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Yu F, Zhu Y, Li S, Hao L, Li N, Ye F, Jiang Z, Hu X. Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies. Front Cell Infect Microbiol 2024; 14:1488527. [PMID: 39717542 PMCID: PMC11663751 DOI: 10.3389/fcimb.2024.1488527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.
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Affiliation(s)
- Fei Yu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yue Zhu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Shenghao Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Liyuan Hao
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Na Li
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Fanghang Ye
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zhi Jiang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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2
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Wang Z, Liu N, Yang Y, Tu Z. The novel mechanism facilitating chronic hepatitis B infection: immunometabolism and epigenetic modification reprogramming. Front Immunol 2024; 15:1349867. [PMID: 38288308 PMCID: PMC10822934 DOI: 10.3389/fimmu.2024.1349867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/02/2024] [Indexed: 01/31/2024] Open
Abstract
Hepatitis B Virus (HBV) infections pose a global public health challenge. Despite extensive research on this disease, the intricate mechanisms underlying persistent HBV infection require further in-depth elucidation. Recent studies have revealed the pivotal roles of immunometabolism and epigenetic reprogramming in chronic HBV infection. Immunometabolism have identified as the process, which link cell metabolic status with innate immunity functions in response to HBV infection, ultimately contributing to the immune system's inability to resolve Chronic Hepatitis B (CHB). Within hepatocytes, HBV replication leads to a stable viral covalently closed circular DNA (cccDNA) minichromosome located in the nucleus, and epigenetic modifications in cccDNA enable persistence of infection. Additionally, the accumulation or depletion of metabolites not only directly affects the function and homeostasis of immune cells but also serves as a substrate for regulating epigenetic modifications, subsequently influencing the expression of antiviral immune genes and facilitating the occurrence of sustained HBV infection. The interaction between immunometabolism and epigenetic modifications has led to a new research field, known as metabolic epigenomics, which may form a mutually reinforcing relationship with CHB. Herein, we review the recent studies on immunometabolism and epigenetic reprogramming in CHB infection and discuss the potential mechanisms of persistent HBV infection. A deeper understanding of these mechanisms will offer novel insights and targets for intervention strategies against chronic HBV infection, thereby providing new hope for the treatment of related diseases.
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Affiliation(s)
- Zhengmin Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Nan Liu
- Institute of Epigenetic Medicine, First Hospital of Jilin University, Changchun, China
| | - Yang Yang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhengkun Tu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
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3
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Ablikim D, Zeng X, Xu C, Zhao M, Yang X, Feng X, Liu J. The Multiple Facets and Disorders of B Cell Functions in Hepatitis B Virus Infection. J Clin Med 2023; 12:jcm12052000. [PMID: 36902786 PMCID: PMC10004556 DOI: 10.3390/jcm12052000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a global public health burden. B cells play a pivotal role in mediating HBV clearance and can participate in the development of anti-HBV adaptive immune responses through multiple mechanisms, such as antibody production, antigen presentation, and immune regulation. However, B cell phenotypic and functional disorders are frequently observed during chronic HBV infection, suggesting the necessity of targeting the disordered anti-HBV B cell responses to design and test new immune therapeutic strategies for the treatment of chronic HBV infection. In this review, we provide a comprehensive summary of the multiple roles of B cells in mediating HBV clearance and pathogenesis as well as the latest developments in understanding the immune dysfunction of B cells in chronic HBV infection. Additionally, we discuss novel immune therapeutic strategies that aim to enhance anti-HBV B cell responses for curing chronic HBV infection.
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Affiliation(s)
- Dilhumare Ablikim
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoqing Zeng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chunli Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengxiao Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
- Correspondence: ; Tel.: +86-186-9615-9826
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4
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Zhong S, Li Q, Wen C, Li Y, Zhou Y, Jin Z, Ye G, Zhao Y, Hou J, Li Y, Tang L. Interferon α facilitates anti-HBV cellular immune response in a B cell-dependent manner. Antiviral Res 2022; 207:105420. [PMID: 36165866 DOI: 10.1016/j.antiviral.2022.105420] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/05/2022] [Accepted: 09/13/2022] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Dissecting the underlying mechanism of T cells remodeling mediated by interferon α (IFN-α) is indispensable for achieving an optimum therapeutic response in chronic hepatitis B (CHB) patients. However, little is known about B cells in this process. This study aims to elucidate the roles of B cells in IFN-α-mediated anti-hepatitis B virus (HBV) cellular immunity. METHOD The effects of B cells on IFN-α-mediated T cell response were investigated in B cell-deficient mouse model with HBV and IFN-α plasmid hydrodynamic injection. Single-cell RNA sequencing was performed to dissect the crosstalk among B cell and T cell subsets and the underlying molecule and pathway signatures on longitudinal blood samples from IFN-α-treated CHB patients. RESULTS B cell depletion impaired the functional T cell subsets, including HBV-specific CD8+ T cells, and engendered a delayed HBV clearance. IFN-α treatment boosted the response of HBV-specific CD8+ T cells, whereas such effects disappeared in B cell-deficient mice. The underlying mechanisms were associated with IFN-α-reinforced connections of B cells toward T cells as mediated by the antigen presentation and costimulatory functions in B cells. CONCLUSION IFN-α orchestrates protective HBV-specific cellular immunity in a B cell-dependent manner.
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Affiliation(s)
- Shihong Zhong
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiong Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chunhua Wen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yifan Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zihan Jin
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guofu Ye
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanda Zhao
- School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Yongyin Li
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Libo Tang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Klarquist J, Cross EW, Thompson SB, Willett B, Aldridge DL, Caffrey-Carr AK, Xu Z, Hunter CA, Getahun A, Kedl RM. B cells promote CD8 T cell primary and memory responses to subunit vaccines. Cell Rep 2021; 36:109591. [PMID: 34433030 PMCID: PMC8456706 DOI: 10.1016/j.celrep.2021.109591] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/22/2021] [Accepted: 08/02/2021] [Indexed: 01/14/2023] Open
Abstract
The relationship between B cells and CD4 T cells has been carefully studied, revealing a collaborative effort in which B cells promote the activation, differentiation, and expansion of CD4 T cells while the so-called “helper” cells provide signals to B cells, influencing their class switching and fate. Interactions between B cells and CD8 T cells are not as well studied, although CD8 T cells exhibit an accelerated contraction after certain infections in B-cell-deficient mice. Here, we find that B cells significantly enhance primary CD8 T cell responses after vaccination. Moreover, memory CD8 numbers and function are impaired in B-cell-deficient animals, leading to increased susceptibility to bacterial challenge. We also show that interleukin-27 production by B cells contributes to their impact on primary, but not memory, CD8 responses. Better understanding of the interactions between CD8 T cells and B cells may aid in the design of more effective future vaccine strategies. Generating cytotoxic CD8 T cell responses with vaccines can greatly improve their efficacy, but inducing adequate numbers of these cells can be challenging. Klarquist et al. reveal that the magnitude, persistence, and function of CD8 T cell vaccine responses depend on B cells.
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Affiliation(s)
- Jared Klarquist
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
| | - Eric W Cross
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Scott B Thompson
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Benjamin Willett
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Daniel L Aldridge
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Alayna K Caffrey-Carr
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Zhenming Xu
- Department of Microbiology, Immunology and Molecular Genetics, The Joe R. & Teresa Lozano Long School of Medicine, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA
| | - Christopher A Hunter
- University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Andrew Getahun
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Ross M Kedl
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
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6
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Hsieh LE, Sidney J, Burns JC, Boyle DL, Firestein GS, Altman Y, Sette A, Franco A. IgG Epitopes Processed and Presented by IgG + B Cells Induce Suppression by Human Thymic-Derived Regulatory T Cells. THE JOURNAL OF IMMUNOLOGY 2021; 206:1194-1203. [PMID: 33579724 DOI: 10.4049/jimmunol.2001009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 01/06/2021] [Indexed: 01/27/2023]
Abstract
We described a human regulatory T cell (Treg) population activated by IgG+ B cells presenting peptides of the heavy C region (Fc) via processing of the surface IgG underlying a model for B cell-Treg cooperation in the human immune regulation. Functionally, Treg inhibited the polarization of naive T cells toward a proinflammatory phenotype in both a cognate and a noncognate fashion. Their fine specificities were similar in healthy donors and patients with rheumatoid arthritis, a systemic autoimmune disease. Four immunodominant Fc peptides bound multiple HLA class II alleles and were recognized by most subjects in the two cohorts. The presentation of Fc peptides that stimulate Treg through the processing of IgG by dendritic cells (DC) occurred in myeloid DC classical DC 1 and classical DC 2. Different routes of Ag processing of the IgG impacted Treg expansion in rheumatoid arthritis patients.
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Affiliation(s)
- Li-En Hsieh
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093
| | - John Sidney
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Jane C Burns
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093
| | - David L Boyle
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093; and
| | - Gary S Firestein
- Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093; and
| | - Yoav Altman
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037
| | - Alessandro Sette
- Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Alessandra Franco
- Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA 92093;
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7
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Li Q, Wang J, Islam H, Kirschning C, Lu H, Hoffmann D, Dittmer U, Lu M. Hepatitis B virus particles activate B cells through the TLR2-MyD88-mTOR axis. Cell Death Dis 2021; 12:34. [PMID: 33414473 PMCID: PMC7791069 DOI: 10.1038/s41419-020-03284-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/18/2020] [Accepted: 11/25/2020] [Indexed: 02/08/2023]
Abstract
Host immune control plays a pivotal role in resolving primary hepatitis-B-virus (HBV) infections. The complex interaction between HBV and host immune cells, however, remains unclear. In this study, the transcriptional profiling of specimens from animals infected with woodchuck hepatitis virus (WHV) indicated TLR2 mRNA accumulation as most strongly impacted during WHV infection resolution as compared to other mRNAs. Analysis of blood transcriptional modules demonstrated that monocytes and B-cells were the predominantly activated cell types in animals that showed resolution of infection, which was similar to the response of TLR2-stimulated PBMCs. Further investigation of TLR2-stimulated B-cells pointed at interactions between activated TLR signaling, Akt-mTOR, and glucose metabolic pathways. Moreover, analysis of B-cells from Tlr2-/-, Trif-/-, Myd88-/-, and Trif/Myd88-/- mice challenged with HBV particles indicated B-cell function and glucose metabolism alterations is TLR2-MyD88-mTOR axis dependent. Overall, our study implicates B-cell TLR2 activation in HBV infection resolution.
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Affiliation(s)
- Qian Li
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.,Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Jun Wang
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.,Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, Jiangsu, China.,Bioinformatics and Computational Biophysics, University of Duisburg-Essen, Essen, Germany
| | - Heba Islam
- Institute of Medical Microbiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Carsten Kirschning
- Institute of Medical Microbiology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Hongzhou Lu
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Daniel Hoffmann
- Bioinformatics and Computational Biophysics, University of Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
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8
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Celardo I, Pace L, Cifaldi L, Gaudio C, Barnaba V. The immune system view of the coronavirus SARS-CoV-2. Biol Direct 2020; 15:30. [PMID: 33371901 PMCID: PMC7769684 DOI: 10.1186/s13062-020-00283-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 11/25/2020] [Indexed: 12/14/2022] Open
Abstract
Knowing the "point of view" of the immune system is essential to understand the characteristic of a pandemic, such as that generated by the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2, responsible for the Coronavirus Disease (COVID)-19. In this review, we will discuss the general host/pathogen interactions dictating protective immune response or immunopathology, addressing the role of immunity or immunopathology in influencing the clinical infection outcome, and debate the potential immunoprophylactic and immunotherapy strategies required to fight the virus infection.
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Affiliation(s)
- Ivana Celardo
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Rome, Italy
| | - Luigia Pace
- Armenise-Harvard Immune Regulation Unit, Italian Institute for Genomic Medicine, FPO IRCCS Candiolo, Turin, Italy
| | - Loredana Cifaldi
- Academic Department of Pediatrics (DPUO),, Ospedale Pediatrico Bambino Gesù,, IRCCS, Rome,, 00165, Italy.,Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, Rome, 00133, Italy
| | - Carlo Gaudio
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Rome, Italy
| | - Vincenzo Barnaba
- Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Rome, Italy.
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9
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Cai Y, Yin W. The Multiple Functions of B Cells in Chronic HBV Infection. Front Immunol 2020; 11:582292. [PMID: 33381113 PMCID: PMC7767983 DOI: 10.3389/fimmu.2020.582292] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the main causes of liver diseases, of which the natural history and clinical outcomes are associated with the role of B cells. As humoral immune cells, B cells play a critical role in the process of anti-HBV antibody production. In addition, some studies have also characterized other B cell subsets involved in antigen presentation and regulating the immune response beyond antibody secretion. However, not all B cell subsets play a positive role in the immune response to chronic HBV infection, and various B cell subsets jointly mediate persistent HBV infection, tolerance, and liver damage. Thus, we further sought to elucidate the multiple functions of B cells to gain novel insight into the understanding of chronic hepatitis B (CHB) pathogenesis. We also reviewed the current immunotherapies targeting B cells to explore novel therapeutic interventions for the treatment of chronic HBV infection.
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Affiliation(s)
- Ying Cai
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenwei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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10
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Mechanisms of HBV immune evasion. Antiviral Res 2020; 179:104816. [PMID: 32387476 DOI: 10.1016/j.antiviral.2020.104816] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/29/2020] [Accepted: 05/03/2020] [Indexed: 02/07/2023]
Abstract
The concept of immune evasion is a longstanding topic of debate during chronic Hepatitis B Virus infection. The 292 million individuals chronically infected by HBV are clear evidence that the virus avoids elimination by the immune system. The exact mechanisms of immune evasion remain undefined and are distinct, but likely interconnected, between innate and adaptive immunity. There is a significant body of evidence that supports peripheral tolerance and exhaustion of adaptive immunity but our understanding of the role that central tolerance plays is still developing. Innate immunity instructs the adaptive immune response and subversion of its functionality will impact both T and B cell responses. However, literature around the interaction of HBV with innate immunity is inconsistent, with reports suggesting that HBV avoids innate recognition, suppresses innate recognition, or activates innate immunity. This complexity has led to confusion and controversy. This review will discuss the mechanisms of central and peripheral tolerance/exhaustion of adaptive immunity in the context of chronic HBV infection. We also cover the interaction of HBV with cells of the innate immune system and propose concepts for the heterogeneity of responses in chronically infected patients.
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11
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Maini MK, Burton AR. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat Rev Gastroenterol Hepatol 2019; 16:662-675. [PMID: 31548710 DOI: 10.1038/s41575-019-0196-9] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2019] [Indexed: 02/06/2023]
Abstract
Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies.
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Affiliation(s)
- Mala K Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
| | - Alice R Burton
- Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK
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12
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Salimzadeh L, Le Bert N, Dutertre CA, Gill US, Newell EW, Frey C, Hung M, Novikov N, Fletcher S, Kennedy PT, Bertoletti A. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest 2018; 128:4573-4587. [PMID: 30084841 PMCID: PMC6159957 DOI: 10.1172/jci121957] [Citation(s) in RCA: 205] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/26/2018] [Indexed: 12/12/2022] Open
Abstract
Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as "baits" for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti-PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell-maturing cytokines and PD-1 blockade.
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Affiliation(s)
- Loghman Salimzadeh
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
- Department of Microbiology and Immunology, National University of Singapore, Singapore
| | - Nina Le Bert
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
| | - Charles-A. Dutertre
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
| | - Upkar S. Gill
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Evan W. Newell
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
| | - Christian Frey
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Magdeleine Hung
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Nikolai Novikov
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Simon Fletcher
- Gilead Sciences Inc., Department of Biology, Foster City, California, USA
| | - Patrick T.F. Kennedy
- Barts Liver Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Antonio Bertoletti
- Emerging Infectious Diseases Program, Duke-NUS Medical School, Singapore
- Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore
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13
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Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L, Alberts E, Davidson BR, Kennedy PT, Gill US, Mauri C, Blair PA, Pelletier N, Maini MK. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest 2018; 128:4588-4603. [PMID: 30091725 PMCID: PMC6159997 DOI: 10.1172/jci121960] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/26/2018] [Indexed: 12/15/2022] Open
Abstract
B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21-CD27- atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1hiatMBC and impairing B cell immunity.
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Affiliation(s)
- Alice R. Burton
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Laura J. Pallett
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Laura E. McCoy
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Kornelija Suveizdyte
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Oliver E. Amin
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Leo Swadling
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Elena Alberts
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
| | - Brian R. Davidson
- Department of Surgery, University College London, London, United Kingdom
| | | | - Upkar S. Gill
- Centre for Immunobiology, Barts and the London, London, United Kingdom
| | - Claudia Mauri
- Division of Medicine, University College London, London, United Kingdom
| | - Paul A. Blair
- Division of Medicine, University College London, London, United Kingdom
| | | | - Mala K. Maini
- Division of Infection and Immunity, Institute of Immunity and Transplantation, and
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14
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Abstract
Antibodies play a crucial role in virus control. The production of antibodies requires virus-specific B cells to encounter viral antigens in lymph nodes, become activated, interact with different immune cells, proliferate and enter specific differentiation programmes. Each step occurs in distinct lymph node niches, requiring a coordinated migration of B cells between different subcompartments. The development of multiphoton intravital microscopy has enabled researchers to begin to elucidate the precise cellular and molecular events by which lymph nodes coordinate humoral responses. This Review discusses recent studies that clarify how viruses interfere with antibody responses, highlighting how these mechanisms relate to our topological and temporal understanding of B cell activation within secondary lymphoid organs.
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Affiliation(s)
- Mirela Kuka
- Division of Immunology, Transplantation and Infectious Diseases and Experimental Imaging Center, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases and Experimental Imaging Center, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Via Olgettina 58, Milan 20132, Italy
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15
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Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis. PLoS One 2015; 10:e0127511. [PMID: 26024529 PMCID: PMC4449162 DOI: 10.1371/journal.pone.0127511] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 04/15/2015] [Indexed: 01/10/2023] Open
Abstract
Background Chronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase. Methods Liver samples from patients with chronic HBV (n = 91), normal liver (n = 55) and regenerating liver (n = 15) were studied. Immunohistochemistry for cell cycle phase markers and HBV antigens was used to determine host cell cycle phase. Hepatocyte-specific telomere length was evaluated by quantitative fluorescent in-situ hybridization (Q-FISH) in conjunction with hepatocyte nuclear area and HBV antigen expression. The effects of induced cell cycle arrest and induced cellular senescence on HBV production were assessed in vitro. Results 13.7% hepatocytes in chronic HBV had entered cell cycle, but expression of markers for S, G2 and M phase was low compared with regenerating liver. Hepatocyte p21 expression was increased (10.9%) in chronic HBV and correlated with liver fibrosis. Mean telomere length was reduced in chronic HBV compared to normal. However, within HBV-affected livers, hepatocytes expressing HBV antigens had longer telomeres. Telomere length declined and hepatocyte nuclear size increased as HBV core antigen (HBcAg) expression shifted from the nucleus to cytoplasm. Nuclear co-expression of HBcAg and p21 was not observed. Cell cycle arrest induced in vitro was associated with increased HBV production, in contrast to
in vitro induction of cellular senescence, which had no effect. Conclusion Chronic HBV infection was associated with hepatocyte G1 cell cycle arrest and accelerated hepatocyte ageing, implying that HBV induced cellular senescence. However, HBV replication was confined to biologically younger hepatocytes. Changes in the cellular location of HBcAg may be related to the onset of cellular senescence.
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16
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Therapeutic antitumor efficacy of B cells loaded with tumor-derived autophagasomes vaccine (DRibbles). J Immunother 2015; 37:383-93. [PMID: 25198526 PMCID: PMC4166015 DOI: 10.1097/cji.0000000000000051] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Supplemental Digital Content is available in the text. Tumor-derived autophagosomes (DRibble) selectively capture tumor-specific antigens and induce a dramatic T-cell activation and expansion when injected into lymph nodes of naive mice. Both dendritic and B cells can efficiently cross-prime antigen-specific T cells. In this report, we demonstrated that a booster vaccination with naive B cells loaded with DRibbles eradicated E.G7-OVA tumors in mice that were previously treated with adoptive transfer naive OT-I T cells and intranodal immunization with DRibbles derived from E.G7 tumors. The antitumor efficacy was accompanied by a heighten number of tumor-specific interferon-γ-producing T cells and antibodies. However, the same treatment in the absence of adoptive T-cell transfer exhibited a limited efficacy. In contrast, when DRibble-loaded B cells were activated with CpG and anti-CD40 antibody before use as booster vaccines, established E.G7 tumors were completely eradicated in the absence of T-cell transfer. Therefore, our results document that B cells could efficiently cross-present tumor-specific antigens captured by DRibbles and suggest that naive B cells can be deployed as an effective and readily accessible source of antigen-presenting cells for cancer immunotherapy clinical trials.
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17
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Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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18
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Çiftdoğan DY, Onay H, Tosun S, Özdemir TR, Özkınay F, Vardar F. IFNG and IFNGR1 gene polymorphisms in children with nonresponse to the hepatitis B vaccine. Future Virol 2014. [DOI: 10.2217/fvl.13.124] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
ABSTRACT: Aim: We investigated the +874 T/A polymorphism in the first intron of the IFNG gene and intronic (CA)n polymorphic microsatellite marker of the IFNGR 1 gene in child nonresponders to hepatitis B vaccination. Materials & methods: A total of 100 children who had anti-HBs antibody levels <10 mIU/ml after vaccination against hepatitis B were included as a nonresponder group and 100 children who had anti-HBs antibody levels >10 mIU/ml after vaccination against hepatitis B were included as a responder group. Results: The frequency of the TT genotype of the IFNG (+874 T/A) gene polymorphism was higher in nonresponders (p = 0.003). The frequencies of alleles 170 and 182 for (CA)n alleles for the intronic (CA)n microsatellite of IFNGR1 were significantly higher in nonresponders (for each, p < 0.05). Conclusion: The TT genotype of the IFNG (+874 T/A) gene, and alleles 170 and 182 for (CA)n alleles for the intronic (CA)n microsatellite of the IFNGR1 gene, may be associated with nonresponse to hepatitis B vaccination.
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Affiliation(s)
- Dilek Yılmaz Çiftdoğan
- Ege University, Faculty of Medicine, Department of Pediatric Infectious Diseases, Bornova, İzmir, Turkey
| | - Hüseyin Onay
- Ege University, Department of Medical Genetics, İzmir, Turkey
| | | | | | - Ferda Özkınay
- Ege University, Department of Medical Genetics, İzmir, Turkey
| | - Fadıl Vardar
- Ege University, Faculty of Medicine, Department of Pediatric Infectious Diseases, Bornova, İzmir, Turkey
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Paroli M, Bellati F, Videtta M, Focaccetti C, Mancone C, Donato T, Antonilli M, Perniola G, Accapezzato D, Napoletano C, Nuti M, Bartolazzi A, Panici PB, Tripodi M, Palombo F, Barnaba V. Discovery of chemotherapy-associated ovarian cancer antigens by interrogating memory T cells. Int J Cancer 2013; 134:1823-34. [PMID: 24150888 DOI: 10.1002/ijc.28515] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 09/02/2013] [Accepted: 09/12/2013] [Indexed: 01/03/2023]
Abstract
According to the immunogenic cell death hypothesis, clinical chemotherapy treatments may result in CD8(+) and CD4(+) T-cell responses against tumor cells. To discover chemotherapy-associated antigens (CAAs), T cells derived from ovarian cancer (OC) patients (who had been treated with appropriate chemotherapy protocols) were interrogated with proteins isolated from primary OC cells. We screened for immunogenicity using two-dimensional electrophoresis gel-eluted OC proteins. Only the selected immunogenic antigens were molecularly characterized by mass-spectrometry-based analysis. Memory T cells that recognized antigens associated with apoptotic (but not live) OC cells were correlated with prolonged survival in response to chemotherapy, supporting the model of chemotherapy-induced apoptosis as an adjuvant of anti-tumor immunity. The strength of both memory CD4(+) and CD8(+) T cells producing either IFN-γ or IL-17 in response to apoptotic OC antigens was also significantly greater in Responders to chemotherapy than in nonresponders. Immunogenicity of some of these antigens was confirmed using recombinant proteins in an independent set of patients. The T-cell interrogation system represents a strategy of reverse tumor immunology that proposes to identify CAAs, which may then be validated as possible prognostic tumor biomarkers or cancer vaccines.
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Affiliation(s)
- Marino Paroli
- Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, Rome, Italy
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20
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Gehring AJ, Haniffa M, Kennedy PT, Ho ZZ, Boni C, Shin A, Banu N, Chia A, Lim SG, Ferrari C, Ginhoux F, Bertoletti A. Mobilizing monocytes to cross-present circulating viral antigen in chronic infection. J Clin Invest 2013; 123:3766-76. [PMID: 23908113 DOI: 10.1172/jci66043] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 06/06/2013] [Indexed: 12/16/2022] Open
Abstract
Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8+ T cells specific for MHC-I-restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivo-isolated APCs did not constitutively activate HBV-specific CD8+ T cells. However, differentiation of HBsAg+ CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells.
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Affiliation(s)
- Adam J Gehring
- Infection and Immunity Programme, Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore.
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21
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Lolli F, Martini H, Citro A, Franceschini D, Portaccio E, Amato MP, Mechelli R, Annibali V, Sidney J, Sette A, Salvetti M, Barnaba V. Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis. J Neuroinflammation 2013; 10:94. [PMID: 23890271 PMCID: PMC3734107 DOI: 10.1186/1742-2094-10-94] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/15/2013] [Indexed: 01/22/2023] Open
Abstract
Background Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology. Methods The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo. Results We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo. Conclusion Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines.
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Affiliation(s)
- Francesco Lolli
- Dipartimento di Scienze Biomediche, Sperimentali e Cliniche and Neurofarba, Università of Firenze, Azienda Ospedaliera di Careggi, Largo Brambilla 6, 50134 Firenze, Italy
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22
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Liang TJ. Current progress in development of hepatitis C virus vaccines. Nat Med 2013; 19:869-78. [PMID: 23836237 PMCID: PMC6263146 DOI: 10.1038/nm.3183] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 02/22/2013] [Indexed: 12/14/2022]
Abstract
Despite major advances in the understanding and treatment of hepatitis C, a preventive vaccine remains elusive. The marked genetic diversity and multiple mechanisms of persistence of hepatitis C virus, combined with the relatively poor immune response of the infected host against the virus, are major barriers. The lack of robust and convenient model systems further hampers the effort to develop an effective vaccine. Advances in our understanding of virus-host interactions and protective immunity in hepatitis C virus infection provide an important roadmap to develop potent and broadly directed vaccine candidates targeting both humoral and cellular immune responses. Multiple approaches to generating and testing viral immunogens have met with variable success. Several candidates have advanced to clinical trials based on promising results in chimpanzees. The ultimate path to a successful preventive vaccine requires comprehensive evaluations of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology and properly designed vaccine trials that can affirm definitive endpoints of efficacy.
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Affiliation(s)
- T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
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23
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Iglesias E. Is there any room for therapeutic vaccination against the HIV-1/AIDS? Hum Vaccin Immunother 2013; 9:1539-44. [PMID: 23571171 DOI: 10.4161/hv.24405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Any therapeutic vaccination approach against HIV-1 must induce CTL and Th1 cells. But, therapeutic vaccination is more than that. For extensive application of a therapeutic vaccine several questions need to be solved in advance to achieve a global impact. In this commentary some of them are addressed. We analyze the epidemiology, sociology, economy and immunopathology related to the HIV/AIDS disease. Also, important technical issues and real possibilities to overcome at least some of the major limitation of the antiretroviral treatments in the pursuit of an effective vaccine are considered. From the integration of previous analyses some conclusions are drawn. Because it is just a commentary some arguments are not unveiled into their full extension. At the end, we discuss some issues in relation to the development of the vaccine candidate TERAVAC-HIV-1 as a case study.
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Affiliation(s)
- Enrique Iglesias
- Centro de Ingeniería Genética y Biotecnología (CIGB); Havana, Cuba
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24
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Zhuang QJ, Qiu LM, Yao XS, Chen Y, Lv H. CD4 + CD25 + regulatory T cells and hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2012; 20:2248-2253. [DOI: 10.11569/wcjd.v20.i24.2248] [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
CD4+ CD25+ regulatory T cells are a recently discovered subset of CD4+ T cell populations that mediate immune suppression. Their unique mode of action and characteristics make them play an important role in autoimmune diseases, transplantation immunology, tumor immunity and anti-infection immunity. Recent studies suggest that regulatory T cells are closely associated with the pathogenesis and outcome of hepatitis B. Here we review recent advances in understanding the relationship between CD4+ CD25+ regulatory T cells and hepatitis B virus infection.
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25
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Franceschini D, Del Porto P, Piconese S, Trella E, Accapezzato D, Paroli M, Morrone S, Piccolella E, Spada E, Mele A, Sidney J, Sette A, Barnaba V. Polyfunctional type-1, -2, and -17 CD8⁺ T cell responses to apoptotic self-antigens correlate with the chronic evolution of hepatitis C virus infection. PLoS Pathog 2012; 8:e1002759. [PMID: 22737070 PMCID: PMC3380931 DOI: 10.1371/journal.ppat.1002759] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Accepted: 05/03/2012] [Indexed: 12/17/2022] Open
Abstract
Caspase-dependent cleavage of antigens associated with apoptotic cells plays a prominent role in the generation of CD8⁺ T cell responses in various infectious diseases. We found that the emergence of a large population of autoreactive CD8⁺ T effector cells specific for apoptotic T cell-associated self-epitopes exceeds the antiviral responses in patients with acute hepatitis C virus infection. Importantly, they endow mixed polyfunctional type-1, type-2 and type-17 responses and correlate with the chronic progression of infection. This evolution is related to the selection of autoreactive CD8⁺ T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients who clear infection. These findings demonstrate a previously undescribed strict link between the emergence of high frequencies of mixed autoreactive CD8⁺ T cells producing a broad array of cytokines (IFN-γ, IL-17, IL-4, IL-2…) and the progression toward chronic disease in a human model of acute infection.
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Affiliation(s)
- Debora Franceschini
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Paola Del Porto
- Dipartimento di Biologia e Biotecnologie “Charles Darwin”, Sapienza Università di Roma, Rome, Italy
| | - Silvia Piconese
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Emanuele Trella
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Daniele Accapezzato
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Marino Paroli
- Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, Rome, Italy
| | - Stefania Morrone
- Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Rome, Italy
| | - Enza Piccolella
- Dipartimento di Biologia e Biotecnologie “Charles Darwin”, Sapienza Università di Roma, Rome, Italy
| | - Enea Spada
- National Centre of Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanità, Rome, Italy
| | - Alfonso Mele
- National Centre of Epidemiology, Surveillance and Health Promotion, Istituto Superiore di Sanità, Rome, Italy
| | - John Sidney
- La Jolla Institute for Allergy and Immunology, San Diego, California, United States of America
| | - Alessandro Sette
- La Jolla Institute for Allergy and Immunology, San Diego, California, United States of America
| | - Vincenzo Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
- Istituto Pasteur - Fondazione Cenci Bolognetti, Rome, Italy
- Fondazione Andrea Cesalpino, Rome, Italy
- * E-mail:
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26
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B Effector Cells Activated by a Chimeric Protein Consisting of IL-2 and the Ectodomain of TGF-β Receptor II Induce Potent Antitumor Immunity. Cancer Res 2012; 72:1210-20. [DOI: 10.1158/0008-5472.can-11-1659] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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27
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Matte-Martone C, Wang X, Anderson B, Jain D, Demetris AJ, McNiff J, Shlomchik MJ, Shlomchik WD. Recipient B cells are not required for graft-versus-host disease induction. Biol Blood Marrow Transplant 2010; 16:1222-30. [PMID: 20338255 PMCID: PMC3135976 DOI: 10.1016/j.bbmt.2010.03.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Accepted: 03/16/2010] [Indexed: 11/15/2022]
Abstract
Recipient antigen presenting cells (APCs) are required for CD8-mediated graft-versus-host disease (GVHD), and have an important and nonredundant role in CD4-mediated GVHD in mouse major histocompatibility complex-matched allogeneic bone marrow transplantation (alloBMT). However, the precise roles of specific recipient APCs-dendritic cells, macrophages, and B cells-are not well defined. If recipient B cells are important APCs they could be depleted with rituximab, an anti-CD20 monoclonal antibody. On the other hand, B cells can downregulate T cell responses, and consequently, B cell depletion could exacerbate GVHD. Patients with B cell lymphomas undergo allogeneic hematopoietic stem cell transplantation (alloSCT) and many are B-cell-deficient because of prior rituximab. We therefore studied the role of recipient B cells in major histocompatibility complex-matched murine models of CD8- and CD4-mediated GVHD by using recipients genetically deficient in B cells and with antibody-mediated depletion of host B cells. In both CD4- and CD8-dependent models, B cell-deficient recipients developed clinical and pathologic GVHD. However, although CD8-mediated GVHD was clinically less severe in hosts genetically deficient in B cells, it was unaffected in anti-CD20-treated recipients. These data indicate that recipient B cells are not important initiators of GVHD, and that efforts to prevent GVHD by APC depletion should focus on other APC subsets.
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Affiliation(s)
- Catherine Matte-Martone
- Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520
- Department of Medicine, Yale University School of Medicine, New Haven, CT 06520
| | | | - Britt Anderson
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT 06520
| | - Anthony J. Demetris
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213
| | - Jennifer McNiff
- Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520
| | - Mark J. Shlomchik
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520
| | - Warren D. Shlomchik
- Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520
- Department of Medicine, Yale University School of Medicine, New Haven, CT 06520
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
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Wu F, Cao J, Jiang J, Yu B, Xu Q. Ruscogenin glycoside (Lm-3) isolated from Liriope muscari improves liver injury by dysfunctioning liver-infiltrating lymphocytes. J Pharm Pharmacol 2010; 53:681-8. [PMID: 11370707 DOI: 10.1211/0022357011775802] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Abstract
The effects of ruscogenin 1-O-[β-d-glucopyranosyl(1 → 2)] [β-d-xylopyranosyl(1 → 3)]-β-d-fucopyranoside (Lm-3) and its aglycone, ruscogenin, on liver injury induced in mice by delayed-type hypersensitivity to picryl chloride have been investigated. Lm-3 and ruscogenin significantly decreased liver injury when given during the effector phase of the delayed-type hypersensitivity reaction. The pretreatment of nonparenchymal cells, but not hepatocytes, with Lm-3 or ruscogenin in-vitro caused a concentration- and time-dependent inhibition against the damage. Lm-3 showed a stronger inhibition against the damage than ruscogenin (IC50: Lm-3 6.3 times 10−10 m, ruscogenin 3.9 times 10−7 m). However, neither Lm-3 nor ruscogenin blocked the hepatotoxic potential of CCl4, when used to pretreat hepatocytes. Moreover, Lm-3 and ruscogenin inhibited concanavalin A-induced lymphocyte proliferation only at high concentrations. These results suggested that Lm-3 and ruscogenin improved the immunological liver injury by selectively causing dysfunction of the liver-infiltrating cells rather than by protecting hepatocyte membranes. Such characteristics would be significant for treating immunologically related liver diseases as well as for developing new drugs.
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Affiliation(s)
- F Wu
- Department of Pharmacology for Chinese Materia Medica, China Pharmaceutical University, Nanjing
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Ferrari C, Mondelli M. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2009:835-857. [DOI: 10.1002/9780470747919.ch51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Franceschini D, Paroli M, Francavilla V, Videtta M, Morrone S, Labbadia G, Cerino A, Mondelli MU, Barnaba V. PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 2009; 119:551-64. [PMID: 19229109 DOI: 10.1172/jci36604] [Citation(s) in RCA: 255] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 01/07/2009] [Indexed: 12/22/2022] Open
Abstract
CD4+CD25+Foxp3+ Tregs suppress autoimmune responses. In addition, they limit T cell responses during chronic infection, thereby minimizing T cell-dependent immunopathology. We sought to investigate how Tregs are regulated in the livers of patients chronically infected with HCV, where they control the balance between an adequate protective immune response and suppression of immunopathology. We found that, despite accumulating and proliferating at sites of infection in the livers of patients chronically infected with HCV, Tregs were relatively less expanded than CD4+CD25+Foxp3- effector T cells. The relative lower expansion of intrahepatic Tregs coincided with their upregulation of programmed death-1 (PD-1). PD-1 expression inversely correlated with both Treg proliferation and clinical markers of immune suppression in vivo. Consistent with the possibility that PD-1 controls Tregs, blockade of the interaction between PD-1 and programmed death-1 ligand 1 (PD-L1) enhanced the in vitro expansion and function of Tregs isolated from the livers of patients chronically infected with HCV. Blockade of the interaction between PD-L1 and B7.1 also improved the proliferation of these cells. Interestingly, both PD-1 and phosphorylated STAT-5 were overexpressed in intrahepatic Tregs in a parallel fashion in steady disease conditions, and in an alternate-fluctuating fashion during the course of severe hepatitis reactivation. Notably, PD-L1 blockade upregulated STAT-5 phosphorylation in Tregs ex vivo. These data suggest that PD-L1 negatively regulates Tregs at sites of chronic inflammation by controlling STAT-5 phosphorylation.
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Affiliation(s)
- Debora Franceschini
- Dipartimento di Medicina Interna, Sapienza Università di Roma, Policlinico Umberto I, viale del Policlinico 155, Rome, Italy
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31
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Boonstra A, Woltman AM, Janssen HLA. Immunology of hepatitis B and hepatitis C virus infections. Best Pract Res Clin Gastroenterol 2008; 22:1049-61. [PMID: 19187866 DOI: 10.1016/j.bpg.2008.11.015] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis B (HBV) and hepatitis C (HCV) viruses are the two major causes of chronic liver inflammation worldwide. Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections also share some important features of the adaptive antiviral immune response. We describe the innate immune response in the early phase following infection, and how these early events may influence the development of the adaptive immune response in these two important viral infections. The mechanisms by which high levels of viral antigens, liver immunological features, the presence of regulatory T cells and impaired dendritic cell functions may maintain the HBV- and HCV-specific immunological failure, characteristic of chronic hepatitis B and C patients, are also evaluated.
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Affiliation(s)
- Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
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32
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Velu V, Saravanan S, Nandakumar S, Shankar EM, Vengatesan A, Jadhav SS, Kulkarni PS, Thyagarajan SP. Relationship between T-lymphocyte cytokine levels and sero-response to hepatitis B vaccines. World J Gastroenterol 2008; 14:3534-40. [PMID: 18567083 PMCID: PMC2716617 DOI: 10.3748/wjg.14.3534] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [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
AIM: To investigate the cellular defects by analyzing the (Th1/Th2) cytokine levels in vaccine responders and non-responders.
METHODS: Peripheral blood mononuclear cell (PBMC) from responders and non-responders were stimulated with or with out recombinant HBsAg or PHA. Broad spectrum of cytokines viz (Th1) IFN-γ, IL-2, TNF-α, IL-12 and (Th2) IL-10, IL-4 were measured after in vitro stimulation with recombinant HBsAg and were compared with respective antibody titers.
RESULTS: A significant decrease (P = 0.001) in Th1 and Th2 cytokines namely, IL-2, INF-γ, TNF-α and IL-10 in non-responders was observed. The level of IL-4 was not significant between the three groups. Furthermore, despite a strong Th1 and Th2 cytokine response, the level of IL-12 was elevated in high-responders compared to other groups (P = 0.001) and demonstrated a positive correlation with anti-HBs titers and Th1 cytokine response.
CONCLUSION: Our findings suggest that unresponsiveness to recombinant hepatitis B vaccines (rHB) is multifactorial, including specific failure of antigen presentation or the lack of both T helper Th1 and Th2 response.
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Chen Y, Mahato RI. siRNA pool targeting different sites of human hepatitis B surface antigen efficiently inhibits HBV infection. J Drug Target 2008; 16:140-8. [PMID: 18274934 PMCID: PMC2778861 DOI: 10.1080/10611860701878750] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The main objective was to determine whether a pool of small interfering RNAs (siRNAs) targeting different regions of hepatitis B virus surface antigen (HBsAg) efficiently inhibits hepatitis B virus (HBV) infection. siRNAs targeting different regions of HBsAg were transfected into HBV-producing HepG2.2.15 cells and at 72 h post-transfection, the culture medium was collected for ELISA to determine HBsAg, while total RNA was isolated from the cells for real-time PCR. Three siRNA sequences that efficiently inhibited HBV infection were converted into small hairpin RNAs (shRNAs) and then cloned into a single plasmid psiSTRIKE driven by a single U6 promoter. These shRNA expressing plasmids were tested for HBsAg gene silencing in HepG2.2.15 cells. A pool of siRNAs targeting HBsAg efficiently inhibited HBV replication and antigen expression when transfected into HepG2.2.15 cells, compared with the use of single siRNA. Similarly, the plasmid encoding three different shRNAs driven by a single U6 promoter was more effective in silencing HBsAg at DNA, mRNA and protein levels compared with the plasmid encoding single shRNA. No apoptotic change was observed in the cells when the plasmid was transfected at a dose of 0.5-2 microg/1 x 10(6) cells after complex formation with Lipofectamine LTX. Furthermore, transfection with siRNA or shRNA did not increase interferon-gamma (IFNs-gamma) release, suggesting no induction of IFN response. In conclusion, a pool of chemically synthesised siRNAs as well as the shRNA expression plasmid encoding multiple shRNAs targeting different regions of HBsAg showed high gene silencing in HepG2.2.15 cells.
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Affiliation(s)
- Yong Chen
- Huaian 4th People's Hospital, Jiangsu, China
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN TN38103-3308
| | - Ram I Mahato
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN TN38103-3308
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34
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Low dose revaccination induces robust protective anti-HBs antibody response in the majority of healthy non-responder neonates. Vaccine 2008; 26:269-76. [DOI: 10.1016/j.vaccine.2007.10.044] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2006] [Revised: 09/06/2007] [Accepted: 10/22/2007] [Indexed: 01/16/2023]
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35
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Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection. Nat Med 2007; 13:1431-9. [PMID: 18026114 DOI: 10.1038/nm1679] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2007] [Accepted: 10/08/2007] [Indexed: 12/20/2022]
Abstract
We found that the proteome of apoptotic T cells includes prominent fragments of cellular proteins generated by caspases and that a high proportion of distinct T cell epitopes in these fragments is recognized by CD8+ T cells during HIV infection. The frequencies of effector CD8+ T cells that are specific for apoptosis-dependent epitopes correlate with the frequency of circulating apoptotic CD4+ T cells in HIV-1-infected individuals. We propose that these self-reactive effector CD8+ T cells may contribute to the systemic immune activation during chronic HIV infection. The caspase-dependent cleavage of proteins associated with apoptotic cells has a key role in the induction of self-reactive CD8+ T cell responses, as the caspase-cleaved fragments are efficiently targeted to the processing machinery and are cross-presented by dendritic cells. These findings demonstrate a previously undescribed role for caspases in immunopathology.
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36
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Rallón NI, Soriano V, Benito JM. [Adaptive cell immune response against the hepatitis C virus infection]. Med Clin (Barc) 2007; 129:469-76. [PMID: 17953913 DOI: 10.1157/13111005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Hepatitis C virus (HCV) infects around 175 million people worldwide and is one of the leading causes of chronic liver disease. Less than one third of patients infected with HCV are able to spontaneously clear the virus during acute infection, while most patients evolve to chronic infection. Control of viral replication has been associated to the cellular component of the host immune response. It is not fully understood what distinguish a successful cellular immune response. An integral interpretation of the numerous experimental findings may allow a better understanding of the immune mechanisms involved in the inability of the immune system to successfully control chronic HCV infection.
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Affiliation(s)
- Norma Ibón Rallón
- Laboratorio de Biología Molecular, Servicio de Enfermedades Infecciosas, Hospital Carlos III, Madrid, España
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37
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Abstract
The need to quantitate and monitor immune responses of large patient cohorts with standardized techniques is increasing due to the growing range of treatment options for hepatitis B and hepatitis C, the development of combination therapies, and candidate experimental vaccines for HCV. In addition, advances in immunological techniques have provided new tools for detailed phenotypic and functional analysis of cellular immune responses. At present, there is substantial variation in laboratory protocols, reagents, controls and analysis and presentation of results. Standardization of immunological assays would therefore allow better comparison of results amongst individual laboratories and patient cohorts. The EASL-sponsored and AASLD-endorsed Monothematic Conference on Clinical Immunology in Viral Hepatitis was held at the University College London, United Kingdom, Oct 7-8, 2006 to bring together investigators with research experience in clinical immunology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections for in-depth discussion, critical evaluation and standardization of immunological assays. This report summarizes the information presented and discussed at the conference, but is not intended to represent a consensus statement. Our aim is to highlight topics and issues that were supported by general agreement and those that were controversial, as well as to provide suggestions for future work.
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Affiliation(s)
- Barbara Rehermann
- Immunology Section, Liver Diseases Branch NIDDK, National Institutes of Health, DHHS, 10 Center Drive, Room 9B16, Bethesda, MD 20892, USA.
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38
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Lapenta C, Santini SM, Spada M, Donati S, Urbani F, Accapezzato D, Franceschini D, Andreotti M, Barnaba V, Belardelli F. IFN-alpha-conditioned dendritic cells are highly efficient in inducing cross-priming CD8(+) T cells against exogenous viral antigens. Eur J Immunol 2006; 36:2046-60. [PMID: 16856207 DOI: 10.1002/eji.200535579] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Dendritic cells (DC) generated after a short-term exposure of monocytes to IFN-alpha and GM-CSF (IFN-DC) are highly effective in inducing cross-priming of CD8(+ )T cells against viral antigens. We have investigated the mechanisms responsible for the special attitude of these DC and compared their activity with that of reference DC. Antigen uptake and endosomal processing capabilities were similar for IFN-DC and IL-4-derived DC. Both DC types efficiently cross-presented soluble HCV NS3 protein to the specific CD8(+) T cell clone, even though IFN-DC were superior in cross-presenting low amounts of viral antigens. Moreover, when DC were pulsed with inactivated HIV-1 and injected into hu-PBL-SCID mice, the generation of virus-specific CD8(+ )T cells was markedly higher in animals immunized with IFN-DC than in mice immunized with CD40L-matured IL-4-DC. Of interest, in experiments with purified CD8(+ )T cells, IFN-DC were superior with respect to CD40L-matured IL-4-DC in inducing in vitro cross-priming of HIV-specific CD8(+ )T cells. This property correlated with enhanced potential to express the specific subunits of the IL-23 and IL-27 cytokines. These results suggest that IFN-DC are directly licensed for an efficient CD8(+) T cell priming by mechanisms likely involving enhanced antigen presentation and special attitude to produce IL-12 family cytokines.
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Affiliation(s)
- Caterina Lapenta
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
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39
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Wang W, Golding B. The cytotoxic T lymphocyte response against a protein antigen does not decrease the antibody response to that antigen although antigen-pulsed B cells can be targets. Immunol Lett 2006; 100:195-201. [PMID: 15916814 DOI: 10.1016/j.imlet.2005.04.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2005] [Accepted: 04/04/2005] [Indexed: 12/30/2022]
Abstract
The role of activated CD8+ T cells in shaping the dynamics of in vivo antigen presentation and immune responses is a subject receiving more attention. We studied whether cytotoxic T lymphocyte (CTL) would limit antibody responses by targeting antigen-specific B cells. A modified in vivo CTL assay was developed and used herein to demonstrate cytotoxicity in vivo, and to show that antigen-specific B cells that process exogenous antigen and present peptide in association with MHC class I can be the targets of CD8+ T cells. B cells from C57BL/6 mice immunized with ovalbumin (OVA)/alum were pulsed with OVA in vitro, and transferred into C57BL/6 recipient mice that had been immunized with vaccinia virus expressing SIINFEKL minigene to generate CD8+ CTL against K(b)/SIINFEKL. OVA-pulsed B220+ B cells from OVA-immunized mice were killed to a greater extent than B220+ B cells from naïve mice (28+/-20% versus 12+/-16%, p=0.0042). However, mice receiving vaccinia-SIINFEKL and generating CTL, did not appear to target endogenous B cells, since both primary and secondary antibody responses to OVA were unaffected. Our findings indicate that CTL responses to the protein antigen do not interfere with endogenous B cell responses, even though exogenous B cells expressing the CTL epitope can be efficiently lysed.
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Affiliation(s)
- Weila Wang
- Laboratory of Plasma Derivatives, Division of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Bethesda, MD 20892, USA.
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40
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Roohi A, Yazdani Y, Khoshnoodi J, Jazayeri SM, Carman WF, Chamankhah M, Rashedan M, Shokri F. Differential reactivity of mouse monoclonal anti-HBs antibodies with recombinant mutant HBs antigens. World J Gastroenterol 2006; 12:5368-74. [PMID: 16981270 PMCID: PMC4088207 DOI: 10.3748/wjg.v12.i33.5368] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the reactivity of a panel of 8 mouse anti-hepatitis B surface antigen (HBsAg) monoclonal antibodies (mAbs) using a collection of 9 recombinant HBsAg mutants with a variety of amino acid substitutions mostly located within the “a” region.
METHODS: The entire HBs genes previously cloned into a mammalian expression vector were transiently transfected into COS7 cells. Two standard unmutated sequences of the ayw and adw subtypes served as controls. Secreted mutant proteins were collected and measured by three commercial diagnostic immunoassays to assess transfection efficiency. Reactivity of anti-HBs mAbs with mutated HBsAgs was determined by sandwich enzyme-linked immunosorbent assay (ELISA).
RESULTS: Reactivity of anti-HBs mAbs with mutated HBsAgs revealed different patterns. While three mutants reacted strongly with all mAbs, two mutants reacted weakly with only two mAbs and the remaining proteins displayed variable degrees of reactivity towards different mAbs. Accordingly, four groups of mAbs with different but overlapping reactivity patterns could be envisaged. One group consisting of two mAbs (37C5-S7 and 35C6-S11) was found to recognize stable linear epitopes conserved in all mutants. Mutations outside the “a” determinant at positions 120 (P→S), 123(T→N) and 161 (M→T) were found to affect reactivity of these mAbs.
CONCLUSION: Our findings could have important implications for biophysical studies, vaccination strategies and immunotherapy of hepatitis B virus (HBV) mutants.
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Affiliation(s)
- Azam Roohi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, PO Box 6446-14133, Tehran, Iran
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41
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Baruah P, Propato A, Dumitriu IE, Rovere-Querini P, Russo V, Fontana R, Accapezzato D, Peri G, Mantovani A, Barnaba V, Manfredi AA. The pattern recognition receptor PTX3 is recruited at the synapse between dying and dendritic cells, and edits the cross-presentation of self, viral, and tumor antigens. Blood 2006; 107:151-8. [PMID: 16166594 DOI: 10.1182/blood-2005-03-1112] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Pentraxins are soluble pattern recognition receptors with a dual role: protection against extracellular microbes and autoimmunity. The mechanisms by which they accomplish these tasks are not yet fully understood. Here we show that the prototypic long pentraxin PTX3 is specifically recruited at both sides of the phagocytic synapse between dendritic cells (DCs) and dying cells and remains stably bound to the apoptotic membranes (estimated half-time > 36 hours). Apoptotic cells per se influence the production of PTX3 by maturing DCs. When both microbial stimuli and dying cells are present, PTX3 behaves as a flexible adaptor of DC function, regulating the maturation program and the secretion of soluble factors. Moreover a key event associated with autoimmunity (ie, the cross-presentation of epitopes expressed by apoptotic cells to T cells) abates in the presence of PTX3, as evaluated using self, viral, and tumor-associated model antigens (vinculin, NS3, and MelanA/MART1). In contrast, PTX3 did not influence the presentation of exogenous soluble antigens, an event required for immunity against extracellular pathogens. These data suggest that PTX3 acts as a third-party agent between microbial stimuli and dying cells, contributing to limit tissue damage under inflammatory conditions and the activation of autoreactive T cells.
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Affiliation(s)
- Paramita Baruah
- Cancer Immunotherapy & Gene Therapy Program, H San Raffaele Institute, Milan, Italy
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42
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Albarran B, Goncalves L, Salmen S, Borges L, Fields H, Soyano A, Montes H, Berrueta L. Profiles of NK, NKT cell activation and cytokine production following vaccination against hepatitis B. APMIS 2005; 113:526-35. [PMID: 16086823 DOI: 10.1111/j.1600-0463.2005.apm_191.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human natural killer (NK) cells (CD56+ CD3-) represent crucial components of the innate immune system especially against viral infections and because their activation can modulate the outcome of the adaptive immune response. NKT cells (CD56+CD3+), a lymphocyte T population characterized by expression of surface markers of NK cells, are known to be abundant in the liver and their activation could be associated with hepatic injury. Using three-color flow cytometry to measure surface receptors and intracellular cytokines, we have explored early activation signals and cytokine production in NK and NKT cells within a group of hepatitis B vaccinated and non-vaccinated individuals. A specific increase of the CD56bright cell population, the activation receptor CD69 and IFN-gamma, was observed in NK cells following incubation with recombinant HBsAg in responders to vaccination. Comparable results were observed in NKT cells showing an increment of CD69, CD25, IL-2 and IFN-gamma expression in responder subjects. These parameters were statistically diminished in non-responder individuals (p<0.05) in both groups of cells. These results demonstrate a diminished activation of these cells in non-responders to the vaccine, suggesting that NK and NKT cells play an important role in the immune response following hepatitis B vaccination.
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Affiliation(s)
- B Albarran
- Institute of Clinical Immunology, University of Los Andes, Merida, Venezuela
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43
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Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, Paroli M, Mondelli MU, Doria M, Torrisi MR, Barnaba V. Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. ACTA ACUST UNITED AC 2005; 202:817-28. [PMID: 16157687 PMCID: PMC2212941 DOI: 10.1084/jem.20051106] [Citation(s) in RCA: 180] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The presentation of exogenous protein antigens in a major histocompatibility complex class I–restricted fashion to CD8+ T cells is called cross-presentation. We demonstrate that cross-presentation of soluble viral antigens (derived from hepatitis C virus [HCV], hepatitis B virus [HBV], or human immunodeficiency virus) to specific CD8+ T cell clones is dramatically improved when antigen-presenting dendritic cells (DCs) are pulsed with the antigen in the presence of chloroquine or ammonium chloride, which reduce acidification of the endocytic system. The export of soluble antigen into the cytosol is considerably higher in chloroquine-treated than in untreated DCs, as detected by confocal microscopy of cultured cells and Western blot analysis comparing endocytic and cytosolic fractions. To pursue our findings in an in vivo setting, we boosted groups of HBV vaccine responder individuals with a further dose of hepatitis B envelope protein vaccine with or without a single dose of chloroquine. Although all individuals showed a boost in antibody titers to HBV, six of nine individuals who were administered chloroquine showed a substantial CD8+ T cell response to HBV antigen, whereas zero of eight without chloroquine lacked a CD8 response. Our results suggest that chloroquine treatment improves CD8 immunity during vaccination.
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Affiliation(s)
- Daniele Accapezzato
- Fondazione Andrea Cesalpino, Dipartimento di Medicina Interna, Università degli Studi di Roma La Sapienza, Rome, Italy
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Duan XZ, Wang M, Li HW, Zhuang H, Xu D, Wang FS. Decreased frequency and function of circulating plasmocytoid dendritic cells (pDC) in hepatitis B virus infected humans. J Clin Immunol 2005; 24:637-46. [PMID: 15622448 DOI: 10.1007/s10875-004-6249-y] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Type 2 precursor plasmacytoid dendritic cells (pDC) represent the most important cell type in antiviral innate immunity. To understand the function of pDC during hepatitis B virus infection, the frequency and function of circulating pDC were analyzed by flow cytometric analysis, and IFN-alpha secretion of total PBMCs was determined by ELISA assay in 25 healthy subjects and 116 patients at various stages of chronic hepatitis B virus infection (CHB). The number of circulating pDC was found to be significantly lower in patients with CHB and associated liver cirrhosis (LC). The ability of PBMCs to secrete IFN-alpha also decreased significantly. There was a corresponding decrease of circulating NK cells and CD8+ T cells. We observed that lamuvidine antiviral therapy restored the number of circulating pDC and there was a reversal of pDC frequency with the control of HBV replication in chronic HBV patients, indicating these subjects are unlikely to be totally immunocompromised. The decrease of pDC was found to be related to nosocomial infections in LC patients. Our results suggest that CHB patients probably have a quantitative and qualitative impairment of circulating pDC or NK cells, which may be associated with HBV persistent infection as well as the nosocomial infections that arise in LC patients.
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Affiliation(s)
- Xue-Zhang Duan
- Research Centre of Biological Therapy, Beijing Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, People's Republic of China
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45
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Castiglioni P, Gerloni M, Cortez-Gonzalez X, Zanetti M. CD8 T cell priming by B lymphocytes is CD4 help dependent. Eur J Immunol 2005; 35:1360-70. [PMID: 15816014 DOI: 10.1002/eji.200425530] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
While it is generally accepted that B lymphocytes can present antigen and activate CD4 T cells, priming of CD8 T cells by B lymphocytes remains controversial. Recently, we showed that mice injected with genetically programmed B lymphocytes generate antigen specific CD4 and CD8 T cell responses in vivo that could also be induced in mice lacking functional dendritic cells. To gain further insights into the requirements for T cell priming by antigen-presenting B lymphocytes, in vitro experiments were performed using ovalbumin (OVA) and OVA-specific TCR-transgenic CD4 and CD8 T cells. We found that while B lymphocytes can directly prime CD4 T cells, the activation of CD8 T cells requires T cell help. Transfer experiments show that help can either be contact dependent or be mediated by soluble factors in the supernatants of activated OVA-specific CD4 T cells. Furthermore, the effect of activated CD4 T cells can be replaced by soluble recombinant IL-4. Collectively, the data show the existence of different requirements for priming of CD4 and CD8 T cells and point to the previously unappreciated fact that the induction of CD8 T cell responses by B lymphocytes requires T cell help.
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Affiliation(s)
- Paola Castiglioni
- The Department of Medicine and Cancer Center, University of California in San Diego, La Jolla, USA
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46
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Kruger A, Adams P, Hammer J, Böcher WO, Schneider PM, Rittner C, Hoehler T. Hepatitis B surface antigen presentation and HLA-DRB1*- lessons from twins and peptide binding studies. Clin Exp Immunol 2005; 140:325-32. [PMID: 15807858 PMCID: PMC1809359 DOI: 10.1111/j.1365-2249.2005.02765.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
The aim of this study was to investigate the underlying mechanisms of the genetic association between certain HLA-DRB1* alleles and the immune response to HBsAg vaccination. Therefore, HBsAg peptide binding to HLA-DR molecules was measured in vitro by peptide binding ELISAs. Additionally, HBsAg-specific T cell reaction and cytokine profile of immune response were analysed ex vivo in ELISPOT assays and DR-restriction of T-cell proliferative responses was investigated with HBsAg specific T cell clones. In addition, we compared HBsAg specific T cell responses of 24 monozygotic and 3 dizygotic twin pairs after HBsAg vaccination. Our results showed that the peptide binding assays did not reflect antigen presentation in vivo. DR alleles associated with vaccination failure like DRB1*0301 and 0701 efficiently presented HBsAg peptides. In 11 of 24 investigated monozygotic twin pairs we observed pronounced differences in the recognition of HBsAg peptides. This study indicates that HLA-DR associations with HBsAg vaccination response are not caused by differences in peptide binding or by a shift in the Th1/Th2 profile. Our findings strongly argue for differences in the T cell recognition of peptide/MHC complexes as the critical event in T cell responsiveness to HBsAg.
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Affiliation(s)
- A Kruger
- Institute for Legal Medicine, Johannes Gutenberg University, Mainz, Germany.
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Pinschewer DD, Perez M, Jeetendra E, Bächi T, Horvath E, Hengartner H, Whitt MA, de la Torre JC, Zinkernagel RM. Kinetics of protective antibodies are determined by the viral surface antigen. J Clin Invest 2004; 114:988-93. [PMID: 15467838 PMCID: PMC518669 DOI: 10.1172/jci22374] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2004] [Accepted: 07/27/2004] [Indexed: 11/17/2022] Open
Abstract
Delayed and weak virus neutralizing antibody (nAb) responses represent a hallmark correlating not only with the establishment of persistent infection but also with unsuccessful vaccine development. Using a reverse genetic approach, we evaluated possible underlying mechanisms in 2 widely studied viral infection models. Swapping the glycoproteins (GPs) of lymphocytic choriomeningitis virus (LCMV, naturally persisting, noncytolytic, inefficient nAb inducer) and vesicular stomatitis virus (VSV, nonpersisting, cytolytic, potent nAb inducer) transferred the only target of nAb's from either virus to the other. We analyzed the nAb response to each of the 2 recombinant and parent viruses in infected mice and found that nAb kinetics were solely determined by the viral surface GP and not by the virus backbone. Moreover, the slowly and poorly nAb-triggering LCMV virion was a potent immunogenic matrix for the more antigenic VSV-GP. These findings indicate that the viral GP determines nAb kinetics largely independently of the specific viral infection context. They further suggest that structural features of viral GPs or coevolutionary adaptation of the virus's GP to the host's naive B cell repertoire, or both, may critically limit nAb kinetics and improvement of vaccine efficacy.
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Affiliation(s)
- Daniel D Pinschewer
- Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Zurich, Switzerland.
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48
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Pinschewer DD, Perez M, Jeetendra E, Bächi T, Horvath E, Hengartner H, Whitt MA, de la Torre JC, Zinkernagel RM. Kinetics of protective antibodies are determined by the viral surface antigen. J Clin Invest 2004. [DOI: 10.1172/jci200422374] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Goncalves L, Albarran B, Salmen S, Borges L, Fields H, Montes H, Soyano A, Diaz Y, Berrueta L. The nonresponse to hepatitis B vaccination is associated with impaired lymphocyte activation. Virology 2004; 326:20-8. [PMID: 15262491 DOI: 10.1016/j.virol.2004.04.042] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2004] [Revised: 03/15/2004] [Accepted: 04/30/2004] [Indexed: 01/01/2023]
Abstract
Nonresponsiveness against hepatitis B vaccination has been described in 4-10% of immunized subjects. We have explored the specific cell response to hepatitis B surface antigen by analyzing: PBMC proliferation, cytokine production (Th1, Th2 profiles, and TGF-beta), and activation molecules on Th cells. A poor proliferative response was demonstrated in nonresponders (P < 0.05). T cells from responders produced all tested cytokines (P < 0.01), in contrast with nonresponders subjects (P < 0.05). Expression of CD69 and CD25 was diminished in T cells from nonresponders (P < 0.01). A reduced expression of CD40L was also detected in T cells from nonresponders (P < 0.01). An elevated correlation coefficient was observed between CD40L on CD4+ cells and antibody production. These results suggest an overall inability of T cells to be activated which could be consistent with potential differences in antigen presentation. In conclusion, our results suggest that an altered Th response may be a consequence of inappropriate early activation events.
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Affiliation(s)
- Loredana Goncalves
- Institute of Clinical Immunology, University of Los Andes, Mérida, Venezuela
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50
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Accapezzato D, Francavilla V, Paroli M, Casciaro M, Chircu LV, Cividini A, Abrignani S, Mondelli MU, Barnaba V. Hepatic expansion of a virus-specific regulatory CD8(+) T cell population in chronic hepatitis C virus infection. J Clin Invest 2004. [PMID: 15057302 DOI: 10.1172/jci200420515] [Citation(s) in RCA: 228] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Regulatory T (T(R)) cells consist of phenotypically and functionally distinct CD4(+) and CD8(+) T cell subsets engaged both in maintaining self-tolerance and in preventing anti-non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host. Here we propose that the proinflammatory function of virus-specific memory effector CCR7(-)CD8(+) T cells, which are massively recruited in the liver, are inefficient (in terms of IFN-gamma production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus-specific CCR7(-)CD8(+) T(R) cells producing considerable amounts of IL-10. These CD8(+) T(R) cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T cell responses that are in turn restored by the addition of neutralizing anti-IL-10. This study provides for the first time to our knowledge direct evidence of the existence of virus-specific CD8(+) T(R) cells that infiltrate the livers of patients with chronic HCV infection, identifies IL-10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8(+) T cell responses.
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Affiliation(s)
- Daniele Accapezzato
- Fondazione Andrea Cesalpino, Dipartimento di Medicina Interna, Università degli Studi di Roma La Sapienza, Rome, Italy
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