operating characteristic (ROC) and calibration curve analyses to estimate these nomogram. The difference analysis found 2028 messenger RNAs (mRNAs), 128 micro RNAs (miRNAs), and 136 long non-coding RNAs (lncRNAs) to be significantly differentially expressed in tumor samples relative to normal samples. We set up a ceRNA network containing 21 protein-coding mRNAs, 12 miRNAs, and 3 lncRNAs. In Kaplan-Meier analysis, 21 of the 36 ceRNAs were considered significant. Of the 22 cell types, resting dendritic cell levels were markedly different in tumor samples versus normal controls. Calibration and ROC curve analysis of the ceRNA network, as well as immune infiltration of tumor showed restful accuracy (3-year survival area under curve (AUC): 0.691, 5-year survival AUC: 0.700; 3-year survival AUC: 0.674, 5-year survival AUC: 0.694). Our data suggest that Tregs, CD4 T cells, mast cells, SNHG1, HMMR and hsa-miR-421 are associated with HCC based on ceRNA immune cells co-expression patterns. On the basis of ceRNA network modeling and immune cell infiltration analysis, our study offers an effective bioinformatics strategy for studying HCC molecular mechanisms and prognosis.
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6
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Panetti C, Kao KC, Joller N. Dampening antiviral immunity can protect the host. FEBS J 2021; 289:634-646. [PMID: 33570771 PMCID: PMC9292735 DOI: 10.1111/febs.15756] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022]
Abstract
Viral infections are very common, and in most cases, the virus is well controlled and eliminated by the immune system. Nevertheless, in some cases, damage of the host tissue inflicted by the virus itself or by the elicited immune response may result in severe disease courses. Thus, regulatory mechanisms are necessary to control virus‐induced and immune pathology. This ensures immune responses are elicited in a potent but controlled manner. In this review, we will outline how immune regulation may contribute to this process. We focus on regulatory T cells and co‐inhibitory receptors and outline how these two regulatory immune components allow for and may even promote potent but not pathologic immune responses. By enabling a balanced immune response, regulatory mechanisms can thus contribute to pathogen control as well as tissue and host protection.
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Affiliation(s)
- Camilla Panetti
- Institute of Experimental Immunology, University of Zurich, Switzerland
| | - Kung-Chi Kao
- Institute of Experimental Immunology, University of Zurich, Switzerland
| | - Nicole Joller
- Institute of Experimental Immunology, University of Zurich, Switzerland
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7
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Estrada Brull A, Rost F, Oderbolz J, Kirchner FR, Leibundgut-Landmann S, Oxenius A, Joller N. CD85k Contributes to Regulatory T Cell Function in Chronic Viral Infections. Int J Mol Sci 2020; 22:E31. [PMID: 33375121 PMCID: PMC7792974 DOI: 10.3390/ijms22010031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 12/16/2020] [Accepted: 12/17/2020] [Indexed: 12/20/2022] Open
Abstract
Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity.
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MESH Headings
- Animals
- Antigens, CD/immunology
- Antigens, CD/metabolism
- Cell Adhesion Molecules, Neuronal/immunology
- Cell Adhesion Molecules, Neuronal/metabolism
- Cell Line
- Cells, Cultured
- Herpesviridae Infections/immunology
- Herpesviridae Infections/metabolism
- Herpesviridae Infections/virology
- Lymphocytic Choriomeningitis/immunology
- Lymphocytic Choriomeningitis/metabolism
- Lymphocytic Choriomeningitis/virology
- Lymphocytic choriomeningitis virus/immunology
- Lymphocytic choriomeningitis virus/physiology
- Membrane Glycoproteins/immunology
- Membrane Glycoproteins/metabolism
- Mice, Inbred C57BL
- Muromegalovirus/immunology
- Muromegalovirus/physiology
- Receptors, Immunologic/immunology
- Receptors, Immunologic/metabolism
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/virology
- Th1 Cells/immunology
- Th1 Cells/metabolism
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Affiliation(s)
- Anna Estrada Brull
- Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; (A.E.B.); (F.R.); (F.R.K.); (S.L.-L.)
| | - Felix Rost
- Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; (A.E.B.); (F.R.); (F.R.K.); (S.L.-L.)
| | - Josua Oderbolz
- ETH Zurich, Institute of Microbiology, 8093 Zurich, Switzerland; (J.O.); (A.O.)
| | - Florian R. Kirchner
- Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; (A.E.B.); (F.R.); (F.R.K.); (S.L.-L.)
- Section of Immunology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland
| | - Salomé Leibundgut-Landmann
- Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; (A.E.B.); (F.R.); (F.R.K.); (S.L.-L.)
- Section of Immunology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland
| | - Annette Oxenius
- ETH Zurich, Institute of Microbiology, 8093 Zurich, Switzerland; (J.O.); (A.O.)
| | - Nicole Joller
- Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland; (A.E.B.); (F.R.); (F.R.K.); (S.L.-L.)
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8
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Tang R, Lei Z, Wang X, Qi Q, He J, Liu D, Wang X, Chen X, Zhu J, Li Y, Zhou S, Su C. Hepatitis B envelope antigen increases Tregs by converting CD4+CD25 - T cells into CD4 +CD25 +Foxp3 + Tregs. Exp Ther Med 2020; 20:3679-3686. [PMID: 32855720 PMCID: PMC7444405 DOI: 10.3892/etm.2020.9107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 07/01/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) can establish a lifelong chronic infection in humans, leading to liver cirrhosis, liver failure and hepatocellular carcinoma. Patients with chronic hepatitis B (CHB) exhibit a weak virus-specific immune response. Regulatory T cells (Tregs) play a key role in regulating the immune response in patients with CHB. Patients with hepatitis B envelope antigen (HBeAg)-positive CHB harbored a higher percentage of Tregs in their peripheral blood than those with HBeAg-negative CHB. However, whether and how HBeAg manipulates the host immune system to increase the population of Tregs remains to be elucidated. The present manuscript describes a preliminary immunological study of HBeAg in a mouse model. Multiple potential CD4+ T cell epitopes in HBeAg were identified using Immune Epitope Database consensus binding prediction. It was demonstrated that HBeAg treatment increased the numbers of Tregs in mouse spleens in vitro and in vivo. Furthermore, it was indicated that the HBeAg-mediated increase in Tregs occurred through the conversion of CD4+CD25- T cells into CD4+CD25+Foxp3+ Tregs. Additionally, in vitro study illustrated that HBeAg stimulated murine spleen cells to produce increased transforming growth factor-β, which is required to enable HBeAg to convert T cells into Tregs. The results of the present study may provide further evidence of the effect of HBeAg on Tregs and aid in the development of novel HBeAg-based immunotherapy for CHB.
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Affiliation(s)
- Rui Tang
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Zhigang Lei
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Xinpeng Wang
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Qianqian Qi
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Jingjing He
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Dan Liu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Xiaoxian Wang
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Xiaojun Chen
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Jifeng Zhu
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Yalin Li
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Sha Zhou
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Chuan Su
- State Key Laboratory of Reproductive Medicine, Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
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Dong Y, Li X, Yu Y, Lv F, Chen Y. JAK/STAT signaling is involved in IL-35-induced inhibition of hepatitis B virus antigen-specific cytotoxic T cell exhaustion in chronic hepatitis B. Life Sci 2020; 252:117663. [PMID: 32302624 DOI: 10.1016/j.lfs.2020.117663] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 03/23/2020] [Accepted: 04/09/2020] [Indexed: 12/19/2022]
Abstract
AIMS Interleukin-35 (IL-35) is a new member of the interleukin-12 family and is composed of the P35 and EB virus-inducible gene 3 subunits. The aims of this study were to examine the roles of IL-35 in the exhaustion of HBV-specific CTLs, as little as known on the subject. MAIN METHODS The relative levels of serum HBV markers were detected using automated biochemical techniques. The HBV DNA copies were measured by RT-qPCR. The expression of inhibitory receptors and the cell cytokines on the surface of CTLs were determined by flow cytometry. The pSTAT1-pSTAT4 protein levels expression was determined by flow cytometry, confocal microscopy and Western blot. KEY FINDINGS Our results showed that IL-35 can activate the Janus kinase 1 (JAK1)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription 1 (STAT1)/STAT4 pathway in CTLs in vitro. Interferon-γ and tumor necrosis alpha-α expression increased in CTLs in the presence of a JAK/STAT-pathway blocker. In addition, we evaluated the expression of the exhaustion-associated molecules programmed death-1, cytotoxic T lymphocyte-associated protein-4, and lymphocyte activation gene-3 in CTLs after adding the JAK-STAT inhibitor The results showed that the expression of exhaustion-associated molecules on the CTL surface decreased after blocking the JAK-STAT pathway. IL-35 inhibited the function of HBV-specific CTLs through the JAK1/TYK2/STAT1/STAT4 pathway, and the function of CTLs was recovered after blocking the JAK/STAT pathway. SIGNIFICANCE These data provide a new experimental basis for immunotherapy for chronic hepatitis B.
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Affiliation(s)
- Yuejiao Dong
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Laboratory Medicine, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China.
| | - Xuefen Li
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Laboratory Medicine, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
| | - Yanying Yu
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Laboratory Medicine, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
| | - Feifei Lv
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Laboratory Medicine, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China
| | - Yu Chen
- Department of Laboratory Medicine, Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Laboratory Medicine, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, China.
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10
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Liang X, Liu P, He Z, Chen X, Xiao X. The effect of maternal use of telbivudine on neonatal CD4 +CD25 + regulatory T cells for the prevention of mother-to-child transmission of hepatitis B virus. Clin Res Hepatol Gastroenterol 2020; 44:195-203. [PMID: 31257091 DOI: 10.1016/j.clinre.2019.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 05/24/2019] [Accepted: 06/07/2019] [Indexed: 02/04/2023]
Abstract
Antiviral treatment could block mother-to-child transmission (MTCT) of hepatitis B virus (HBV) effectively. We examined whether maternal use of telbivudine (LdT) could decrease the proportion of CD4+CD25+ regulatory T cells and explored the immunological mechanism. A total of 89 pregnant women with HBsAg positive were enrolled, where 30 pregnant women with HBeAg negative (viral load<106 IU/ml) and the other 59 pregnant women with HBeAg positive (viral load≥106 IU/ml) were followed in the study. The women with high viral load were divided to the LdT-treated group where they were prescribed with 600mg LdT daily (29 cases) during the third trimester of pregnancy or to the non-treated group (30 cases) on a voluntary basis. Samples of neonates were taken for analyzing CD4+CD25+ Tregs with flow cytometric techniques. A more significant decrease in the proportion of CD4+CD25+Tregs in neonatal peripheral blood had been observed with maternal use of telbivudine (2.8%±1.1%) than those without any treatment (7.0%±1.6%, P< 0.01). None of the infants in the LdT-treated group were HBsAg positive at 7 months of age. In addition, neonates whose mothers received telbivudine had a significant improvement in cellular immune function, as indicated by the proportion of CD8+ T cells. For HBV carriers with high viral load, maternal use of LdT may be useful in regulating neonatal immune function involved in mother-to-child transmission of hepatitis B virus.
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Affiliation(s)
- Xinyuan Liang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510630, China
| | - Peiyan Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510630, China
| | - Zonglin He
- International school, Jinan University, Guangzhou 510630, China
| | - Xin Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510630, China
| | - Xiaomin Xiao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510630, China.
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Lim CJ, Lee YH, Pan L, Lai L, Chua C, Wasser M, Lim TKH, Yeong J, Toh HC, Lee SY, Chan CY, Goh BK, Chung A, Heikenwälder M, Ng IO, Chow P, Albani S, Chew V. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut 2019; 68:916-927. [PMID: 29970455 DOI: 10.1136/gutjnl-2018-316510] [Citation(s) in RCA: 237] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics. METHODS We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays. RESULTS In-depth interrogation of the immune landscapes showed that regulatory T cells (TREG) and CD8+ resident memory T cells (TRM) were enriched in HBV-related HCC, whereas Tim-3+CD8+ T cells and CD244+ natural killer cells were enriched in non-viral-related HCC. NGS of isolated TREG and TRM from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. TREG and TRM from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1+ TREG could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that TREG and TRM contributed to overall patient survival: TREG were associated with a poor prognosis and TRM were associated with a good prognosis in HCC. CONCLUSION We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics.
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Affiliation(s)
- Chun Jye Lim
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Yun Hua Lee
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Lu Pan
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Liyun Lai
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Camillus Chua
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Martin Wasser
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Tony Kiat Hon Lim
- Department of Pathology, Singapore General Hospital, Singapore, Singapore.,Duke-NUS Medical School, Singapore, Singapore
| | - Joe Yeong
- Department of Pathology, Singapore General Hospital, Singapore, Singapore.,Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Han Chong Toh
- Duke-NUS Medical School, Singapore, Singapore.,National Cancer Centre, Singapore, Singapore
| | - Ser Yee Lee
- Duke-NUS Medical School, Singapore, Singapore.,National Cancer Centre, Singapore, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Chung Yip Chan
- Duke-NUS Medical School, Singapore, Singapore.,National Cancer Centre, Singapore, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Brian Kp Goh
- Duke-NUS Medical School, Singapore, Singapore.,National Cancer Centre, Singapore, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Alexander Chung
- Duke-NUS Medical School, Singapore, Singapore.,National Cancer Centre, Singapore, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Irene Ol Ng
- Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Pierce Chow
- Duke-NUS Medical School, Singapore, Singapore.,National Cancer Centre, Singapore, Singapore.,Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Salvatore Albani
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
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12
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Zheng J, Ou Z, Xu Y, Xia Z, Lin X, Jin S, Liu Y, Wu J. Hepatitis B virus-specific effector CD8 + T cells are an important determinant of disease prognosis: A meta-analysis. Vaccine 2019; 37:2439-2446. [PMID: 30935741 DOI: 10.1016/j.vaccine.2019.03.058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 03/22/2019] [Accepted: 03/25/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV)-specific effector CD8+ T cells are critical for viral clearance. To determine the effects of HBV-specific effector CD8+ T cells on HBV infection, we performed a meta-analysis of the available literature. METHODS Electronic database searches identified appropriately designed studies that detected specific CD8+ T cells in HBV-infected patients. Our main endpoints were the course of infection, seroconversion of HBV "e" antigen (HBeAg), the level of HBVDNA, and alanine aminotransferase (ALT) activity. We used a fixed/random model for analysis, according to the results of a heterogeneity test (P value of Q-squared, I2). RESULTS Our searches found five eligible articles. Pooled estimation of the reported results showed that levels of specific CD8+ T cells were significantly higher in patients with acute hepatitis B than in patients with chronic hepatitis B (odds ratio [OR] = 76.30, 95% confidence interval [CI]: 15.37-378.70). With respect to chronic hepatitis B, patients with <107 copies/ml HBVDNA had higher levels of specific CD8+ T cells relative to patients with >107 copies/ml HBVDNA, but the difference had no statistics significance (OR: 3.89, 95% CI: 0.71-21.33). Patients with negative HBeAg or positive anti-HBeAg antibody (anti-HBe) results had significantly higher levels of specific CD8+ T cells versus patients with positive HBeAg results (OR: 5.82, 95% CI: 1.41-24.13). There were no significant associations between the levels of specific CD8+ T cells and serum ALT activity (OR = 0.86, 95% CI: 0.01-74.15). CONCLUSION HBV-specific effector CD8+ T cells influence the disease activity in HBV-infected patients in various ways and determine prognosis by eliminating the virus. Therefore, efforts of studying HBV-specific effector CD8+ T cells focused vaccine are potentially needed.
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Affiliation(s)
- Juzeng Zheng
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Zhanfan Ou
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yilun Xu
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Ziqiang Xia
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Xianfan Lin
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Sisi Jin
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Yang Liu
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Jinming Wu
- Department of Gastroenterology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China.
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13
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Hayashi M, Abe K, Fujita M, Okai K, Takahashi A, Ohira H. Hepatitis B Virus Reactivation in a Patient with Nonalcoholic Steatohepatitis 41 Months after Rituximab-containing Chemotherapy. Intern Med 2019; 58:375-380. [PMID: 30210131 PMCID: PMC6395117 DOI: 10.2169/internalmedicine.1587-18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Hepatitis B virus (HBV) reactivation occasionally occurs long after immunosuppressive therapy. The characteristics of late HBV reactivation remain unclear. We herein present a case of HBV reactivation in a patient with nonalcoholic steatohepatitis (NASH) more than 3 years after rituximab-containing chemotherapy for diffuse large B-cell lymphoma. Increased transaminase levels, which were induced by NASH, were observed after chemotherapy and were alleviated with statin treatment. HBV reactivation was identified incidentally. The patient developed hepatitis that improved with entecavir therapy. Our case might indicate that the presence of NASH is associated with HBV reactivation long after treatment and that statins, as immune-modulatory agents, affect HBV reactivation.
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Affiliation(s)
- Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Ken Okai
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Japan
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14
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Immunomodulatory Effects of Combination Therapy with Bushen Formula plus Entecavir for Chronic Hepatitis B Patients. J Immunol Res 2019; 2019:8983903. [PMID: 30766891 PMCID: PMC6350602 DOI: 10.1155/2019/8983903] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/03/2018] [Indexed: 02/07/2023] Open
Abstract
Aim To compare the clinical efficacy of the combination therapy with Bushen formula (BSF) plus entecavir (ETV) in naïve chronic hepatitis B (CHB) patients and that in CHB patients with partial virological response to ETV and explore the relevant immunoregulatory mechanism. Materials and Methods Two hundred and twenty CHB patients were enrolled in the historical prospective cohort study. Patients were categorized into a treatment group (T-Group: combination therapy with BSF plus ETV) and a control group (C-Group: ETV). Patients in T-Group and C-Group were grouped into T1/C1 (treatment-naïve patients) and T2/C2 (patients with partial virological response to ETV). Biochemical assessment, viral load quantitation, and HBV markers were tested. Chinese medicine symptom complex score was evaluated and recorded as well. In addition, peripheral blood mononuclear cells were separated from blood samples in 56 patients and 11 healthy donors. The frequencies of Th1, Treg, and dendritic cells (DCs) and expression levels of PD-1/PD-L1 were examined by flow cytometry. Results In treatment-naïve CHB patients, complete viral suppression rates in HBeAg(−) patients were higher than those in HBeAg(+) patients in both T and C groups. In patients with partial virological response to ETV, the rate of HBsAg decline ≥ 20% in HBeAg(+) patients of T2-Group was higher than that in HBeAg(+) patients of C2-Group. A significant reduction of Chinese medicine symptom complex score was only observed in T-Group. The study of mechanism showed that, compared with healthy controls, Th1 and DC frequencies were decreased in all CHB patients, while Treg frequency was increased only in treatment-naïve patients. In addition, compared with healthy controls, PD-1 expression levels on Th1 and Treg were increased in all patients and PD-L1 expression levels on DCs were increased only in treatment-naïve patients. In treatment-naïve patients, the combination therapy with BSF plus ETV increased Th1 and DC frequencies and decreased Treg frequency, which was correlated with HBsAg decline. In addition, in patients with partial virological response to ETV, the combination therapy downregulated PD-L1 levels on DCs and the frequency of Treg, which was related with HBsAg decline. Conclusions In patients with partial virological response to ETV, HBeAg(+) patients tend to achieve ideal effects after the combination therapy with BSF plus ETV, which may correlate with the decrease of Treg frequency and the downregulation of PD-L1 levels on DCs.
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15
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Yeo SJ, Lee HS, Jang BI, Kim ES, Jeon SW, Kim SK, Kim KO, Lee YJ, Lee HJ, Park KS, Jung YJ, Kim EY, Yang CH. Nonimmunity against hepatitis B virus infection in patients newly diagnosed with inflammatory bowel disease. Intest Res 2018; 16:400-408. [PMID: 30090039 PMCID: PMC6077318 DOI: 10.5217/ir.2018.16.3.400] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/15/2018] [Accepted: 01/16/2018] [Indexed: 12/16/2022] Open
Abstract
Background/Aims This study aimed to elucidate the prevalence of hepatitis B virus (HBV) serologic markers in Korean patients newly diagnosed with, but not yet treated for inflammatory bowel disease (IBD). Methods We prospectively enrolled 210 patients newly diagnosed with IBD (109 with ulcerative colitis and 101 with Crohn's disease). Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were measured and compared with those of 1,100 sex- and age-matched controls. Results The prevalence of chronic HBV infection (positive HBsAg, positive anti-HBc, and negative anti-HBs results) and past infection (negative HBsAg, positive anti-HBc, and positive or negative anti-HBs results) were not significantly different between the patients and controls (chronic HBV infection: IBD, 3.8% vs. control, 4.9%, P=0.596; past infection: IBD, 26.2% vs. control, 28.8%, P=0.625). The patients with IBD aged <20 years were at a higher susceptibility risk (nonimmune) for HBV infection than the controls (IBD, 41.5% vs. control, 22.4%; P=0.018). In the multivariate analysis, an age of <20 years (P=0.024) and symptom duration of ≥12 months before diagnosis (P=0.027) were identified as independent risk factors for nonimmunity against HBV infection. Conclusions The patients newly diagnosed with IBD were susceptible to HBV infection. The frequency of nonimmunity was high, especially in the patients aged <20 years and those with a longer duration of symptoms before diagnosis. Therefore, it is necessary to screen for HBV serologic markers and generate a detailed vaccination plan for patients newly diagnosed with IBD.
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Affiliation(s)
- Seong Jae Yeo
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Seong Woo Jeon
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sung Kook Kim
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Yoo Jin Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Hyun Jik Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Kyung Sik Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Yun Jin Jung
- Department of Internal Medicine, Daegu Fatima Hospital, Daegu, Korea
| | - Eun Young Kim
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea
| | - Chang Heon Yang
- Department of Internal Medicine, Dongguk University School of Medicine, Gyeongju, Korea
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16
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Xia Y, Jin X, Yu X, Li X, Du B, Liu Z, Shi Y, Li N, Zhang S. Expression profiles of transcription factors for special CD4+ T-cell subsets in peripheral blood mononuclear cells from patients with hepatitis B virus infection. Medicine (Baltimore) 2018; 97:e11438. [PMID: 30045265 PMCID: PMC6078757 DOI: 10.1097/md.0000000000011438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
This study is to characterize the transcription factor expression profiles for the peripheral CD4 T-cell subsets, and analyze its associations with the clinical measures of the hepatitis B virus (HBV) infection.Totally 275 subjects were included. The expression levels of transcription factors (T-bet, GATA-3, Foxp3, RORγt, and Bcl-6) in the peripheral blood mononuclear cells (PBMCs) were determined by the real-time fluorimetry quantitative PCR (FQ-PCR).Lowest expression levels of all these transcription factors were observed for the HBsAb(-) group, which were higher in the HBsAb(+) and RHB groups. The T-bet/GATA-3 ratios in the CHB and RHB groups were significantly lower than the HBsAb(-) group, whereas the RORγt/Foxp3 ratios in the AHB and RHB groups were significantly higher than the CHB and HBsAb(+) groups. Furthermore, the RORγt mRNA expression levels were significantly different among groups with different disease severities or with different alanine aminotransferase (ALT) levels. The asymptomatic carrier (AsC) group and the group with ALT ≤ 40 had the highest express level. The mRNA expression levels of T-bet, GATA-3, Foxp3, and RORγt varied along with the aspartate aminotransferase (AST) levels, with AST ≤ 40 having the highest expression levels. In addition, significant differences were observed in the transcription factor expression levels between the group with the serum HBV DNA load of (1.000-9.999) × 10 copies/mL and other groups.Expression profile of critical transcription factors for peripheral CD4 T-cell subsets may indicate clinical outcomes of HBV infection.
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Affiliation(s)
- Yan Xia
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Xi Jin
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Xueyuan Yu
- Clinical Laboratory, the Affiliated Nanjing Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu
| | - Xingku Li
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Bo Du
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Zhen Liu
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Yuguang Shi
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
| | - Na Li
- Clinical Laboratory, Suihua First Hospital, Suihua, Heilongjiang, China
| | - Shuyun Zhang
- Scientific Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
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17
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Li MH, Zhang D, Zhang L, Qu XJ, Lu Y, Shen G, Wu SL, Chang M, Liu RY, Hu LP, Hao HX, Hua WH, Song SJ, Wan G, Liu SA, Xie Y. Ratios of T-helper 2 Cells to T-helper 1 Cells and Cytokine Levels in Patients with Hepatitis B. Chin Med J (Engl) 2018; 130:1810-1815. [PMID: 28748854 PMCID: PMC5547833 DOI: 10.4103/0366-6999.211541] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hepatitis B is an immune response-mediated disease. The aim of this study was to explore the differences of ratios of T-helper (Th) 2 cells to Th1 cells and cytokine levels in acute hepatitis B (AHB) patients and chronic hepatitis B virus (HBV)-infected patients in immune-tolerance and immune-active phases. METHODS Thirty chronic HBV-infected patients in the immune-tolerant phase (IT group) and 50 chronic hepatitis B patients in the immune-active (clearance) phase (IC group), 32 AHB patients (AHB group), and 13 healthy individuals (HI group) were enrolled in the study. Th cell proportions in peripheral blood, cytokine levels in plasma, and serum levels of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen were detected. RESULTS The Th1 cell percentage and Th2/Th1 ratio in the HBV infection group (including IT, IC, and AHB groups) were significantly different from those in HI group (24.10% ± 8.66% and 1.72 ± 0.61 vs. 15.16% ± 4.34% and 2.40 ± 0.74, respectively; all P < 0.001). However, there were no differences in the Th1 cell percentages and Th2/Th1 ratios among the IT, IC, and AHB groups. In HBV infection group, the median levels of Flt3 ligand (Flt3L), interferon (IFN)-γ, and interleukin (IL)-17A were significantly lower than those in HI group (29.26 pg/ml, 33.72 pg/ml, and 12.27 pg/ml vs. 108.54 pg/ml, 66.48 pg/ml, and 35.96 pg/ml, respectively; all P < 0.05). IFN-α2, IL-10, and transforming growth factor (TGF)-β2 median levels in hepatitis group (including patients in AHB and IC groups) were significantly higher than those in IT group (40.14 pg/ml, 13.58 pg/ml, and 557.41 pg/ml vs. 16.74 pg/ml, 6.80 pg/ml, and 419.01 pg/ml, respectively; all P < 0.05), while patients in hepatitis group had significant lower Flt3L level than IT patients (30.77 vs. 59.96 pg/ml, P = 0.021). Compared with IC group, patients in AHB group had significant higher median levels of IL-10, TGF-β1, and TGF-β2 (22.77 pg/ml, 10,447.00 pg/ml, and 782.28 pg/ml vs. 8.66 pg/ml, 3755.50 pg/ml, and 482.87 pg/ml, respectively; all P < 0.05). CONCLUSIONS Compared with chronic HBV-infected patients in immune-tolerance phase, chronic HBV-infected patients in immune-active phase and AHB patients had similar Th2/Th1 ratios, significantly higher levels of IFN-α2, IL-10, and TGF-β. AHB patients had significantly higher IL-10 and TGF-β levels than chronic HBV-infected patients in immune-active phase.
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Affiliation(s)
- Ming-Hui Li
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Dan Zhang
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Lu Zhang
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xiao-Jing Qu
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yao Lu
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ge Shen
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shu-Ling Wu
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Min Chang
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Ru-Yu Liu
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Lei-Ping Hu
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Hong-Xiao Hao
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wen-Hao Hua
- Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shu-Jing Song
- Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Gang Wan
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Shun-Ai Liu
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Yao Xie
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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18
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Memory Regulatory T cells Increase Only In Inflammatory Phase of Chronic Hepatitis B Infection and Related to Galectin-9/Tim-3 interaction. Sci Rep 2017; 7:15280. [PMID: 29127350 PMCID: PMC5681652 DOI: 10.1038/s41598-017-15527-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 10/30/2017] [Indexed: 12/29/2022] Open
Abstract
CD4+Foxp3+ regulatory T cells (Tregs) are the main immune suppressors with subpopulation of inflamed-tissue related memory Tregs (mTregs) and non-related resting Treg (rTregs). Previously, Treg was proposed to be the cause of chronicity of hepatitis B virus (HBV) infection but with controversies. We then investigated the role of mTregs in distinct immune phases of chronic HBV infection, especially the non-inflammatory versus inflammatory phases. It was found mTregs but not rTregs increased only in the inflammatory phase and correlated with serum alanine aminotransferase (ALT) level. These mTregs accumulated in the inflamed liver, expressed significantly higher Tim-3, CCR4, CCR5 and fewer CCR7, and possessed potent suppressive function. These mTregs mainly originated from natural Tregs because of high Helios expression. Hierarchical clustering analysis showed higher frequency of mTreg was concordant with higher serum ALT and galectin-9 levels. Furthermore, galectin-9 could expand mTregs through galectin-9/Tim-3 interaction. In conclusion, increased mTregs are found only in inflammatory phase of chronic HBV infection. Galectin-9, associated with liver inflammation, contributes to the expansion of mTregs through galectin-9/Tim-3 interaction. Therefore, this expansion of mTregs only reflects as an immune regulatory mechanism to limit the on-going liver damages rather than the cause of chronicity of HBV infection.
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de Wolf ACMT, van Aalst S, Ludwig IS, Bodinham CL, Lewis DJ, van der Zee R, van Eden W, Broere F. Regulatory T cell frequencies and phenotypes following anti-viral vaccination. PLoS One 2017; 12:e0179942. [PMID: 28658271 PMCID: PMC5489208 DOI: 10.1371/journal.pone.0179942] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 05/31/2017] [Indexed: 12/27/2022] Open
Abstract
Regulatory T cells (Treg) function in the prevention of excessive inflammation and maintenance of immunological homeostasis. However, these cells may also interfere with resolution of infections or with immune reactions following vaccination. Effects of Treg on vaccine responses are nowadays investigated, but the impact of vaccination on Treg homeostasis is still largely unknown. This may be a relevant safety aspect, since loss of tolerance through reduced Treg may trigger autoimmunity. In exploratory clinical trials, healthy adults were vaccinated with an influenza subunit vaccine plus or minus the adjuvant MF59®, an adjuvanted hepatitis B subunit vaccine or a live attenuated yellow fever vaccine. Frequencies and phenotypes of resting (rTreg) and activated (aTreg) subpopulations of circulating CD4+ Treg were determined and compared to placebo immunization. Vaccination with influenza vaccines did not result in significant changes in Treg frequencies and phenotypes. Vaccination with the hepatitis B vaccine led to slightly increased frequencies of both rTreg and aTreg subpopulations and a decrease in expression of functionality marker CD39 on aTreg. The live attenuated vaccine resulted in a decrease in rTreg frequency, and an increase in expression of activation marker CD25 on both subpopulations, possibly indicating a conversion from resting to migratory aTreg due to vaccine virus replication. To study the more local effects of vaccination on Treg in lymphoid organs, we immunized mice and analyzed the CD4+ Treg frequency and phenotype in draining lymph nodes and spleen. Vaccination resulted in a transient local decrease in Treg frequency in lymph nodes, followed by a systemic Treg increase in the spleen. Taken together, we showed that vaccination with vaccines with an already established safe profile have only minimal impact on frequencies and characteristics of Treg over time. These findings may serve as a bench-mark of inter-individual variation of Treg frequencies and phenotypes following vaccination.
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Affiliation(s)
- A. Charlotte M. T. de Wolf
- Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands
| | - Susan van Aalst
- Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands
| | - Irene S. Ludwig
- Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands
| | - Caroline L. Bodinham
- Surrey Clinical Research Centre, University of Surrey, Guildford, United Kingdom
| | - David J. Lewis
- Surrey Clinical Research Centre, University of Surrey, Guildford, United Kingdom
| | - Ruurd van der Zee
- Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands
| | - Willem van Eden
- Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands
| | - Femke Broere
- Division of Immunology, Department of Infectious Diseases & Immunology, Utrecht University, Utrecht, The Netherlands
- * E-mail:
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Lobaina Y, Michel ML. Chronic hepatitis B: Immunological profile and current therapeutic vaccines in clinical trials. Vaccine 2017; 35:2308-2314. [PMID: 28351734 DOI: 10.1016/j.vaccine.2017.03.049] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Revised: 02/07/2017] [Accepted: 03/14/2017] [Indexed: 12/17/2022]
Abstract
More than 250million people worldwide are chronically infected with hepatitis B virus (CHB), and over half a million die each year due to CHB-associated liver complications such as cirrhosis and hepatocellular carcinoma. The translation of immunological knowledge about CHB into therapeutic strategies aiming to a sustainable hepatitis B virus (HBV) clearance has been challenging. In recent years, however, the understanding on the immune effectors required to overcome chronicity has notably increased thanks to preclinical and clinical research. Therapeutic vaccination may prove to be useful for treating CHB patients when coupled with current antiviral agents and other immunomodulatory strategies. This review summarizes current data and future perspectives on therapeutic vaccination. Other treatment alternatives that could be combined with vaccines for a complete cure from hepatitis B virus infection are also discussed.
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Affiliation(s)
- Yadira Lobaina
- Vaccine Department, Center for Genetic Engineering and Biotechnology, Havana, Cuba.
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Li Z, Li N, Li F, Zhou Z, Sang J, Chen Y, Han Q, Lv Y, Liu Z. Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma. Medicine (Baltimore) 2016; 95:e5749. [PMID: 28033288 PMCID: PMC5207584 DOI: 10.1097/md.0000000000005749] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.
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Affiliation(s)
- Zhu Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Fang Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Zhihua Zhou
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Jiao Sang
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Yanping Chen
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
- Department of Infectious Diseases, Yanan University Affiliated Hospital, Yanan
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University
- Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’ an, Shaanxi, China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
- Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’ an, Shaanxi, China
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Regulatory T-cells promote hepatitis B virus infection and hepatocellular carcinoma progression. Chronic Dis Transl Med 2016; 2:67-80. [PMID: 29063027 PMCID: PMC5643754 DOI: 10.1016/j.cdtm.2016.09.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Indexed: 02/08/2023] Open
Abstract
Regulatory T-cells (Tregs), known for their immune suppressive function, have been reported in higher numbers, with activated phenotypes and greater potency, in hepatitis B virus (HBV)-related liver diseases than in normal conditions. The numbers, phenotypes, and function of intrahepatic and/or tumor-infiltrating Tregs in HBV-related liver diseases also differ from those of Tregs in the peripheral blood. By inhibiting the function of effector T-cells (Teffs), Tregs play a substantial role in the formation and maintenance of the liver's suppressive microenvironment, which might account for the progression of HBV-related hepatitis and hepatocellular carcinoma (HCC). In acute hepatitis B virus infection, Tregs can safeguard the liver from damage at the cost of prolonged antiviral processes, which results in chronic HBV infection in the liver. Furthermore, Tregs play a role in the development of cirrhosis, the transformation of cirrhosis to HCC, and the progression and metastasis of HCC. Higher levels of Tregs in the peripheral blood and/or tumor sites signify a poorer prognosis in HBV-related liver conditions, and observational data from mouse models and human patients support the theory that depleting Tregs may be therapeutic in HBV-related liver diseases by inducing antiviral and antitumor immunity.
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Abstract
Hepatitis B virus (HBV) infection is a worldwide health problem, with approximately one third of populations have been infected, among which 3-5% of adults and more than 90% of children developed to chronic HBV infection. Host immune factors play essential roles in the outcome of HBV infection. Thus, ineffective immune response against HBV may result in persistent virus replications and liver necroinflammations, then lead to chronic HBV infection, liver cirrhosis, and even hepatocellular carcinoma. Cytokine balance was shown to be an important immune characteristic in the development and progression of hepatitis B, as well as in an effective antiviral immunity. Large numbers of cytokines are not only involved in the initiation and regulation of immune responses but also contributing directly or indirectly to the inhibition of virus replication. Besides, cytokines initiate downstream signaling pathway activities by binding to specific receptors expressed on the target cells and play important roles in the responses against viral infections and, therefore, might affect susceptibility to HBV and/or the natural course of the infection. Since cytokines are the primary causes of inflammation and mediates liver injury after HBV infection, we have discussed recent advances on the roles of various cytokines [including T helper type 1 cells (Th1), Th2, Th17, regulatory T cells (Treg)-related cytokines] in different phases of HBV infection and cytokine-related mechanisms for impaired viral control and liver damage during HBV infection. We then focus on experimental therapeutic applications of cytokines to gain a better understanding of this newly emerging aspect of disease pathogenesis.
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Wang H, Wu B, Li L, Hu L, Lin J, Jiang C, Cai G, Shen Q. Hepatic expansion of virus-specific CD8 +BTLA + T cells with regulatory properties in chronic hepatitis B virus infection. Cell Immunol 2016; 311:36-45. [PMID: 27743606 DOI: 10.1016/j.cellimm.2016.10.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 10/03/2016] [Accepted: 10/06/2016] [Indexed: 01/06/2023]
Abstract
Similar to programmed death-1 (PD-1), B and T lymphocyte attenuator (BTLA) is a co-inhibitory molecule of the CD28 family. PD-1 is involved in T cell exhaustion during chronic viral infection. However, the role of BTLA in virus-specific T cells is poorly defined. Here we investigated the expression and function of BTLA in T cells from patients with chronic hepatitis B virus (HBV) infection. The phenotype of peripheral and intrahepatic HBV-specific T cells from 43 patients with chronic HBV infection was assessed by flow cytometry. Functional evaluation was analyzed by T cell expansion and cytokine secretion after different treatments. In chronic HBV patients, a subset of inefficient interferon-γ producing antigen-specific CD8+ T cells recruited to the liver expressed high BTLA levels. The BTLA+ HBV-specific CD8+ T cell suppressive function was antigen-specific, at least in the induction phase, because they were only activated by a pool of HBV peptides but not with a pool of unrelated peptides. Suppression of T cell responses was restored by a BTLA signaling blockade and neutralizing IL-10, indicating that BTLA signaling-mediated IL-10 secretion plays a key role in suppression. This study provides important evidence that there is a subset of liver infiltrated virus-specific CD8+BTLA+ regulatory T cells in patients with chronic HBV infection. This subset of cells plays a pivotal role in controlling hepatic effector CD8+ T cell responses through BTLA signaling mediated regulatory factor IL-10 production.
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Affiliation(s)
- Huaizhou Wang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China; Department of Experimental Diagnosis, Changhai Hospital, The Second Military Medical University, Shanghai, PR China
| | - Beiying Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China
| | - Lei Li
- Department of Clinical Pathology, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China
| | - Liang Hu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China
| | - Jiafei Lin
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China
| | - Cen Jiang
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China
| | - Gang Cai
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, PR China.
| | - Qian Shen
- Department of Experimental Diagnosis, Changhai Hospital, The Second Military Medical University, Shanghai, PR China
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Tavakolpour S, Alavian SM, Sali S. Manipulation of Regulatory Cells' Responses to Treatments for Chronic Hepatitis B Virus Infection. HEPATITIS MONTHLY 2016; 16:e37927. [PMID: 27630728 PMCID: PMC5010887 DOI: 10.5812/hepatmon.37927] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 04/14/2016] [Accepted: 04/20/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Identification of effective treatments in hepatitis B virus (HBV) infection remains a controversial topic. Although the currently approved drugs for HBV control the disease's progression and also limit associated outcomes, these drugs may not fully eradicate HBV infection. In addition to better managing patients with chronic hepatitis B (CHB) infection, the induction of seroclearance by these drugs has been a commonly discussed topic in recent years. OBJECTIVES In this study, we focused on treating CHB infection via the manipulation of T cells' responses to identify possible approaches to cure CHB. MATERIALS AND METHODS All studies relevant to the role of cellular and humoral responses in HBV infection (especially regulatory cells) were investigated via a systematic search of different databases, including PubMed, Scopus, and Google Scholar. Considering extracted data and also our unpublished data regarding the association between regulatory cytokines and CHB, we introduced a novel approach for the induction of seroclearance. RESULTS Considering the increased levels of regulatory cytokines and also regulatory T cells (Tregs) during CHB, it seems that these cells are deeply involved in CHB infection. The inhibition of regulatory T cells may reverse the dysfunction of effector T cells in patients with CHB infection. In order to inhibit Tregs' responses, different types of approaches could be employed to restore the impaired function of effector T cells. The blockade of IL-10, IL-35, CTLA-4, PD-1, and TIM-3 were discussed throughout this study. Regardless of the efficacy of these methods, CHB patients may experience serious liver injuries due to the cytotoxic action of CD8+ T cells. Antiviral therapy and a decrease in HBV DNA to undetectable levels could also significantly reduce the risk of the hepatitis B flare. CONCLUSIONS The inhibition of Tregs is a novel therapeutic approach to cure chronically HBV infected patients. However, further studies are needed to investigate the safety and efficacy of this approach.
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Affiliation(s)
- Soheil Tavakolpour
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqyiatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqyiatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Seyed Moayed Alavian, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Baqyiatallah University of Medical Sciences, Tehran, IR Iran. Tel/Fax: +98-2181264070, E-mail:
| | - Shahnaz Sali
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
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Dai K, Huang L, Sun X, Yang L, Gong Z. Hepatic CD206-positive macrophages express amphiregulin to promote the immunosuppressive activity of regulatory T cells in HBV infection. J Leukoc Biol 2015. [PMID: 26216935 DOI: 10.1189/jlb.4a0415-152r] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Hepatitis B virus is a major cause of chronic liver inflammation worldwide. Innate and adaptive immune responses work together to restrain or eliminate hepatitis B virus in the liver. Compromised or failed adaptive immune response results in persistent virus replication and spread. How to promote antiviral immunity is a research focus for hepatitis B virus prevention and therapy. In this study, we investigated the role of macrophages in the regulation of antiviral immunity. We found that F4/80(+)CD206(+)CD80(lo/+) macrophages were a particular hepatic macrophage subset that expressed amphiregulin in our mouse hepatitis B virus infection model. CD206(+) macrophage-derived amphiregulin promoted the immunosuppressive activity of intrahepatic regulatory T cells, demonstrated by higher expression of CTLA-4, ICOS, and CD39, as well as stronger inhibition of antiviral function of CD8(+) T cells. Amphiregulin-neutralizing antibody diminished the effect of CD206(+) macrophages on regulatory T cells. In addition, we found that CD206(+) macrophage-derived amphiregulin activated mammalian target of rapamycin signaling in regulatory T cells, and this mammalian target of rapamycin activation was essential for promotion of regulatory T cell activity by CD206(+) macrophages. Adoptive transfer of CD206(+) macrophages into hepatitis B virus-infected mice increased cytoplasmic hepatitis B virus DNA in hepatocytes and also increased serum hepatitis B surface antigen. The antiviral activity of CD8(+) T cells was decreased after macrophage transfer. Therefore, our research indicated that amphiregulin produced by CD206(+) macrophages plays an important role in modulating regulatory T cell function and subsequently restrains the antiviral activity of CD8(+) T cells. Our study offers new insights into the immunomodulation in hepatitis B virus infection.
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Affiliation(s)
- Kai Dai
- *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China
| | - Ling Huang
- *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China
| | - Xiaomei Sun
- *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China
| | - Lihua Yang
- *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China
| | - Zuojiong Gong
- *Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China; and Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China
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27
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Mathew RO, Mason DL, Song R, Tryniszewski T, Kennedy JS. Role of T-regulatory cells in the response to hepatitis B vaccine in hemodialysis patients. Hemodial Int 2015; 20:242-52. [PMID: 26104830 DOI: 10.1111/hdi.12326] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Human disease elicits a complex array of biological processes that results in long-term protective immunological memory to infectious agents. Chronic kidney disease is known to impair induction of sustained immunological memory to hepatitis B vaccine (HBVax) antigens. We asked the question: Does end-stage renal disease promote changes in subtypes of regulatory T (Treg) cells that correlate with diminished amnestic response to HBVax antigen compared to healthy controls? The study design and setting was a prospective observational cohort at a veterans affairs medical center. End-stage renal disease patients on hemodialysis (HD) were compared with individuals with self-reported normal kidney function. All subjects received HBVax. Peripheral blood was sampled for assessment for Treg cells pre and post vaccination. CD4+ FOXP3 Treg numbers were similar between HD and healthy subjects during a 14-day time period post vaccination. HD subjcts had lower anti-HBSag antibody than CON (control) subjects (330 ± 108.7 vs. 663.1 ± 129.7 IU/mL; P = 0.063). Hemodialysis subjects with resting Tregs higher than the median value in our cohort demonstrated a significantly lower change in HBsAB at 30 days post booster vaccination (P = 0.030). No such relationship was found for the activated Treg subset among HD subjects, or either subset among CON subsets. In our limited comparison study of 11 HD and 8 CON subjects, Treg subsets did not differ between the two groups; but differences in the suppressive Treg numbers in the HD group could explain the altered antibody response to HBVax and is worthy of further study.
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Affiliation(s)
- Roy O Mathew
- Department of Medicine, Division of Nephrology, Stratton Veterans Affair Medical Center, Albany, New York, USA.,Department of Medicine, Albany Medical College, Albany, New York, USA
| | - Darius L Mason
- Department of Medicine, Division of Nephrology, Stratton Veterans Affair Medical Center, Albany, New York, USA.,Division of Nephrology, Albany College of Pharmacy and Health Sciences, Albany, New York, USA
| | - Renjie Song
- Biochemistry & Immunology Core Facility at Wadsworth Center, New York State Department of Health, Albany, New York, USA
| | | | - Jeffrey S Kennedy
- Translational Medicine, Albany Medical College, Albany, New York, USA
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Boer MC, Joosten SA, Ottenhoff THM. Regulatory T-Cells at the Interface between Human Host and Pathogens in Infectious Diseases and Vaccination. Front Immunol 2015; 6:217. [PMID: 26029205 PMCID: PMC4426762 DOI: 10.3389/fimmu.2015.00217] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 04/20/2015] [Indexed: 12/20/2022] Open
Abstract
Regulatory T-cells (Tregs) act at the interface of host and pathogen interactions in human infectious diseases. Tregs are induced by a wide range of pathogens, but distinct effects of Tregs have been demonstrated for different pathogens and in different stages of infection. Moreover, Tregs that are induced by a specific pathogen may non-specifically suppress immunity against other microbes and parasites. Thus, Treg effects need to be assessed not only in homologous but also in heterologous infections and vaccinations. Though Tregs protect the human host against excessive inflammation, they probably also increase the risk of pathogen persistence and chronic disease, and the possibility of disease reactivation later in life. Mycobacterium leprae and Mycobacterium tuberculosis, causing leprosy and tuberculosis, respectively, are among the most ancient microbes known to mankind, and are master manipulators of the immune system toward tolerance and pathogen persistence. The majority of mycobacterial infections occur in settings co-endemic for viral, parasitic, and (other) bacterial coinfections. In this paper, we discuss recent insights in the activation and activity of Tregs in human infectious diseases, with emphasis on early, late, and non-specific effects in disease, coinfections, and vaccination. We highlight mycobacterial infections as important models of modulation of host responses and vaccine-induced immunity by Tregs.
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Affiliation(s)
- Mardi C Boer
- Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands
| | - Simone A Joosten
- Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center , Leiden , Netherlands
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29
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IL-35 inhibits HBV antigen-specific IFN-γ-producing CTLs in vitro. Clin Sci (Lond) 2015; 129:395-404. [PMID: 25869609 DOI: 10.1042/cs20140511] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 04/14/2015] [Indexed: 12/16/2022]
Abstract
Interleukin (IL)-35 is an inhibitory cytokine consisting of IL-12A and Epstein-Barr virus-induced gene 3 (Ebi3) and is required by regulatory T-cells (Tregs) for maximal activity. During chronic hepatitis B virus (HBV) infection, Tregs have immunosuppressive effects on HBV-specific T helper (Th) cells, yet little is known about the complex regulation of Tregs and their contribution to the inadequate immune system response to the virus. In the present study, we investigated whether IL-35 is involved in HBV-related cellular immune responses. Cluster of differentiation (CD)4(+) T-cells from peripheral blood were derived from healthy volunteers, resolved HBV individuals and chronic active hepatitis B patients and stimulated with CD3/28-conjugated beads. We analysed mRNA and protein levels of IL-35 and assessed the inhibitory effect of IL-35 on HBV core antigen-specific cytotoxic T lymphocytes (CTLs), dendritic cells (DCs) and effector T-cells (Teffs). Correlation analyses between liver inflammation and HBV DNA load were conducted. Results show that chronic HBV patients harbour significantly higher levels of Ebi3 mRNA and protein in CD4(+) T-cells compared with healthy volunteers and resolved HBV individuals. IL-35 suppressed the proliferation of HBV antigen-specific CTLs and interferon (IFN)-γ production in vitro. Ex vivo, IL-35 decreased the proliferation of CD4(+)CD45RA(+) naïve T-cells, especially in CD4(+)CD25(-)CD45RA(+) naïve Teffs. IL-35 inhibited the expansion of CD11c(+) DCs. Our data indicate that IL-35 is highly expressed in chronic HBV CD4(+) T-cells and plays an important role in the inhibition of the cellular immune response in chronic HBV.
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30
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Dai K, Huang L, Chen J, Yang L, Gong Z. Amphiregulin promotes the immunosuppressive activity of intrahepatic CD4 + regulatory T cells to impair CD8 + T-cell immunity against hepatitis B virus infection. Immunology 2015; 144:506-517. [PMID: 25298208 DOI: 10.1111/imm.12400] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 09/25/2014] [Accepted: 10/03/2014] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) infection causes liver diseases and hepatocellular carcinoma. Immunotolerance in HBV-infected patients is one of the factors that incur failure of HBV clearance and persistent HBV amplification. However, the mechanisms underlying immunotolerance after HBV infection are yet to be thoroughly understood. Using a novel HBV mouse model, we found for the first time that epidermal growth factor receptor (EGFR) is up-regulated on intrahepatic regulatory T (Treg) cells in HBV-infected mouse livers. The EGFR-positive Treg cells are more immunosuppressive than EGFR-negative Treg cells, demonstrated by higher expression of immunosuppressive cytokines and robust inhibition of CD8+ T-cell proliferation in vitro. Furthermore, EGFR-positive Treg cells potently restrain CD8+ T-cell-mediated anti-viral activity, leading to higher HBV burden in hepatocytes. Amphiregulin, a cytokine of the EGF family, is significantly up-regulated in HBV-infected livers, but the cellular sources of amphiregulin are still elusive. Amphiregulin promotes the immunosuppressive activity of EGFR-positive Treg cells in vitro, so as to profoundly inhibit production of anti-viral components in CD8+ T cells. Taken together, our discovery elucidated a novel mechanism contributing to immunotolerance and viral amplification after HBV infection. Our study may provide new clues for developing therapeutic strategies against HBV infection.
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Affiliation(s)
- Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ling Huang
- Department of Cardiology, the Central Hospital of Wuhan, Wuhan, China
| | - Jing Chen
- Department of Emergency, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lihua Yang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuojiong Gong
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
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31
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Kondo Y, Shimosegawa T. Significant roles of regulatory T cells and myeloid derived suppressor cells in hepatitis B virus persistent infection and hepatitis B virus-related HCCs. Int J Mol Sci 2015; 16:3307-22. [PMID: 25654227 PMCID: PMC4346897 DOI: 10.3390/ijms16023307] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 01/26/2015] [Accepted: 01/28/2015] [Indexed: 12/12/2022] Open
Abstract
The adaptive immune system, including type1 helper T cells (Th1 cells), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs), plays an important role in the control of hepatitis B virus (HBV). On the other hand, regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) suppress the immune reaction in HBV and hepatocellular carcinoma (HCC). Excessive activation of immune suppressive cells could contribute to the persistent infection of HBV and the progression of HCC. The frequency and/or function of Tregs could affect the natural course in chronic hepatitis B patients and the treatment response. In addition to the suppressive function of MDSCs, MDSCs could affect the induction and function of Tregs. Therefore, we should understand in detail the mechanism by which Tregs and MDSCs are induced to control HBV persistent infection and HBV-related HCC. Immune suppressive cells, including Tregs and MDSCs, contribute to the difficulty in inducing an effective immune response for HBV persistent infection and HBV-related HCC. In this review, we focus on the Tregs and MDSCs that could be potential targets for immune therapy of chronic hepatitis B and HBV-related HCC.
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Affiliation(s)
- Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine 1-1 Seiryo, Aoba, Sendai City, Miyagi 980-8574, Japan.
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine 1-1 Seiryo, Aoba, Sendai City, Miyagi 980-8574, Japan.
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32
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Schon HT, Weiskirchen R. Immunomodulatory effects of transforming growth factor-β in the liver. Hepatobiliary Surg Nutr 2015; 3:386-406. [PMID: 25568862 DOI: 10.3978/j.issn.2304-3881.2014.11.06] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Accepted: 10/20/2014] [Indexed: 12/12/2022]
Abstract
Members of the transforming growth factor-β (TGF-β) family are potent regulatory cytokines that affect multiple cell types of the immune system mediating pro-inflammatory or anti-inflammatory responses. In the liver, TGF-β is produced by a multitude of non-parenchymal liver cells including hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), and dendritic cells (DCs) as well as natural killer (NK) T cells among other hepatic lymphocytes. The effect of TGF-β on other cells is highly versatile. In concert with other soluble factors, it controls the maturation, differentiation and activity of various T cell subsets that either prevent or actuate infections, graft-versus-host reactions, immune diseases, and cancer formation. During the last decades, it became evident that some TGFB1 polymorphisms are associated with the pathogenesis of hepatic disease and that plasma TGF-β is a suitable biomarker to detect liver lesions. Moreover, since TGF-β has capacity to influence the quantity and quality of T cell subsets as well as their activity, it is obvious that a well-balanced TGF-β activity is essential for liver homeostasis. In the present review, we highlight some pivotal functions of TGF-β in hepatic immunobiology. We discuss its regulatory function on adaptive immunity, the impact on differentiation of various T cell subsets, its crosstalk with Toll like receptor signaling, and its contribution to functional impairment of the liver.
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Affiliation(s)
- Hans-Theo Schon
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
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33
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Morii S, Doi Y, Makita T, Takeda S, Saito S, Okabe S. A case of de novo hepatitis B associated with statin administered at 64 months later following allogeneic hematopoietic stem cells transplantation. KANZO 2015; 56:661-667. [DOI: 10.2957/kanzo.56.661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Shinji Morii
- Department of Gastroenterology, Matsudo City Hospital
| | - Yoko Doi
- Department of Gastroenterology, Matsudo City Hospital
| | - Tomoo Makita
- Department of Gastroenterology, Matsudo City Hospital
| | | | - Shuichi Saito
- Department of Gastroenterology, Matsudo City Hospital
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34
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Balmasova IP, Yushchuk ND, Mynbaev OA, Alla NR, Malova ES, Shi Z, Gao CL. Immunopathogenesis of chronic hepatitis B. World J Gastroenterol 2014; 20:14156-14171. [PMID: 25339804 PMCID: PMC4202346 DOI: 10.3748/wjg.v20.i39.14156] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 04/23/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) is a widespread infectious disease with unfavorable outcomes and life-threatening consequences for patients, in spite of modern vaccination and antiviral treatment modalities. Cutting-edge experimental approaches have demonstrated key pathways that involve cross-talk between viral particles and host immune cells. All events, including penetration of hepatitis B virus (HBV) particles into host cells, establishing persistence, and chronization of CHB infection, and possibility of complete elimination of HBV particles are controlled by the immune system. Researchers have paid special attention to the replication capacity of HBV in host cells, which is associated with cellular changes that reflect presentation of viral antigens and variability of HBV antigen features. In addition, specific HBV proteins have an immune-modulating ability to initiate molecular mechanisms that “avoid” control by the immune system. The relationship between immunological shifts and chronic infection stages has been intensively studied since it was recognized that the immune system is a direct participant in the recurrent (cyclic) nature of CHB. Understanding the wide diversity of molecular pathways and the crosstalk between innate and adaptive immune system components will provide fresh insight into CHB immune pathogenesis and the possibilities of developing new treatment strategies for this disease.
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35
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Pan ZQ, Lv H, Qiu LM. Advances in understanding relationship between peripheral blood CD4 +CD25 + regulatory T cells and antiviral treatment in CHB patients. Shijie Huaren Xiaohua Zazhi 2014; 22:2851-2856. [DOI: 10.11569/wcjd.v22.i20.2851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The immunosuppressive function of CD4+ CD25+ regulatory T cells may closely associate with the occurrence, development and prognosis of CHB patients. The change and function of CD4+CD25+ regulatory T cells in CHB patients undergoing antiviral treatment have aroused the attention of scholars. Here we review the types, immunophenotypes, and function of CD4+CD25+ regulatory T cells, as well as the relationship between peripheral blood CD4+CD25+ regulatory T cells and antiviral treatment in CHB patients.
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36
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Zhao HQ, Li WM, Lu ZQ, Yao YM. Roles of Tregs in development of hepatocellular carcinoma: A meta-analysis. World J Gastroenterol 2014; 20:7971-7978. [PMID: 24976734 PMCID: PMC4069325 DOI: 10.3748/wjg.v20.i24.7971] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 02/14/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess systematically the association between regulatory T cells (Tregs) and hepatocellular carcinoma (HCC).
METHODS: We searched Medline, Embase and Wanfang databases for literature on the populations of Tregs in HCC patients and controls, using the pooled OR and 95%CIs for assessment. There were no limitations with respect to publication date or language. The references of qualifying articles were also searched. We excluded studies with unclear data or overlapping studies. Twenty-three studies met our criteria, and the quality of these studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN). The meta-analysis of association between Tregs and HCC was undertaken using the random-effects approach, as described by DerSimonian and Laird. Subgroup analysis was performed when at least three studies were available. Potential publication bias was assessed by visual inspection of the funnel plot, and an asymmetric plot suggested possible publication bias.
RESULTS: Twenty-three studies with a total of 1279 HCC patients and 547 healthy volunteers as controls were enrolled. The frequency of circulating Tregs in HCC patients was 87% higher than in healthy controls (OR = 1.87, 95%CI: 1.49-2.34). The frequency of Tregs in the HCC tumor microenvironment was significantly higher than that in tumor-surrounding tissue and biopsy specimens from healthy livers (OR = 4.04, 95%CI: 2.10-7.79, P = 0.000; OR = 2.869, 95%CI: 2.16-3.82, P = 0.000). However, subgroup analyses based on the different types of tumors or patient characteristics such as tumor size, tumor number or α fetoprotein (AFP) levels in HCC patients, showed that populations of Tregs as a whole were not significantly changed between groups (P > 0.05 for all).
CONCLUSION: There is an obvious association between Tregs and pathogenesis of HCC. Further well-designed clinical studies are warranted to illustrate the potential role of Tregs in HCC.
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37
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Wang L, Zou ZQ, Liu CX, Liu XZ. Immunotherapeutic interventions in chronic hepatitis B virus infection: a review. J Immunol Methods 2014; 407:1-8. [PMID: 24747918 DOI: 10.1016/j.jim.2014.04.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 02/20/2014] [Accepted: 04/02/2014] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a public health challenge worldwide. Antiviral agents (nucleos(t)ide analogues, NAs) and immune-based therapies (IFN-α or Pegylated-IFN-α) are two therapeutic approaches available currently against chronic hepatitis B (CHB). However, these approaches are associated with the development of acquired drug resistance or poor response rates and are accompanied by numerous side effects. Furthermore, due to defective innate and adaptive immune responses, HBV cannot be effectively controlled or completely eliminated, which may ultimately result in liver decompensation and hepatocelluar carcinoma. The imperative for development of new approaches targeting CHB cannot be overstated. Various immunotherapeutic interventions have been tried as adjuvants to inhibit HBV replication. In this paper, we will review immunotherapeutic interventions in the treatment of CHB.
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Affiliation(s)
- Li Wang
- Infectious Disease Hospital of Yantai, Huanshan Road 62, Zhifu District, 264001, Yantai, Shandong, China.
| | - Zhi Qiang Zou
- Infectious Disease Hospital of Yantai, Huanshan Road 62, Zhifu District, 264001, Yantai, Shandong, China
| | - Cheng Xia Liu
- Digestive Department, Affiliated Hospital of Binzhou Medical College, Huanghe Second Road 661, 256603, Shandong, China
| | - Xiang Zhong Liu
- Infectious Disease Hospital of Yantai, Huanshan Road 62, Zhifu District, 264001, Yantai, Shandong, China
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38
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Lv H, Pan ZQ, Hu SY, Qiu LM. CD4 +CD25 + regulatory T cells and different states of HBV infection. Shijie Huaren Xiaohua Zazhi 2014; 22:1373-1377. [DOI: 10.11569/wcjd.v22.i10.1373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
CD4+CD25+ regulatory T cells are a recently discovered subset of CD4+ T cell population that mediates immune suppression. Recent studies suggested that regulatory T cells are closely associated with the prognosis of different states of HBV infection. Here we review the types, mechanisms of action and immunophenotypes of CD4+CD25+ regulatory T cells, as well as their relationship with different states of HBV infection.
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39
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Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis. Vaccine 2014; 32:2265-74. [DOI: 10.1016/j.vaccine.2014.02.072] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 12/31/2013] [Accepted: 02/25/2014] [Indexed: 11/17/2022]
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40
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Pan Q, Yu Y, Tang Z, Xi M, Jiang H, Xun Y, Liu X, Liu H, Hu J, Zang G. Increased levels of IL-21 responses are associated with the severity of liver injury in patients with chronic active hepatitis B. J Viral Hepat 2014; 21:e78-88. [PMID: 24611989 DOI: 10.1111/jvh.12242] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 01/22/2014] [Indexed: 12/11/2022]
Abstract
Interleukin-21 (IL-21) participates in tissue damage in various immune-mediated diseases. Its role in the pathogenesis of chronic active hepatitis B (CAHB) has not been clarified. The frequency of circulating IL-21(+) T cells and the levels of serum and intrahepatic IL-21 have been characterized in 70 CAHB patients, 32 inactive carrier (IC), 18 chronic hepatitis C (CHC) and 20 healthy controls (HC). Their potential association with liver injury was analysed. The percentages of IL-21(+) CD3(+) CD8(-) and IL-21(+) CD3(+) CD8(+) T cells and the levels of serum IL-21 in CAHB patients were significantly higher than that in the IC, CHC patients and HC (P < 0.001) and were correlated positively with the levels of serum alanine aminotransferase (ALT, r = 0.424, P < 0.001; r = 0.392, P = 0.001) and aspartate aminotransferase (AST, r = 0.388, P = 0.001; r = 0.329, P = 0.005) in CAHB patients, respectively. The levels of IL-21 expression in the liver tissues were associated significantly with increased degrees of inflammation and fibrosis in CAHB patients (P < 0.01 or P < 0.05). Our findings suggest that aberrant IL-21 responses may be associated with the progression of CHB.
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Affiliation(s)
- Q Pan
- Department of Infectious Disease, Shanghai Sixth People's Hospital affiliated to Shanghai Jiaotong University, Shanghai, China
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41
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Karimi-Googheri M, Daneshvar H, Nosratabadi R, Zare-Bidaki M, Hassanshahi G, Ebrahim M, Arababadi MK, Kennedy D. Important roles played by TGF-β in hepatitis B infection. J Med Virol 2013; 86:102-8. [PMID: 24009084 DOI: 10.1002/jmv.23727] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2013] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) which includes, fulminant, acute, chronic, asymptomatic, and occult HBV infection is the most prevalent virus that leads to human liver diseases. Chronic, asymptomatic, and occult infection can induce further sever diseases such as hepatocellular carcinoma (HCC) and cirrhosis of the liver. The underlying mechanisms that allow progression of the prolonged forms of the infection and subsequent HCC or cirrhosis of the liver are yet to be clarified. However, many researchers have suggested that immunological and genetic parameters may play important roles in the etiology of hepatitis B. Transforming growth factor beta (TGF-β) is an important cytokine with dual regulatory functions in the immune system and in the responses against viral infections. However, the pathways and mechanisms controlling these are not fully understood. The crucial roles of TGF-β in the development of Th17 and T regulatory lymphocytes, the main cell types involved in autoimmunity and destructive immune related diseases, have been documented and this provides insights into TGF-β function during hepatitis infection and subsequent HCC and cirrhosis of the liver. Recent findings also confirm that TGF-β directly alters hepatocyte function during hepatitis B, hence, the aim of this review is to address the current data regarding the association and status of TGF-β with hepatitis B infection and its related disorders including HCC and cirrhosis of the liver.
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42
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Wu DC. Hepatitis B virus reactivation associated with atorvastatin. Int J Infect Dis 2013; 17:e1069-70. [PMID: 23725984 DOI: 10.1016/j.ijid.2013.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 04/10/2013] [Accepted: 04/11/2013] [Indexed: 11/17/2022] Open
Abstract
It is well known that statins may cause elevation of liver enzymes, but the association of statins with hepatitis B reactivation has never been reported before. A case of hepatitis B reactivation induced by atorvastatin is reported herein. Atorvastatin not only caused significant increases in aminotransferases, but also caused ongoing viral replication by evidence of a several-log increase in hepatitis B virus. The reactivation recovered spontaneously by discontinuation of atorvastatin. The evolving concept of a double-edged sword with regard to statins in patients with hepatitis B is discussed.
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Affiliation(s)
- Du Chu Wu
- Department of Internal Medicine, Charles B. Wang Community Health Center, 168 Canal Street, New York, NY 10013, USA.
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