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Selim MA, Suef RA, Saied E, Abdel-Maksoud MA, Almutairi SM, Aufy M, Mousa AA, Mansour MTM, Farag MMS. Peripheral NK cell phenotypic alteration and dysfunctional state post hepatitis B subviral particles stimulation in CHB patients: evading immune surveillance. Front Immunol 2024; 15:1427519. [PMID: 39328404 PMCID: PMC11424423 DOI: 10.3389/fimmu.2024.1427519] [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: 05/03/2024] [Accepted: 08/15/2024] [Indexed: 09/28/2024] Open
Abstract
Background The relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus. Methods NK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification. Results In CHB patients, in vitro exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 + NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors. Conclusion These findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.
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Affiliation(s)
- Mohamed A Selim
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Reda A Suef
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Ebrahim Saied
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Mostafa A Abdel-Maksoud
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Saeedah Musaed Almutairi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Aufy
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
| | - Adel A Mousa
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
| | - Mohamed T M Mansour
- Virology and Immunology Department, National Cancer Institute, Cairo University and Childern's Cancer Hospital, Cairo, Egypt
| | - Mohamed M S Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt
- Biomedical Research Department, Armed Forces College of Medicine (AFCM), Cairo, Egypt
- The Regional Centre for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
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2
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Shin SK, Oh S, Chun SK, Ahn MJ, Lee SM, Kim K, Kang H, Lee J, Shin SP, Lee J, Jung YK. Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma. J Gastroenterol Hepatol 2024; 39:1717-1727. [PMID: 38800890 DOI: 10.1111/jgh.16584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 03/14/2024] [Accepted: 04/11/2024] [Indexed: 05/29/2024]
Abstract
Natural killer (NK) cells are one of the key members of innate immunity that predominantly reside in the liver, potentiating immune responses against viral infections or malignant tumors. It has been reported that changes in cell numbers and function of NK cells are associated with the development and progression of chronic liver diseases (CLDs) including non-alcoholic fatty liver disease, alcoholic liver disease, and chronic viral hepatitis. Also, it is known that the crosstalk between NK cells and hepatic stellate cells plays an important role in liver fibrosis and cirrhosis. In particular, the impaired functions of NK cells observed in CLDs consequently contribute to occurrence and progression of hepatocellular carcinoma (HCC). Chronic infections by hepatitis B or C viruses counteract the anti-tumor immunity of the host by producing the sheddases. Soluble major histocompatibility complex class I polypeptide-related sequence A (sMICA), released from the cell surfaces by sheddases, disrupts the interaction and affects the function of NK cells. Recently, the MICA/B-NK stimulatory receptor NK group 2 member D (NKG2D) axis has been extensively studied in HCC. HCC patients with low membrane-bound MICA or high sMICA concentration have been associated with poor prognosis. Therefore, reversing the sMICA-mediated downregulation of NKG2D has been proposed as an attractive strategy to enhance both innate and adaptive immune responses against HCC. This review aims to summarize recent studies on NK cell immune signatures and its roles in CLD and hepatocellular carcinogenesis and discusses the therapeutic approaches of MICA/B-NKG2D-based or NK cell-based immunotherapy for HCC.
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Affiliation(s)
- Seung Kak Shin
- Division of Gastroenterology and Hepatology, Department of Internal medicine, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, South Korea
| | - Sooyeon Oh
- Chaum Life Center, School of Medicine, CHA University, Seoul, South Korea
| | - Su-Kyung Chun
- Chaum Life Center, School of Medicine, CHA University, Seoul, South Korea
| | - Min-Ji Ahn
- Center for Research and Development, CHA Advanced Research Institute, Seoul, South Korea
| | - Seung-Min Lee
- Center for Research and Development, CHA Advanced Research Institute, Seoul, South Korea
| | - Kayun Kim
- School of Medicine, CHA University, Seoul, South Korea
| | - Hogyeong Kang
- School of Medicine, CHA University, Seoul, South Korea
| | - Jeongwoo Lee
- School of Medicine, CHA University, Seoul, South Korea
| | - Suk Pyo Shin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Jooho Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, South Korea
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3
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Arai J, Okumura A, Kato N, Ito K. Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review. Hepatol Res 2024; 54:420-428. [PMID: 38536662 DOI: 10.1111/hepr.14038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/26/2024] [Accepted: 03/09/2024] [Indexed: 05/03/2024]
Abstract
The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%-50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.
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Affiliation(s)
- Jun Arai
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Akinori Okumura
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, Nagakute, Aichi, Japan
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4
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Hillaire MLB, Lawrence P, Lagrange B. IFN-γ: A Crucial Player in the Fight Against HBV Infection? Immune Netw 2023; 23:e30. [PMID: 37670813 PMCID: PMC10475827 DOI: 10.4110/in.2023.23.e30] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 05/04/2023] [Accepted: 05/21/2023] [Indexed: 09/07/2023] Open
Abstract
About 0.8 million people die because of hepatitis B virus (HBV) infection each year. In around 5% of infected adults, the immune system is ineffective in countering HBV infection, leading to chronic hepatitis B (CHB). CHB is associated with hepatocellular carcinoma, which can lead to patient death. Unfortunately, although current treatments against CHB allow control of HBV infection, they are unable to achieve complete eradication of the virus. Cytokines of the IFN family represent part of the innate immune system and are key players in virus elimination. IFN secretion induces the expression of interferon stimulated genes, producing proteins that have antiviral properties and that are essential to cell-autonomous immunity. IFN-α is commonly used as a therapeutic approach for CHB. In addition, IFN-γ has been identified as the main IFN family member responsible for HBV eradication during acute infection. In this review, we summarize the key evidence gained from cellular or animal models of HBV replication or infection concerning the potential anti-HBV roles of IFN-γ with a particular focus on some IFN-γ-inducible genes.
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Affiliation(s)
| | - Philip Lawrence
- Confluence: Sciences et Humanités (EA 1598), Université Catholique de Lyon, Lyon, France
| | - Brice Lagrange
- Confluence: Sciences et Humanités (EA 1598), Université Catholique de Lyon, Lyon, France
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5
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Lee DH, Chung SW, Lee JH, Kim HY, Chung GE, Kim MS, Yang BR, Nam JY, Lee YB, Kim YJ, Yoon JH. Association of Chronic Hepatitis B Infection and Antiviral Treatment With the Development of the Extrahepatic Malignancies: A Nationwide Cohort Study. J Clin Oncol 2022; 40:3394-3405. [PMID: 35561284 DOI: 10.1200/jco.21.01285] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Epidemiologic studies suggest that chronic hepatitis B (CHB) is a risk factor for various primary extrahepatic malignancies. Our aim was to evaluate the associations of CHB and nucleos(t)ide analog (NA) treatment with the risk of the development of extrahepatic malignancies. PATIENTS AND METHODS We conducted an 18-month landmark analysis using nationwide claims data from the National Health Insurance Service of South Korea. Patients newly diagnosed with CHB in 2012-2014 (n = 90,944) and matched-controls (n = 685,436) were included. Patients with CHB were further classified as the NA-treated (CHB+/NA+, n = 6,539) or the NA-untreated (CHB+/NA-, n = 84,405) group. Inverse probability of treatment weighting analysis was applied to balance the treatment groups. Time-varying Cox analysis was performed to evaluate time-varying effect of NA treatment. The primary outcome was the development of any primary extrahepatic malignancy. Development of intrahepatic malignancy and death were considered as competing events. RESULTS During the study period (median = 47.4 months), 30,413 patients (3.9%) developed any extrahepatic malignancy. The CHB+/NA- group had a higher overall risk of extrahepatic malignancy than the CHB+/NA+ group (adjusted subdistribution hazard ratio [aSHR] = 1.28; 95% CI, 1.12 to 1.45; P < .001) or controls (aSHR = 1.22; 95% CI, 1.18 to 1.26; P < .001). There was no difference in the risk of extrahepatic malignancy between the CHB+/NA+ group and the controls (CHB+/NA+ v control: aSHR = 0.96; 95% CI, 0.84 to 1.08; P = .48). In time-varying Cox analysis, the CHB+/NA- patients were associated with a higher risk of extrahepatic malignancy than the CHB+/NA+ patients (aSHR = 1.37; 95% CI, 1.23 to 1.52; P < .001). CONCLUSION Patients with CHB have an elevated risk of developing primary extrahepatic malignancy. Long-term NA treatment was associated with a lower risk of extrahepatic malignancy development among patients with CHB.
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Affiliation(s)
- Dong Hyeon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Sung Won Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Hwi Young Kim
- Department of Internal Medicine, Ewha Womans University Medical Center, Ewha Womans University College of Medicine, Seoul, South Korea
| | - Goh Eun Chung
- Department of Internal Medicine, Healthcare System Gangnam Center Seoul National University Hospital, Seoul, South Korea
| | - Mi-Sook Kim
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea
| | - Bo Ram Yang
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul, South Korea.,College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Joon Yeul Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
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6
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Zhang Y, Wu Y, Shen W, Wang B, Yuan X. Crosstalk between NK cells and hepatic stellate cells in liver fibrosis (Review). Mol Med Rep 2022; 25:208. [PMID: 35506449 PMCID: PMC9133963 DOI: 10.3892/mmr.2022.12724] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/19/2022] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis is a common pathological process of chronic liver diseases, including viral hepatitis and alcoholic liver disease, and ultimately progresses to irreversible cirrhosis and cancer. Hepatic stellate cells (HSCs) are activated to produce amounts of collagens in response to liver injury, thus triggering the initiation and progression of fibrogenesis. Natural killer (NK) cells serve as the essential component of hepatic innate immunity and are considered to alleviate fibrosis by killing activated HSCs. Current antifibrotic interventions have improved fibrosis, but fail to halt its progression in the advanced stage. Clarifying the interaction between NK cells and HSCs will provide clues to the pathogenesis and potential therapies for advanced liver fibrosis.
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Affiliation(s)
- Yang Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Yuan Wu
- The Graduate School, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Wenjuan Shen
- Department of Gynaecology, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Bingyu Wang
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
| | - Xingxing Yuan
- Department of Gastroenterology, Heilongjiang Academy of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China
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7
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Wang J, Hou H, Mao L, Wang F, Yu J, Luo Y, Lin Q, Sun Z. TIGIT Signaling Pathway Regulates Natural Killer Cell Function in Chronic Hepatitis B Virus Infection. Front Med (Lausanne) 2022; 8:816474. [PMID: 35265633 PMCID: PMC8898961 DOI: 10.3389/fmed.2021.816474] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/29/2021] [Indexed: 12/24/2022] Open
Abstract
Background and Objective Persistent infection of hepatitis B virus (HBV) and liver damage in immune active chronic hepatitis B (CHB) could be partly due to the overreaction of natural killer (NK) cells, including pro-inflammatory cytokine secretion and cytotoxicity. An immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine–based inhibitory motif (ITIM) domain (TIGIT) is specifically expressed in NK cells. This study aims to investigate the role of the TIGIT signaling pathway in regulating NK cell functions in patients with CHB. Method We comparatively assessed the expression of TIGIT in NK cells of patients with immune active CHB (CHB-IA), carriers of immune control chronic HBV (CHB-IC), and healthy controls (HCs), and then explored mechanisms of the TIGIT signaling pathway in regulating NK cell-mediated liver injury by different molecular assessments. Result The expression of TIGIT in NK cells was enhanced in CHB-IC but was reduced in CHB-IA compared with the HC group. In patients with CHB-IA, the expression of TIGIT was inversely correlated with intensity of the liver damage. Moreover, TIGIT-NK cells show higher IFN-γ secretion capability, degranulation activity, and cytotoxicity but lower apoptosis than TIGIT+ NK cells. Blockade of the TIGIT pathway with anti-TIGIT antibody increased NK cell function, while activation of the TIGIT pathway with TIGIT Fc and CD155 Fc chimera protein down-regulated NK cell function. Conclusion Our data showed that the TIGIT signaling pathway participates in NK cell impairment, which could be used as a new therapeutic target to protect patients with chronic HBV infection from severe liver injury.
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Affiliation(s)
- Juan Wang
- Department of Blood Transfusion, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyan Hou
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Lie Mao
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Wang
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yu
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Luo
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qun Lin
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ziyong Sun
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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8
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Jafarzadeh A, Naseri A, Shojaie L, Nemati M, Jafarzadeh S, Bannazadeh Baghi H, Hamblin MR, Akhlagh SA, Mirzaei H. MicroRNA-155 and antiviral immune responses. Int Immunopharmacol 2021; 101:108188. [PMID: 34626873 DOI: 10.1016/j.intimp.2021.108188] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/19/2021] [Accepted: 09/20/2021] [Indexed: 02/08/2023]
Abstract
The microRNA, miR-155 regulates both adaptive and innate immune responses. In viral infections, miR-155 can affect both innate immunity (interferon response, natural killer cell activity, and macrophage polarization) and adaptive immunity (including generation of anti-viral antibodies, CD8+ cytotoxic T lymphocytes, Th17, Th2, Th1, Tfh and Treg cells). In many viral infections, the proper and timely regulation of miR-155 expression is critical for the induction of an effective anti-virus immune response and viral clearance without any harmful immunopathologic consequences. MiR-155 may also exert pro-viral effects, mainly through the inhibition of the anti-viral interferon response. Thus, dysregulated expression of miR-155 can result in virus persistence and disruption of the normal response to viral infections. This review provides a thorough discussion of the role of miR-155 in immune responses and immunopathologic reactions during viral infections, and highlights its potential as a therapeutic target.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Alma Naseri
- Department of Immunology, Islamic Azadi university of Zahedan, Zahedan, Iran
| | - Layla Shojaie
- Research Center for Liver Diseases, Keck School of Medicine, Department of Medicine, University of Southern California, Los angeles, CA, USA
| | - Maryam Nemati
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Sara Jafarzadeh
- Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Hossein Bannazadeh Baghi
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | | | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
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Serum HBV pregenomic RNA exhibited opposite associations with NKdim and NKbright cell immunity in treatment-naïve chronic hepatitis B patients. Biosci Rep 2021; 41:229068. [PMID: 34151357 PMCID: PMC8255538 DOI: 10.1042/bsr20210600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 11/17/2022] Open
Abstract
Hepatitis B virus (HBV) pregenomic RNA (pgRNA) is a new biomarker that reflects HBV replication, but its relationship with natural killer (NK) cell immunity in chronic hepatitis B (CHB) is unknown. We assessed serum HBV pgRNA levels in 323 CHB patients by reverse transcription-polymerase chain reaction, assessed cytokine production and activation and inhibitory markers of NK cells by flow cytometry, and measured serum cytokines by enzyme-linked immunosorbent assays (ELISAs). Among the different CHB phases, the serum HBV pgRNA level was highest in the immune-tolerant (IT) and immune-active (IA) phases. Regarding NK and NKdim cells, HBV pgRNA was negatively associated with frequencies, but positively associated with NKp44 and NKp46 expression (activation markers). Regarding NKbright cells, serum HBV pgRNA was positively associated with frequency and programmed cell death protein 1 (PD1) expression (inhibitory marker), but negatively associated with NKp44 and NKp46. Serum HBV pgRNA was not associated with NKp30 (activation marker) on NK cells or subsets. Lastly, serum HBV pgRNA was positively correlated with the levels of serum IL-7 and IL-12P40 (NK cell-promoting cytokines) and negatively correlated with serum prostaglandin E2 (PGE2) level (which negatively regulates NK cells). In conclusion, we found varied relationships between serum HBV pgRNA and NK cells and subsets, indicating that HBV pgRNA may play a complicated role in NK cell-related immunity, providing new information on HBV and host immunity.
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10
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Wijaya RS, Read SA, Schibeci S, Han S, Azardaryany MK, van der Poorten D, Lin R, Yuen L, Lam V, Douglas MW, George J, Ahlenstiel G. Expansion of dysfunctional CD56-CD16+ NK cells in chronic hepatitis B patients. Liver Int 2021; 41:969-981. [PMID: 33411395 DOI: 10.1111/liv.14784] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 11/12/2020] [Accepted: 12/28/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Natural killer (NK) cells are primary innate effector cells that play an important role in the control of human viral infections. During chronic viral infection, NK cells undergo significant changes in phenotype, function and subset distribution, including the appearance of CD56-CD16+ (CD56-) NK cells, previously identified in chronic human immunodeficiency virus (HIV) and hepatitis C virus infection. However, the presence of CD56- NK cells in the pathogenesis of chronic hepatitis B (CHB) remains unknown. METHODS Phenotype and function of CD56- NK cells from patients with CHB (n = 28) were assessed using flow cytometry and in vitro stimulation with HBV antigen. RESULTS CHB patients had a higher frequency of CD56- NK cells compared to healthy controls in peripheral blood (6.2% vs 1.4%, P < .0001). Compared to CD56+ NK cells, CD56- NK cells had increased expression of inhibitory receptors, and reduced expression of activating receptors, as measured by MFI and qPCR. CD56- NK cells were less responsive to target cell and cytokine stimulation compared to their CD56+ counterparts. In addition, CD56- NK cells demonstrated defective dendritic cells (DCs) interactions resulting in reduced DCs maturation, lower expression of NK CD69 and impaired capacity of NK cells to eliminate immature DCs in co-culture studies. Finally, frequency of CD56- NK cells was positively correlated with serum HBV DNA levels. CONCLUSION Chronic HBV infection induces the expansion of highly dysfunctional of CD56- NK cells that likely contribute to inefficient innate and adaptive antiviral immune response in chronic HBV infection.
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Affiliation(s)
- Ratna S Wijaya
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.,Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia
| | - Scott A Read
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.,Blacktown Clinical School, Western Sydney University, Blacktown, NSW, Australia.,Blacktown Hospital, Blacktown, NSW, Australia
| | - Stephen Schibeci
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
| | - Shuanglin Han
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
| | - Mahmoud K Azardaryany
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia
| | | | - Rita Lin
- Westmead Hospital, University of Sydney, Westmead, NSW, Australia
| | - Lawrence Yuen
- Westmead Hospital, University of Sydney, Westmead, NSW, Australia.,Discipline of Surgery, University of Sydney, Westmead, NSW, Australia
| | - Vincent Lam
- Westmead Hospital, University of Sydney, Westmead, NSW, Australia.,Discipline of Surgery, University of Sydney, Westmead, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.,Westmead Hospital, University of Sydney, Westmead, NSW, Australia.,Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.,Westmead Hospital, University of Sydney, Westmead, NSW, Australia
| | - Golo Ahlenstiel
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.,Blacktown Clinical School, Western Sydney University, Blacktown, NSW, Australia.,Blacktown Hospital, Blacktown, NSW, Australia
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11
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Zhou Y, He Y, Chang Y, Peng X, Zhao R, Peng M, Hu P, Ren H, Chen M, Xu H. The Characteristics of Natural Killer Cells and T Cells Vary With the Natural History of Chronic Hepatitis B in Children. Front Pediatr 2021; 9:736023. [PMID: 34900857 PMCID: PMC8656424 DOI: 10.3389/fped.2021.736023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022] Open
Abstract
Background and Aims: The immune status of children with chronic hepatitis B (CHB) in different phases is still unclear. The aim of this study was to investigate the phenotype and cytokine-producing ability of natural killer (NK) and T cells and to better understand the immune characteristics of children with different phases of CHB. Methods: Treatment-naive children with CHB were divided into groups with different clinical phases of CHB. Fresh peripheral blood drawn from hepatitis B virus (HBV)-infected and healthy children was processed to perform flow cytometric analysis. Results: A total of 112 treatment-naive children with CHB and 16 comparable healthy controls were included in this study. The expression of HLA-DR on NK cells and CD38 on T cells were upregulated, especially in the IA phase, in children with CHB compared with healthy controls. The ability of circulating NK cells instead of CD8+ T cells to produce IFN-γ in children with CHB was slightly increased, but TNF-α production seemed to be decreased compared with that in healthy controls. The expression of some activation markers varied among children with different phases of CHB, especially the higher CD38 expression found on T cells in the IA phase. Regression analysis revealed that IFN-γ and TNF-α production by NK cells and CD8+ T cells seemed to have positive correlations with ALT elevation and an activated status of NK cells or T cells. Conclusion: NK cells and T cells tended to be phenotypically activated (especially in the IA phase) in children with CHB compared with healthy controls. However, their cytokine-producing function was not obviously elevated, especially IFN-γ production by CD8+ T cells. More studies investigating the mechanism and observing the longitudinal changes in the immune status in children with CHB are needed.
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Affiliation(s)
- Yingzhi Zhou
- Ministry of Education Key Laboratory of Child Development and Disorders, Department of Infection, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, Chongqing, China
| | - Yi He
- Ministry of Education Key Laboratory of Child Development and Disorders, Department of Infection, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, Chongqing, China
| | - Yunan Chang
- Ministry of Education Key Laboratory of Child Development and Disorders, Department of Infection, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, Chongqing, China
| | - Xiaorong Peng
- Ministry of Education Key Laboratory of Child Development and Disorders, Department of Infection, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, Chongqing, China
| | - Ruiqiu Zhao
- Ministry of Education Key Laboratory of Child Development and Disorders, Department of Infection, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- 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
| | - Peng Hu
- 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
| | - Hong Ren
- 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
| | - Min Chen
- 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
| | - Hongmei Xu
- Ministry of Education Key Laboratory of Child Development and Disorders, Department of Infection, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Child Infection and Immunity, Chongqing Medical University, Chongqing, China
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12
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Song T, Li L, Su B, Liu L, Liu Y, Yang X, Zhang Q, Guo N, Zhang T, Sun G, Wu H. NKG2C+ natural killer cell function improves the control of HBV replication in individuals with acute HIV infection coinfected with HBV. Medicine (Baltimore) 2020; 99:e20073. [PMID: 32358389 PMCID: PMC7440068 DOI: 10.1097/md.0000000000020073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Individuals infected with hepatitis B virus (HBV) are often coinfected with human immunodeficiency virus (HIV). However, individuals with chronic HBV infection living with acute HIV infection have a significantly lower HBV viral load, along with higher HBeAg and HBsAg loss than HBV-infected individuals alone. Here, we investigated the possible role of natural killer cells (NK cell) function in this progressive course to explore the relationship between phenotypic/functional changes in NK cells during acute HIV infection and HBV clearance in patients with HIV/HBV coinfection.Peripheral blood NK cells from 38 patients with primary HIV infection, including 20 with untreated HIV infection and 18 treatment-naïve patients with HIV/HBV coinfection and 16 patients with chronic HBV infection, were enrolled in this study.We found that the HIV/HBV-coinfected individuals had higher levels of NK cells than the HBV-infected individuals, due to expansion of the CD56 NK cell population. The proportion of NK cells in CD56 and CD56 NK subsets was not found significant difference between HIV/HBV-coinfected and HBV-infected individuals. However, NKG2C levels on NK cells and subsets were significantly higher in HIV/HBV-coinfected individuals than in HBV-infected individuals, whereas NKG2A levels were unaffected or decreased. In addition, the levels of degranulation CD107a, cytotoxicity and IFN-γ production of NK cells were increased in HIV/HBV-coinfected individuals than in HBV-infected individuals. The level of IL-10 production of NK cells was decreased in HIV/HBV-coinfected individuals than in HBV-infected individuals. Furthermore, the level of HBV-DNA was inversely correlated with the proportion of NKG2C and NKG2CNKG2A NK cells, while positively correlated with the proportion of NKG2A and NKG2CNKG2A NK cells. IFN-γ production was inversely correlated with levels of HBV-DNA, but the CD107a expression and IL-10 production of NK cells were not correlated with HBV-DNA levels.These results demonstrate that the upregulation of NKG2C expression, but not of NKG2A expression on the surface of NK cells increases cytolytic capacity and the amounts of cytokines produced and may play a crucial role in HBV clearance during HIV/HBV-coinfection.
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Affiliation(s)
- Ting Song
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Li Li
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Bin Su
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Lifeng Liu
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Yan Liu
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Xiaodong Yang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Qiuyue Zhang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Na Guo
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Tong Zhang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
| | - Guizhen Sun
- Department of Clinical Laboratory, Beijing Youan hospital, Capital Medical University, Beijing, China
| | - Hao Wu
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University
- Beijing Key Laboratory for HIV/AIDS Research
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13
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A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy. Cancers (Basel) 2020; 12:cancers12030745. [PMID: 32245188 PMCID: PMC7140088 DOI: 10.3390/cancers12030745] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/15/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023] Open
Abstract
The chemotherapeutics sorafenib and regorafenib inhibit shedding of MHC class I-related chain A (MICA) from hepatocellular carcinoma (HCC) cells by suppressing a disintegrin and metalloprotease 9 (ADAM9). MICA is a ligand for natural killer (NK) group 2 member D (NKG2D) and is expressed on tumor cells to elicit attack by NK cells. This study measured ADAM9 mRNA levels in blood samples of advanced HCC patients (n = 10). In newly diagnosed patients (n = 5), the plasma ADAM9 mRNA level was significantly higher than that in healthy controls (3.001 versus 1.00, p < 0.05). Among four patients treated with nivolumab therapy, two patients with clinical response to nivolumab showed significant decreases in fold changes of serum ADAM9 mRNA level from 573.98 to 262.58 and from 323.88 to 85.52 (p < 0.05); however, two patients with no response to nivolumab did not. Using the Cancer Genome Atlas database, we found that higher expression of ADAM9 in tumor tissues was associated with poorer survival of HCC patients (log-rank p = 0.00039), while ADAM10 and ADAM17 exhibited no such association. In addition, ADAM9 expression showed a positive correlation with the expression of inhibitory checkpoint molecules. This study, though small in sample size, clearly suggested that ADAM9 mRNA might serve as biomarker predicting clinical response and that the ADAM9-MICA-NKG2D system can be a good therapeutic target for HCC immunotherapy. Future studies are warranted to validate these findings.
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14
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Ganesan M, Eikenberry A, Poluektova LY, Kharbanda KK, Osna NA. Role of alcohol in pathogenesis of hepatitis B virus infection. World J Gastroenterol 2020; 26:883-903. [PMID: 32206001 PMCID: PMC7081008 DOI: 10.3748/wjg.v26.i9.883] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/09/2020] [Accepted: 02/15/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) and alcohol abuse often contribute to the development of end-stage liver disease. Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically. Importantly, the mechanism by which alcohol promotes the progression of HBV-associated liver disease are not completely understood. Potential mechanisms include a suppressed immune response, oxidative stress, endoplasmic reticulum and Golgi apparatus stresses, and increased HBV replication. Certainly, more research is necessary to gain a better understanding of these mechanisms such that treatment(s) to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed. In this review, we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Allison Eikenberry
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68105, United States
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15
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Fisicaro P, Rossi M, Vecchi A, Acerbi G, Barili V, Laccabue D, Montali I, Zecca A, Penna A, Missale G, Ferrari C, Boni C. The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy. Int J Mol Sci 2019; 20:ijms20205080. [PMID: 31614928 PMCID: PMC6834135 DOI: 10.3390/ijms20205080] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022] Open
Abstract
Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines and by exerting cytotoxic functions against virus-infected cells. However, in patients with chronic hepatitis B, NK cells have been described to be more pathogenic than protective with preserved cytolytic activity but with a poor capacity to produce anti-viral cytokines. In addition, NK cells can exert a regulatory activity and possibly suppress adaptive immune responses in the setting of persistent viral infections. Consequently, a potential drawback of NK-cell targeted modulatory interventions is that they can potentiate the suppressive NK cell effect on virus-specific T cells, which further causes impairment of exhausted anti-viral T cell functions. Thus, clinically useful NK-cell modulatory strategies should be not only suited to improve positive anti-viral NK cell functions but also to abrogate T cell suppression by NK cell-mediated T cell killing. This review outlines the main NK cell features with a particular focus on CHB infection. It describes different mechanisms involved in NK-T cell interplay as well as how NK cells can have positive anti-viral effector functions and negative suppressive effects on T cells activity. This review discusses how modulation of their balance can have potential therapeutic implications.
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Affiliation(s)
- Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Marzia Rossi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Greta Acerbi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Valeria Barili
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Diletta Laccabue
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Ilaria Montali
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Alessandra Zecca
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Gabriele Missale
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Carlo Ferrari
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
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16
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Wang WT, Zhao XQ, Li GP, Chen YZ, Wang L, Han MF, Li WN, Chen T, Chen G, Xu D, Ning Q, Zhao XP. Immune response pattern varies with the natural history of chronic hepatitis B. World J Gastroenterol 2019; 25:1950-1963. [PMID: 31086463 PMCID: PMC6487378 DOI: 10.3748/wjg.v25.i16.1950] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 03/12/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant (IT), immune active (IA), inactive carrier (IC) and hepatitis B envelope antigen (HBeAg)-negative hepatitis (ENEG).
AIM To investigate the immune status of natural killer (NK) and T cells in different phases of chronic hepatitis B.
METHODS The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus (HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.
RESULTS The ability of NK cells to produce IFN-γ was markedly attenuated in HBV-infected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEG phases, as evidenced by the upregulation of NKp44 in CD56bright NK cells and CD69 in CD56dim NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-α expression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.
CONCLUSION Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.
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Affiliation(s)
- Wen-Tao Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xue-Qi Zhao
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Gui-Ping Li
- Department of Heart Function Examination, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Yi-Zhi Chen
- Department of Pathophysiology, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Lin Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Mei-Fang Han
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wei-Na Li
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Tao Chen
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Guang Chen
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Dong Xu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Xi-Ping Zhao
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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17
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Li L, Wang L, Huang C, Diao L, Zhang Y, Zhang X, Xu J, Zeng Y. Chronic hepatitis B infection alters peripheral immune response in women with reproductive failure. Am J Reprod Immunol 2019; 81:e13083. [PMID: 30604518 DOI: 10.1111/aji.13083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/30/2018] [Accepted: 11/30/2018] [Indexed: 02/06/2023] Open
Abstract
PROBLEM Does hepatitis B infection affect peripheral blood immune response in women with reproductive failure? METHOD OF STUDY Two hundred and twenty-seven women, including 10 HBsAg+ HBeAg+ , 27 HBsAg+ HBeAg- hepatitis sero-positive women, and 190 women without HBV infection, formed the study population. Their peripheral immune responses containing lymphocyte subsets, cytokine production, expression of cell surface markers and intracellular toxicity molecules, and pregnancy outcomes were retrospectively compared. RESULTS Comparing with HBsAg+ HBeAg- carriers and HBsAg- group, HBsAg+ HBeAg+ group had lower rates of CD3+ CD4+ helper T cells (31.7% vs 38.0% and 36.8%, P < 0.05, respectively), but higher frequency of CD19+ B cells (17.8% vs 14.0% and 13.2%, P < 0.05 and P < 0.01, respectively). NK cells in HBsAg+ HBeAg+ patients showed lower cytotoxic activity than that in two other groups (P < 0.05). Comparing with HBsAg- patients, HBsAg+ HBeAg+ group exhibited decreased expression of the activating receptor NKG2D (56.2% vs 66.1%, P < 0.05), as well as reduced expression of granzyme B (54.8% vs 70.5%, P < 0.05), perforin (49.9% vs 65.0%, P < 0.05), and granulysin (52.0% vs 67.9%, P < 0.01). Generally, a higher clinical pregnancy rate (85.7% vs 56.9%) and higher early miscarriage rate (33.3% vs 20.3%) were noticed in HBsAg+ HBeAg+ group than HBsAg- group. CONCLUSION Chronic HBV infection alters peripheral immune responses by upregulating B-cell frequency, decreasing CD3+ CD4+ helper T cells, and decreasing peripheral NK function and toxicity. These may influence pregnancy outcome on HBV-infected patients, and the pathogenesis of HBV infection on pregnancy outcome deserves to be further studied.
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Affiliation(s)
- Longfei Li
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Linlin Wang
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Chunyu Huang
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Lianghui Diao
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Yongnu Zhang
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Xu Zhang
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Jian Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Yong Zeng
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
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18
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Golsaz-Shirazi F, Amiri MM, Shokri F. Immune function of plasmacytoid dendritic cells, natural killer cells, and their crosstalk in HBV infection. Rev Med Virol 2018; 28:e2007. [PMID: 30175481 DOI: 10.1002/rmv.2007] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 06/25/2018] [Accepted: 07/16/2018] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus infection is a major health problem, with over 245 million chronic carriers worldwide. This persistent infection is thought to be associated with inefficient innate and adaptive immune responses. Natural killer cells (NK cells) and plasmacytoid dendritic cells (pDCs) are the major innate immune cells which respond to viral infection at the early phase and are considered major components of the antiviral immune response. In this review, we summarize recent findings regarding the role of NK cells, pDCs, and their cross-talk in HBV infection and its chronicity. Although the data regarding the biological function of pDCs and NK cells in HBV infection is still controversial, many studies show that in chronic HBV infection, the cytotoxicity of NK cells is retained, while their capacity to secrete cytokines is strongly impaired. In addition, interferon-α production by pDCs is impaired during chronic HBV infection, and the virus interferes with pDC-NK cell interaction.
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Affiliation(s)
- Forough Golsaz-Shirazi
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Amiri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fazel Shokri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, Tehran, Iran
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19
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Cho H, Ahn H, Lee DH, Lee JH, Jung YJ, Chang Y, Nam JY, Cho YY, Lee DH, Cho EJ, Yu SJ, Lee JM, Kim YJ, Yoon JH. Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals. J Viral Hepat 2018; 25:707-717. [PMID: 29316069 DOI: 10.1111/jvh.12855] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 11/13/2017] [Indexed: 12/15/2022]
Abstract
Nucleos(t)ide analogues (NAs) have been shown to decrease the risk of hepatocellular carcinoma (HCC) recurrence. This study evaluated whether high-potency NAs (entecavir and tenofovir disoproxil fumarate [TDF]) reduce the risk of tumour recurrence more potently than low-potency NAs after curative treatment of hepatitis B virus (HBV)-related HCC. This study included 607 consecutive HBV-related HCC patients treated with surgical resection or radiofrequency ablation. The patients were categorized into three groups according to antiviral treatment: group A (no antiviral; n = 261), group B (low-potency NA; n = 90) and group C (high-potency NA; n = 256). The primary end-point was recurrence-free survival (RFS). During the duration of follow-up, the median RFS was 29.4, 25.1, and 88.2 months in groups A, B and C, respectively (P < .001, log-rank test). The multivariate Cox analysis indicated that group C had a significantly longer RFS than both group A (adjusted hazard ratio [HR] = 0.39, P < .001) and group B (adjusted HR = 0.47, P < .001). When baseline characteristics were balanced using inverse probability weighting, group C still had a significantly longer RFS than group A (adjusted HR = 0.46, P < .001) and group B (adjusted HR = 0.59, P = .007). Group C had significantly lower risk of viral breakthrough than group B (HR = 0.19, P < .001). Viral breakthrough was an independent risk factor for shorter RFS among groups B and C (adjusted HR = 2.03, P = .007, time-dependent Cox analysis). Antiviral agents with high genetic barrier to resistance (entecavir and TDF) reduced the risk of HCC recurrence compared with other antivirals and no antiviral treatment, especially in patients with high baseline viral load.
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Affiliation(s)
- H Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H Ahn
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - J-H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Jung
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - Y Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J Y Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y Y Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - D H Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - E J Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S J Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J M Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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20
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Li X, Zhou L, Gu L, Gu Y, Chen L, Lian Y, Huang Y. Veritable antiviral capacity of natural killer cells in chronic HBV infection: an argument for an earlier anti-virus treatment. J Transl Med 2017; 15:220. [PMID: 29089040 PMCID: PMC5663047 DOI: 10.1186/s12967-017-1318-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 10/17/2017] [Indexed: 12/15/2022] Open
Abstract
Background There is limited information on innate immunity, especially natural killer (NK) cell function, in different chronic hepatitis B (CHB) stages. Therefore, we examined whether the clinical staging strategy accurately reflects veritable NK cell immunity. Methods A total of 237 eligible CHB patients and 22 healthy controls were enrolled in our study. Demographic and clinical data were collected, and the CHB phases (immune active-IA, immune tolerant phase-IT, inactive CHB-IC, and grey zone-GZ) were classified according to the latest American Association for the Study of Liver Disease guidelines. Peripheral blood mononuclear cells from patients and healthy controls were tested for NK cell frequency, phenotype and function using flow cytometry. Results A significant decrease in activating receptor NKp44 and NKp46 expression and significant increase of exhaustion molecule Tim-3 expression were observed in NK cells from CHB patients. Reduced cytokine secretion and preserved or elevated cytotoxic function were also observed. Patients in the IT group exhibited comparable cytokine secretion and cytolytic capacity as age-matched IA patients. NK cell anti-viral functions were preserved in GZ patients. Some of the NK cell function in patients who were excluded from treatment by the current treatment guidelines was less compromised than patients who qualified for treatment. Conclusion Our findings provide evidence of veritable NK cell immunity during different natural history phases in treatment-naïve patients with chronic HBV Infection. Chronic HBV infection hindered NK cell function in CHB patients. However, the presumed IT and GZ statuses of CHB patients based on the clinical parameters may not accurately reflect the inner immune status of these patients and should be reconsidered. Some patients excluded from treatment by the current treatment guidelines may be able to be selected as candidates for treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1318-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaoyan Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
| | - Liang Zhou
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
| | - Yurong Gu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
| | - Lubiao Chen
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China
| | - Yuehua Huang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, China.
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21
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Ge J, Huang Z, Liu H, Chen J, Xie Z, Chen Z, Peng J, Sun J, Hou J, Zhang X. Lower Expression of MicroRNA-155 Contributes to Dysfunction of Natural Killer Cells in Patients with Chronic Hepatitis B. Front Immunol 2017; 8:1173. [PMID: 29018442 PMCID: PMC5614978 DOI: 10.3389/fimmu.2017.01173] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 09/05/2017] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs have been reported to be regulated in different ways in a variety of liver diseases. As a key modulator of cellular function in both innate and adaptive immunity, the role of miR-155 in chronic hepatitis B virus infection remains largely unknown. Here, we investigated the expression and function of miR-155 in chronic hepatitis B (CHB) patients. It was found that miR-155 expression in peripheral blood mononuclear cells (PBMCs) was lower in CHB patients than healthy controls (HC). Among CHB infection, immune-active (IA) patients with abnormal alanine aminotransferase (ALT) levels had relatively higher miR-155 expression in PBMCs and serum than immune-tolerant carriers, but were comparable to inactive carriers. Moreover, there was a positive correlation between miR-155 expression and ALT levels in CHB patients. Particularly, miR-155 expression in natural killer (NK) cells was significantly downregulated in IA patients compared with HC. Inversely, suppressor of cytokine signaling 1 (SOCS1), a target of miR-155, was upregulated in NK cells of IA patients. Overexpression of miR-155 in NK cells from IA patients led to a decrease in SOCS1 expression and an increase of IFN-γ production. Finally, accompanied by the normalization of ALT, miR-155 expression in PBMCs gradually decreased during telbivudine or peg-IFN-α-2a therapy. Interestingly, higher miR-155 expression at baseline was associated with better response to telbivudine therapy, but not peg-IFN-α-2a. In conclusion, our data suggested that miR-155 downregulation in NK cells of IA patients impaired IFN-γ production by targeting SOCS1, which may contribute to immune dysfunction during CHB infection. Additionally, baseline miR-155 expression could predict the treatment response to telbivudine therapy.
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Affiliation(s)
- Jun Ge
- 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
| | - Zuxiong Huang
- Department of Hepatology, Mengchao Haptobiliary Hospital of Fujian Medical University, Fuzhou, China.,Department of Hepatology, Affiliated Infectious Disease Hospital of Fujian Medical University, Fuzhou, China
| | - Hongyan Liu
- 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
| | - Jiehua Chen
- 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
| | - Zhanglian Xie
- 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
| | - Zide Chen
- 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
| | - Jie Peng
- 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
| | - Jian Sun
- 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
| | - 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
| | - Xiaoyong Zhang
- 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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22
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Di Bona D, Aiello A, Colomba C, Bilancia M, Accardi G, Rubino R, Giannitrapani L, Tuttolomondo A, Cascio A, Caiaffa MF, Rizzo S, Di Lorenzo G, Candore G, Duro G, Macchia L, Montalto G, Caruso C. KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection. J Viral Hepat 2017; 24:768-775. [PMID: 28211154 DOI: 10.1111/jvh.12698] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 02/04/2017] [Indexed: 12/12/2022]
Abstract
Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA-KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA-C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA-A-Bw4 and HLA-C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.
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Affiliation(s)
- D Di Bona
- Dipartimento dell'Emergenza e dei Trapianti d'Organo, Università di Bari Aldo Moro, Bari, Italy
| | - A Aiello
- Dipartimento di Biopatologia e Biotecnologie Mediche, Università di Palermo, Palermo, Italy
| | - C Colomba
- Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile "G. D'Alessandro", Università di Palermo, Palermo, Italy
| | - M Bilancia
- Dipartmento Jonico in Sistemi Giuridici ed Economici del Mediterraneo: Società, Ambiente, Culture, Università di Bari Aldo Moro, Bari, Italy
| | - G Accardi
- Dipartimento di Biopatologia e Biotecnologie Mediche, Università di Palermo, Palermo, Italy
| | - R Rubino
- Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile "G. D'Alessandro", Università di Palermo, Palermo, Italy
| | - L Giannitrapani
- Dipartimento BioMedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Palermo, Italy
| | - A Tuttolomondo
- Dipartimento BioMedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Palermo, Italy
| | - A Cascio
- Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile "G. D'Alessandro", Università di Palermo, Palermo, Italy
| | - M F Caiaffa
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Foggia, Foggia, Italy
| | - S Rizzo
- Unità Operativa di Medicina Trasfusionale, AOUP, Palermo, Italy
| | - G Di Lorenzo
- Dipartimento BioMedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Palermo, Italy
| | - G Candore
- Dipartimento di Biopatologia e Biotecnologie Mediche, Università di Palermo, Palermo, Italy.,Unità Operativa di Medicina Trasfusionale, AOUP, Palermo, Italy
| | - G Duro
- Istituto di Biomedicina ed Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Palermo, Italy
| | - L Macchia
- Dipartimento dell'Emergenza e dei Trapianti d'Organo, Università di Bari Aldo Moro, Bari, Italy
| | - G Montalto
- Dipartimento BioMedico di Medicina Interna e Specialistica, Università degli Studi di Palermo, Palermo, Italy
| | - C Caruso
- Dipartimento di Biopatologia e Biotecnologie Mediche, Università di Palermo, Palermo, Italy.,Unità Operativa di Medicina Trasfusionale, AOUP, Palermo, Italy
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- Dipartimento di Biopatologia e Biotecnologie Mediche, Università di Palermo, Palermo, Italy.,Unità Operativa di Medicina Trasfusionale, AOUP, Palermo, Italy
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23
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Carlomagno S, Falco M, Bono M, Alicata C, Garbarino L, Mazzocco M, Moretta L, Moretta A, Sivori S. KIR3DS1-Mediated Recognition of HLA-*B51: Modulation of KIR3DS1 Responsiveness by Self HLA-B Allotypes and Effect on NK Cell Licensing. Front Immunol 2017; 8:581. [PMID: 28603523 PMCID: PMC5445109 DOI: 10.3389/fimmu.2017.00581] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 05/01/2017] [Indexed: 12/24/2022] Open
Abstract
Several studies described an association between killer-cell immunoglobulin-like receptor (KIR)/HLA gene combinations and clinical outcomes in various diseases. In particular, an important combined role for KIR3DS1 and HLA-B Bw4-I80 in controlling viral infections and a higher protection against leukemic relapses in donor equipped with activating KIRs in haplo-HSCT has been described. Here, we show that KIR3DS1 mediates positive signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells and that this activation occurs only in Bw4-I80neg individuals, including those carrying particular KIR/HLA combination settings. In addition, killing of HLA-B*51 transfected target cells mediated by KIR3DS1+/NKG2A+ natural killer (NK) cell clones from Bw4-I80neg donors could be partially inhibited by antibody-mediated masking of KIR3DS1. Interestingly, KIR3DS1-mediated recognition of HLA-B*51 could be better appreciated under experimental conditions in which the function of NKG2D was reduced by mAb-mediated blocking. This experimental approach may mimic the compromised function of NKG2D occurring in certain viral infections. We also show that, in KIR3DS1+/NKG2A+ NK cell clones derived from an HLA-B Bw4-T80 donor carrying 2 KIR3DS1 gene copy numbers, the positive signal generated by the engagement of KIR3DS1 by HLA-B*51 resulted in a more efficient killing of HLA-B*51-transfected target cells. Moreover, in these clones, a direct correlation between KIR3DS1 and NKG2D surface density was detected, while the expression of NKp46 was inversely correlated with that of KIR3DS1. Finally, we analyzed KIR3DS1+/NKG2A+ NK cell clones from a HLA-B Bw4neg donor carrying cytoplasmic KIR3DL1. Although these clones expressed lower levels of surface KIR3DS1, they displayed responses comparable to those of NK cell clones derived from HLA-B Bw4neg donors that expressed surface KIR3DL1. Altogether these data suggest that, in particular KIR/HLA combinations, KIR3DS1 may play a role in the process of human NK cell education.
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Affiliation(s)
- Simona Carlomagno
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
| | | | - Maria Bono
- Istituto Giannina Gaslini, Genova, Italy
| | - Claudia Alicata
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.,Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
| | - Lucia Garbarino
- S.C. Laboratorio di Istocompatibilità e IBMDR, E.O. Ospedali Galliera, Genova, Italy
| | - Michela Mazzocco
- S.C. Laboratorio di Istocompatibilità e IBMDR, E.O. Ospedali Galliera, Genova, Italy
| | - Lorenzo Moretta
- Dipartimento di Immunologia, IRCCS Ospedale Bambin Gesù, Roma, Italy
| | - Alessandro Moretta
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.,Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
| | - Simona Sivori
- Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.,Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
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24
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NK cell phenotypic and functional shifts coincide with specific clinical phases in the natural history of chronic HBV infection. Antiviral Res 2017; 140:18-24. [DOI: 10.1016/j.antiviral.2017.01.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 12/03/2016] [Accepted: 01/10/2017] [Indexed: 12/23/2022]
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25
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Yoshioka T, Tatsumi T, Miyagi T, Mukai K, Nishio K, Nishio A, Yokoyama Y, Suda T, Kegasawa T, Shigekawa M, Hikita H, Sakamori R, Takehara T. Frequency and role of NKp46 and NKG2A in hepatitis B virus infection. PLoS One 2017; 12:e0174103. [PMID: 28328926 PMCID: PMC5362099 DOI: 10.1371/journal.pone.0174103] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 03/04/2017] [Indexed: 12/20/2022] Open
Abstract
Background and Aim Natural Killer (NK) cells are involved in the control of viral infection. However, the role of NK cells in chronic hepatitis B (CHB) remains unclear. This study investigated the frequencies and roles of NK cells in CHB, with a focus on activating receptor NKp46 and inhibitory receptor NKG2A. Patients/Method Peripheral blood lymphocytes were obtained from 71 CHB patients and 37 healthy subjects (HS). The expressions of NKp46 and NKG2A were analyzed using flow cytometry. The role of NKp46-ligand was assessed using an in vitro co-culture system. Cytotoxicity and IFN-γ production in NK cells were evaluated using RT-PCR and flow cytometry. Results CHB patients were classified into treatment-naïve patients with low HBV DNA titer (CHB-L; n = 28), high HBV DNA titer (CHB-H; n = 24) by the cut-off level of serum HBV DNA 4 log copies/ml, and patients receiving nucleos(t)ide analogue (CHB-NA; n = 19). The expressions of NKp46 and NKG2A were higher in CHB-H than in HS/CHB-L/CHB-NA. HepG2.2.15 had higher NKp46-ligand expression than HepG2. When NK cells from HS were co-cultured with HepG2.2.15, inhibition of the NKp46 and NKp46-ligand interaction by anti-NKp46 antibody significantly reduced cytolysis of HepG2.2.15 and IFN-γ production. However, those reductions were not observed in co-culture with HepG2. Additionally, NK cells that highly expressed NKp46 also highly expressed NKG2A (NKp46highNKG2Ahigh subset). The frequencies of NKp46highNKG2Ahigh subset in CHB-H were higher than those in HS/CHB-L/CHB-NA. Among treatment-naïve CHB patients, the frequencies of NKp46highNKG2Ahigh subset were positively correlated with serum ALT (P<0.01, r = 0.45) and HBV DNA (P<0.01, r = 0.59) levels. The expressions of Fas-L, STAT1, TRAIL and CD107a were higher and IFN-γ expression was lower in the NKp46highNKG2Ahigh subset than in the other subsets. Conclusion The NKp46 and NKp46-ligand interaction contributes to NK cell activation. A novel NK cell subset, the NKp46highNKG2Ahigh subset, may be associated with liver injury and HBV replication.
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Affiliation(s)
- Teppei Yoshioka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takuya Miyagi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kaori Mukai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kumiko Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshinobu Yokoyama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takahiro Suda
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tadashi Kegasawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Minoru Shigekawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail:
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26
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Koumbi L, Pollicino T, Raimondo G, Kumar N, Karayiannis P, Khakoo SI. Hepatitis B viral replication influences the expression of natural killer cell ligands. Ann Gastroenterol 2016; 29:348-357. [PMID: 27366037 PMCID: PMC4923822 DOI: 10.20524/aog.2016.0036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 03/28/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is accounting for over one million deaths annually due to immune-mediated chronic liver damage. Natural killer (NK) cells are abundant in the liver and contribute in HBV persistence. NK cytotoxic effects are controlled by signals from activating and inhibitory receptors. HBV may circumvent host antiviral immunity via the regulation of NK receptors and their ligands. We investigated the effect of viral replication and HBeAg mutations on NK mediators expression in the livers of chronic HBV (CHB) patients and in cell cultures. METHODS HBV monomers bearing hotspot mutations in the basal core promoter and precore region were transfected into HepG2 cells using a plasmid-free assay. Serum viremia and liver HBV RNA were measured in 19 CHB patients. The expression of HBV RNA and of NKG2D ligands, B7H6, DNAX accessory molecule-1, lectin-like transcript 1 (LLT1), LFA-1 and TRAIL was measured in the livers of CHB patients and transfected cells. RESULTS In general, high HBV replication in CHB patients and cell lines upregulated the mRNA of all NK cell ligands and particularly the inhibitory NK cell ligand, LLT1. The exception was the NKG2D ligand, MICA, that was significantly decreased in patients with high serum viremia and intrahepatic HBV RNA levels. CONCLUSIONS HBV replication has differential effects on NK cell ligands suggesting a potential escape mechanisms through up-regulation of LLT1 and down-regulation of MICA. A general trend towards upregulating NK cell ligands can be counteracted by decreasing MICA and hence weakening NK surveillance.
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Affiliation(s)
- Lemonica Koumbi
- Department of Medicine, Hepatology and Gastroenterology Section, Imperial College, St. Mary’s Campus, London, UK (Lemonia Koumbi, Naveenta Kumar)
| | - Teresa Pollicino
- Department of Pediatric, Gynecologic, Microbiologic, and Biomedical Sciences, University Hospital of Messina, Messina, Italy (Teresa Pollicino)
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy (Giovanni Raimondo)
| | - Naveenta Kumar
- Department of Medicine, Hepatology and Gastroenterology Section, Imperial College, St. Mary’s Campus, London, UK (Lemonia Koumbi, Naveenta Kumar)
| | - Peter Karayiannis
- University of Nicosia Medical School, Nicosia, Cyprus (Peter Karayiannis)
| | - Salim I. Khakoo
- Henry Welcome Laboratories, Southampton General Hospital, Southampton, UK (Salim I. Khakoo)
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Chávez-Blanco A, Chacón-Salinas R, Dominguez-Gomez G, Gonzalez-Fierro A, Perez-Cardenas E, Taja-Chayeb L, Trejo-Becerril C, Duenas-Gonzalez A. Viral inhibitors of NKG2D ligands for tumor surveillance. Expert Opin Ther Targets 2016; 20:1375-1387. [PMID: 27322108 DOI: 10.1080/14728222.2016.1202928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Natural Killer cells (NK) are key for the innate immune response against tumors and viral infections. Several viral proteins evade host immune response and target the NK cell receptor NKG2D and its ligands. Areas covered: This review aimed to describe the viruses and their proteins that interfere with the NKG2D receptor and their ligands, and how these interactions lead to immune evasion, host protection, and tissue damage from acute and chronic viral infections. Expert opinion: The study of viral proteins has already impacted the field of oncology. A prime example is the HBV vaccine and the development of antiviral drugs for HIV, Hepatitis C, and the family of Herpesviridae viruses. The NKG2D system seems to be a rational therapeutic target. Nevertheless, an effective cytotoxic response by NK cells is mediated by a network of activating and inhibitory receptors, the integration of which determines if the NK cell becomes cytotoxic or permissive. Immunotherapeutic agents that increase the antitumor lytic activity of NK cells through modulating activation and inhibitory signaling of NK cells are being developed. Nevertheless, more research is needed to dissect the integrative mechanism of NK cells function to fully exploit their antitumor and antiviral effector mechanisms.
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Affiliation(s)
- Alma Chávez-Blanco
- a Division of Basic Research , Instituto Nacional de Cancerología , Mexico City , Mexico
| | - Rommel Chacón-Salinas
- b Departamento de Inmunología , Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN , Mexico City , México
| | | | - Aurora Gonzalez-Fierro
- a Division of Basic Research , Instituto Nacional de Cancerología , Mexico City , Mexico
| | - Enrique Perez-Cardenas
- a Division of Basic Research , Instituto Nacional de Cancerología , Mexico City , Mexico
| | - Lucia Taja-Chayeb
- a Division of Basic Research , Instituto Nacional de Cancerología , Mexico City , Mexico
| | | | - Alfonso Duenas-Gonzalez
- c Unidad de Investigacion Biomedica en Cancer , Instituto de Investigaciones Biomédicas UNAM/Instituto Nacional de Cancerología , Mexico City , Mexico.,d Unidad de Investigacion Basica Aplicada , ISSEMyM Cancer Center , Toluca , Mexico
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Kao WY, Yang SH, Liu WJ, Yeh MY, Lin CL, Liu CJ, Huang CJ, Lin SM, Lee SD, Chen PJ, Yu MW. Genome-wide identification of blood DNA methylation patterns associated with early-onset hepatocellular carcinoma development in hepatitis B carriers. Mol Carcinog 2016; 56:425-435. [PMID: 27254796 DOI: 10.1002/mc.22505] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 04/25/2016] [Accepted: 05/31/2016] [Indexed: 01/26/2023]
Abstract
The etiology of early-onset hepatocellular carcinoma (HCC) among hepatitis B virus (HBV) carriers remains unclear. DNA methylation levels in peripheral leukocytes have been associated with different environmental exposures and immune or inflammatory response. We aimed to identify methylation signatures of peripheral leukocytes that could track hepatitis B progression to HCC, especially for early-onset HCC. We first performed an epigenome-wide association analysis on 48 matched case-control pairs in a nested case-control study within a 22-yr follow-up cohort of HBV carriers. Through this analysis we found that progression to early-onset HCC involved methylation variable positions across the genome, in which a substantial proportion displayed significant variation due to HBV viral load, chronic hepatitis status, and/or leukocyte subtype composition, and these associations were significantly enriched among genes in immune pathways. Methylation at probes cg00300879, cg06872964, and cg07080864, that are located within the proximal promoter of CNKSR1, IFI44L, and PENK, respectively, was validated by bisulfite pyrosequencing and findings were replicated in a case-sibling study of early-onset HCC (134 cases vs. 174 sibling controls). Furthermore, a high methylation score, constructed using the three probes, was predictive for the risk of early-onset HCC in two datasets (adjusted-odds ratios = 0.21-0.32, P ≤ 0.0206). This association was also observed for late-onset HCC (adjusted-odds ratio = 0.42-0.47, P ≤ 0.0194) in a nested case-control study (120 cases vs. 178 controls). In prospective analysis, change in the score was detected 5-9 yr before HCC onset. Blood-based methylation profiling provides new insights into the complexity of virus-host interaction underlying HBV-related HCC, holding promise for the disease risk management. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Wei-Yi Kao
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Shu-Han Yang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Wen-Jie Liu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Meng-Yin Yeh
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chi-Jung Huang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Shi-Ming Lin
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Whei Yu
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
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Ghosh S, Nandi M, Pal S, Mukhopadhyay D, Chakraborty BC, Khatun M, Bhowmick D, Mondal RK, Das S, Das K, Ghosh R, Banerjee S, Santra A, Chatterjee M, Chowdhury A, Datta S. Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigen-negative chronic hepatitis B virus infection. Clin Microbiol Infect 2016; 22:733.e9-733.e19. [PMID: 27208430 DOI: 10.1016/j.cmi.2016.05.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/05/2016] [Accepted: 05/09/2016] [Indexed: 12/13/2022]
Abstract
Hepatitis B e-antigen negative (e(-)) chronic HBV infection (CHI) encompasses a heterogeneous clinical spectrum ranging from inactive carrier (IC) state to e(-) chronic hepatitis B (CHB), cirrhosis and hepatic decompensation. In the backdrop of dysfunctional virus-specific T cells, natural killer (NK) cells are emerging as innate effectors in CHI. We characterized CD3(-) CD56(+) NK cells in clinically well-defined, treatment-naive e(-) patients in IC, e(-)CHB or decompensated liver cirrhosis (LC) phase to appraise their role in disease progression. The NK cell frequencies increased progressively with disease severity (IC 8.2%, e(-)CHB 13.2% and LC 14.4%). Higher proportion of NK cells from LC/e(-)CHB expressed CD69, NKp46, NKp44, TRAIL and perforin, the last two being prominent features of CD56(bright) and CD56(dim) NK subsets, respectively. The frequencies of CD3(-) CD56(+) NK cells together with TRAIL(+) CD56(bright) and Perforin(+) CD56(dim) NK cells correlated positively with serum alanine transaminase levels in e(-)CHB/LC. K562 cell-stimulated NK cells from e(-)CHB/LC exhibited significantly greater degranulation but diminished interferon-γ production than IC. Further, Perforin(+) NK cell frequency inversely correlated with autologous CD4(+) T-cell count in e(-) patients and ligands of NK receptors were over-expressed in CD4(+) T cells from e(-)CHB/LC relative to IC. Co-culture of sorted CD56(dim) NK cells and CD4(+) T cells from e(-)CHB showed enhanced CD4(+) T-cell apoptosis, which was reduced by perforin inhibitor, concanamycin A, suggesting a possible perforin-dependent NK cell-mediated CD4(+) T-cell depletion. Moreover, greater incidence of perforin-expressing NK cells and decline in CD4(+) T cells were noticed intrahepatically in e(-)CHB than IC. Collectively, NK cells contribute to the progression of e(-)CHI by enhanced TRAIL- and perforin-dependent cytolytic activity and by restraining anti-viral immunity through reduced interferon-γ secretion and perforin-mediated CD4(+) T-cell lysis.
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Affiliation(s)
- S Ghosh
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - M Nandi
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - S Pal
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - D Mukhopadhyay
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - B C Chakraborty
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - M Khatun
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - D Bhowmick
- CU-BD Centre of Excellence for Nanobiotechnology, Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, India
| | - R K Mondal
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - S Das
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - K Das
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - R Ghosh
- Division of Gastrointestinal and Liver Pathology, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - S Banerjee
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - A Santra
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - M Chatterjee
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - A Chowdhury
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - S Datta
- Department of Hepatology and Centre for Liver Research, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
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Zhou P, Zhong XZ, Liao HH. New immunotherapy strategies for antiviral treatment of chronic hepatitis B. Shijie Huaren Xiaohua Zazhi 2016; 24:1832-1839. [DOI: 10.11569/wcjd.v24.i12.1832] [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
At present, chronic hepatitis B (CHB) is treated with nucleoside analogues and interferon-α (IFN-α), which can achieve good clinical effects, but cannot completely cure CHB. Main reasons are the immune tolerance or immune failure in the body's immune system, and the persistence of covalently closed circular DNA (cccDNA) in HBV infected hepatocytes. Therefore, the development of antiviral drugs which can completely eliminate cccDNA and of immunotherapy strategies to break the immune tolerance and reactivate the immune system is of clinical significance for curing CHB. This review focuses on recent progress in research of immune therapeutic strategies for CHB, such as lymphotoxin β receptor (LT-βR) agonists, therapeutic vaccines, Toll-like receptor (TLR) agonists, programmed death 1 (PD-1) blockade, genetically engineered T cells, interleukin (IL)-12 and so on.
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Santos JC, de Deus DMV, de Moura IMF, Lopes EP, Alves MRB, Coêlho MRCD. Association between the IFNA1 (-2Cx2192;T) Polymorphism and Increased IFNAR1 Gene Expression Levels in Chronic Hepatitis B Infection. Intervirology 2016; 58:393-402. [PMID: 27101083 DOI: 10.1159/000444365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 01/31/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Single nucleotide polymorphisms and variant expression of some interferon (IFN) genes in individuals with chronic hepatitis B virus (HBV) infection might be related to higher viral load and disease complications. Thereby, whole blood samples of 208 patients (94 chronic HBV-infected patients and 114 HBV immune subjects) were analyzed to investigate the association between IFNG (-5Ax2192;G), IFNA1 (-2Cx2192;T) and IFNAR1 (-97Tx2192;C) genes with their expression levels and HBV viral load. METHODS Genotyping was performed by high-resolution melting analysis with quantitative PCR (qPCR). Viral load quantification and gene expression were also carried out using qPCR. RESULTS Chronic HBV-infected subjects with IFNA1 CT genotype and T allele were more likely to develop protection against HBV when compared to immune subjects with wild-type genotype (IFNA1 CT/CC: OR = 0.45, p = 0.01, and T/C allele: OR = 0.55; p < 0.01). In patients with IFNAR1 wild-type TT genotype, the expression levels of this receptor may explain the lower viral load (r(2) = 0.40; p = 0.04) and protection against chronic infection. CONCLUSIONS These findings suggest that the polymorphic variant of IFNA1 (-2) gene is associated with chronic HBV infection, and high expression levels of the IFNAR1 gene and low levels of IFNA1 might contribute to the pathogenesis of chronic infection in these subjects.
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Affiliation(s)
- Joelma Carvalho Santos
- Postgraduate Program in Tropical Medicine, Center for Health Sciences, Universidade Federal de Pernambuco (UFPE), Recife, Brazil
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Liu Y, Gao LF, Liang XH, Ma CH. Role of Tim-3 in hepatitis B virus infection: An overview. World J Gastroenterol 2016; 22:2294-2303. [PMID: 26900291 PMCID: PMC4735003 DOI: 10.3748/wjg.v22.i7.2294] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Revised: 10/08/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection has received increasing public attention. HBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the above-mentioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of HBV-related liver disease and suggest new therapeutic methods for intervention.
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33
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Zhang QF, Shao JY, Yin WW, Xia Y, Chen L, Wang X, Hu HD, Hu P, Ren H, Zhang DZ. Altered Immune Profiles of Natural Killer Cells in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0160171. [PMID: 27513564 PMCID: PMC4981347 DOI: 10.1371/journal.pone.0160171] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 07/14/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells are the main effective component of the innate immune system that responds to chronic hepatitis B (CHB) infection. Although numerous studies have reported the immune profiles of NK cells in CHB patients, they are limited by inconsistent results. Thus, we performed a meta-analysis to characterize reliably the immune profiles of NK cells after CHB infection, specifically frequency, phenotype, and function. METHODS A literature search of the computer databases MEDLINE, PUBMED, EMBASE, and Cochrane Center Register of Controlled Trails was performed and 19 studies were selected. The standard mean difference (SMD) and 95% confidence interval (CI) of each continuous variable was estimated with a fixed effects model when I2 < 50% for the test for heterogeneity, or the random effects model otherwise. Publication bias was evaluated using Begg's and Egger's tests. RESULTS The meta-analysis of publications that reported frequency of peripheral NK cells showed that NK cell levels in CHB patients were significantly lower compared with that of healthy controls. A higher frequency of CD56bright NK subsets was found in CHB patients, but the CD56dim NK subsets of CHB patients and healthy controls were similar. CHB patients before and after antiviral therapy with nucleotide analogues (NUCs) showed no statistical difference in NK frequency. The activating receptors were upregulated, whereas inhibitory receptors were comparable in the peripheral NK cells of CHB individuals and healthy controls. NK cells of CHB patients displayed higher cytotoxic potency as evidenced by CD107a protein levels and conserved potency to produce interferon-gamma (IFNγ), compared with their healthy counterparts. CONCLUSION Our results revealed that CHB patients had a lower frequency of NK cells compared with healthy individuals not treatable with antiviral NUC therapy. With an activating phenotype, NK cells in CHB patients showed better cytotoxic potency and conserved IFNγ production.
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Affiliation(s)
- Qiong-Fang Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Jian-Ying Shao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Wen-Wei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Yang Xia
- Department of Urinary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqiong, China
| | - Ling Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Xing Wang
- Department of Orthopedic Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqiong, China
| | - Huai-Dong Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Da-Zhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
- * E-mail:
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Li HJ, Zhai NC, Song HX, Yang Y, Cui A, Li TY, Tu ZK. The Role of Immune Cells in Chronic HBV Infection. J Clin Transl Hepatol 2015; 3:277-83. [PMID: 26807384 PMCID: PMC4721896 DOI: 10.14218/jcth.2015.00026] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 10/20/2015] [Accepted: 10/28/2015] [Indexed: 12/20/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases that may progress to liver cirrhosis and hepatocellular carcinoma. Host immune responses are important factors that determine whether HBV infection is cleared or persists. After infection, viral replication occurs inside hepatocytes, and the secretion of infectious virions can take place at high rates for decades. Consequently, HBV DNA and viral proteins, like HBV early antigen (HBeAg) and HBV surface antigen (HBsAg), can be easily detected in serum. Chronic infection with HBV is the result of an ineffective antiviral immune response towards the virus. In this review, we discuss the role of immune cells in chronic HBV infection.
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Affiliation(s)
- Hai-Jun Li
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Nai-Cui Zhai
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Hong-Xiao Song
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Yang Yang
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
| | - An Cui
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Tian-Yang Li
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
| | - Zheng-Kun Tu
- Department of Translational Medicine, The First Hospital, Jilin University, Changchun, Jilin, China
- Correspondence to: Zheng-Kun Tu, The First Hospital, Jilin University, Changchun 130061, Jilin, China. Tel: +86-0431-88783044, Fax: +86-0431-88783044, E-mail:
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35
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Zhang E, Kosinska A, Lu M, Yan H, Roggendorf M. Current status of immunomodulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: Search for the "magic bullet" to kill cccDNA. Antiviral Res 2015; 123:193-203. [PMID: 26476376 DOI: 10.1016/j.antiviral.2015.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/09/2015] [Accepted: 10/09/2015] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B (CHB) is currently treated with IFN-α and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus-specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis".
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Affiliation(s)
- Ejuan Zhang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Anna Kosinska
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Huimin Yan
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Michael Roggendorf
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
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Wu SF, Wang WJ, Gao YQ. Natural killer cells in hepatitis B virus infection. Braz J Infect Dis 2015; 19:417-25. [PMID: 26119852 PMCID: PMC9427491 DOI: 10.1016/j.bjid.2015.05.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Revised: 05/02/2015] [Accepted: 05/05/2015] [Indexed: 12/21/2022] Open
Abstract
Natural killer cells are a unique type of lymphocytes with cytotoxic capacity, and play important roles against tumors and infections. Recently, natural killer cells have been increasingly valued in their effects in hepatitis B virus infection. Since hepatitis B virus is not cytopathic, the subsequent antiviral immune responses of the host are responsible for sustaining the liver injury, which may result in cirrhosis and even hepatocellular carcinoma. Many studies have confirmed that natural killer cells participate in anti-hepatitis B virus responses both in the early phase after infection and in the chronic phase via cytolysis, degranulation, and cytokine secretion. However, natural killer cells play dichotomic roles: they exert antiviral and immunoregulatory functions whilst contribute to the pathogenesis of liver injury. Here, we review the roles of natural killer cells in hepatitis B virus infection, introducing novel therapeutic strategies for controlling hepatitis B virus infection via the modulation of natural killer cells.
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Affiliation(s)
- Shao-fei Wu
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-jing Wang
- Department of Gynecology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue-qiu Gao
- Department of Hepatopathy, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Pollicino T, Koumbi L. Role natural killer group 2D-ligand interactions in hepatitis B infection. World J Hepatol 2015; 7:819-824. [PMID: 25937859 PMCID: PMC4411524 DOI: 10.4254/wjh.v7.i6.819] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 02/17/2015] [Accepted: 03/16/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is the leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide, in spite of prophylactic vaccination and antiviral treatment modalities. The immunopathogenesis of HBV infection has been intensively studied and is propelled by complex interactions between the virus and the host immune system. Natural killer group 2D (NKG2D) is a well-characterized activating receptor, expressed on natural killer (NK) cells, NK T cells and CD8(+) cytotoxic T cells. This receptor is present in both humans and mice and binds to a diverge family of ligands that resemble the MHC-class I molecules. Increasing evidence shows that NKG2D-ligand interactions are critical in the establishment of HBV persistence and the development of liver injury and HCC. The expression of NKG2D ligands depends on the presence of several polymorphisms and is also modulated post-transcriptionally by HBV. While it is known that HBV circumvents host's innate immunity via the NKG2D pathway but the exact mechanisms involved are still elusive. This letter discusses previous accomplishments on the role of NKG2D ligand regulation in the development of chronic HBV, liver injury and HCC.
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Affiliation(s)
- Teresa Pollicino
- Teresa Pollicino, Department of Pediatric, Gynecologic, Microbiologic, and Biomedical Sciences, University Hospital of Messina, 98124 Messina, Italy
| | - Lemonica Koumbi
- Teresa Pollicino, Department of Pediatric, Gynecologic, Microbiologic, and Biomedical Sciences, University Hospital of Messina, 98124 Messina, Italy
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Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death globally. Above well-known risk factors for HCC development ranging from various toxins to diseases such as diabetes mellitus, chronic infection with hepatitis B virus and hepatitis C virus (HCV) poses the most serious threat, constituting the cause in more than 80 % of cases. In addition to the viral genes intensively investigated, the pathophysiological importance of host genetic factors has also been greatly and increasingly appreciated. Genome-wide association studies (GWAS) comprehensively search the host genome at the single-nucleotide level, and have successfully identified the genomic region associated with a whole variety of diseases. With respect to HCC, there have been reports from several groups on single nucleotide polymorphisms (SNPs) associated with hepatocarcinogenesis, among which was our GWAS discovering MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for HCV-induced HCC. MICA is a natural killer (NK) group 2D (NKG2D) ligand, whose interaction with NKG2D triggers NK cell-mediated cytotoxicity toward the target cells, and is a key molecule in tumor immune surveillance as its expression is induced on stressed cells such as transformed tumor cells for the detection by NK cells. In this review, the latest understanding of the MICA-NKG2D system in viral HCC, particularly focused on its antitumor properties and the involvement of MICA SNPs, is summarized, followed by a discussion of targets for state-of-the-art cancer immunotherapy with personalized medicine in view.
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Wu SF, Zhou ZH, Sun XH, Zhu XJ, Li M, Zhang X, Gao YQ. Role of natural kill cells in hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2014; 22:5636-5642. [DOI: 10.11569/wcjd.v22.i36.5636] [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
Natural killer (NK) cells are a unique group of lymphocytes with cytotoxicity, playing an important role in anti-tumor and anti-infection activities. Recently, NK cells are increasingly recognized to play a role during hepatitis B virus (HBV) infection. Studies have confirmed NK cells participate in anti-HBV responses by secreting cytokines, mediating apoptosis and killing target cells, indicating a potential strategy for controlling HBV infection via regulation of NK cell functions. This review discusses the contribution of NK cells to HBV elimination, liver injury, and other parts of immune system and the formulation of new therapeutic strategies.
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Li X, Wang Y, Chen Y. Cellular immune response in patients with chronic hepatitis B virus infection. Microb Pathog 2014; 74:59-62. [PMID: 25128091 DOI: 10.1016/j.micpath.2014.07.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 07/30/2014] [Accepted: 07/31/2014] [Indexed: 02/08/2023]
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