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Cao Z, Yao Y, Cai M, Zhang C, Liu Y, Xin H, An B, Wang H, Lu Y, Li Z, Chen Y, Huang Y, Xin M, Li R, Qian Z, Zhou Y, Xiang X, Moreau R, Xie Q. Blood markers for type-1, -2, and -3 inflammation are associated with severity of acutely decompensated cirrhosis. J Hepatol 2025; 82:836-850. [PMID: 39490592 DOI: 10.1016/j.jhep.2024.10.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/27/2024] [Accepted: 10/16/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND & AIMS In patients with acutely decompensated cirrhosis (ADC) who present with clinically apparent precipitants (i.e., infections, acute liver injury), alterations in blood markers of inflammation associate with progression toward severe phenotypes (e.g., acute-on-chronic liver failure [ACLF]). However, it is unclear whether alterations in blood inflammatory markers associate with progression of ADC independently of precipitants. METHODS We prospectively enrolled 394 patients admitted for ADC who were classified into four phenotypes of increasing severity: no organ dysfunction (n = 168), organ dysfunction alone (n = 72), organ failure without ACLF (n = 91), and ACLF (n = 63). Clinical blood cell counts and serum levels of inflammatory markers (including soluble markers related to type-1, type-2, and type-3 inflammation) were obtained at enrollment. Ordinal regression with adjacent categories logit model adjusted for confounders (including precipitants) was used to analyze associations between changes in each blood inflammatory marker and the worsening of ADC. RESULTS Inflammatory markers that were associated with a higher risk of progressing to the next more severe stage were as follows: increasing neutrophil counts (adjusted common odds ratio [cOR] 1.17, 95% CI 1.06-1.28); increasing levels of the type-2 cytokine interleukin (IL)-25 (cOR 1.21, 95% CI 1.06-1.39), type-3 cytokines IL-6 (cOR 1.15, 95% CI 1.02-1.28) and IL-22 (cOR 1.16, 95% CI 1.03-1.30), or anti-inflammatory soluble CD163 (cOR 1.94, 95% CI 1.58-2.38); decreasing lymphocyte counts (cOR 0.77, 95% CI 0.68-0.87); or decreasing levels of the type-1 cytokine IFN-γ (cOR 0.85, 95% CI 0.75-0.95). CONCLUSIONS Among patients with ADC, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with an increased risk of progressing toward ACLF, independently of the presence of clinically apparent precipitants. IMPACT AND IMPLICATIONS This study reveals that among patients with acutely decompensated cirrhosis, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with increased risk of progressing toward acute-on-chronic liver failure, independently of the presence of clinically apparent precipitants. These findings raise questions about the role of impaired barrier tissues and dysregulated production of blood immune cells in the pathophysiology of severe phenotypes of acutely decompensated cirrhosis, stimulating research to identify potential new biomarkers and targets for novel therapeutic approaches.
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Affiliation(s)
- Zhujun Cao
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yujing Yao
- Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Minghao Cai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenxi Zhang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuhan Liu
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haiguang Xin
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baoyan An
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yide Lu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziqiang Li
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yaoxing Chen
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Huang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Xin
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruokun Li
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuping Qian
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Nursing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Zhou
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain; Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité, Centre de Recherche sur l'Inflammation (CRI), Paris, France; Assistance Publique - Hôpitaux de Paris (APHP), Service d'Hépatologie, Hôpital, Beaujon, Clichy, France.
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Wan H, Zhang YX, Shan GY, Cheng JY, Qiao DR, Liu YY, Shi WN, Li HJ. Antiviral therapy for hepatitis B virus infection is beneficial for the prognosis hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:93983. [PMID: 39817121 PMCID: PMC11664622 DOI: 10.4251/wjgo.v17.i1.93983] [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] [Received: 03/09/2024] [Revised: 09/20/2024] [Accepted: 09/29/2024] [Indexed: 12/12/2024] Open
Abstract
In this editorial, we comment on the article by Mu et al, published in the recent issue of the World Journal of Gastrointestinal Oncology. We pay special attention to the immune tolerance mechanism caused by hepatitis B virus (HBV) infection, the pathogenesis of hepatocellular carcinoma (HCC), and the role of antiviral therapy in treating HCC related to HBV infection. HBV infection leads to systemic innate immune tolerance by directly inhibiting pattern recognition receptor recognition and antiviral signaling pathways, as well as by inhibiting the immune functions of macrophages, natural killer cells and dendritic cells. In addition, HBV leads to an immunosuppressive cascade by expressing inhibitory molecules to induce exhaustion of HBV-specific cluster of differentiation 8 + T cells, ultimately leading to long-term viral infection. The loss of immune cell function caused by HBV infection ultimately leads to HCC. Long-term antiviral therapy can improve the prognosis of patients with HCC and prevent tumor recurrence and metastasis.
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Affiliation(s)
- Hui Wan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Yu-Xin Zhang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guan-Yue Shan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Jun-Ya Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Duan-Rui Qiao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Yi-Ying Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Wen-Na Shi
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Hai-Jun Li
- Institute of Liver Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
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Kwok TY, Hui RWH, Mao X, Ling GS, Wong DKH, Huang FY, Fung J, Seto WK, Yuen MF, Mak LY. Cigarette Smoking Is Associated With Lower Chance of Hepatitis B Surface Antigen Seroclearance and Altered Host Immunity. J Viral Hepat 2024; 31:847-856. [PMID: 39248338 DOI: 10.1111/jvh.14007] [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: 06/16/2024] [Revised: 08/12/2024] [Accepted: 08/25/2024] [Indexed: 09/10/2024]
Abstract
Cigarette smoking is associated with worse clinical outcomes in patients with chronic hepatitis B (CHB) infection, but the effects on hepatitis B surface antigen (HBsAg) seroclearance are unclear. This study aimed to investigate the effect of active smoking on HBsAg seroclearance (SC) and its impact on peripheral blood lymphocytes in patients with CHB infection. Longitudinal follow-up data was retrieved in 7833 antiviral-treated CHB subjects identified from a centralised electronic patient record database (Part 1). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs) from 27 CHB-infected patients (6 active smokers; 13 with SC) was performed by flow cytometry to assess programmed death-1 (PD-1) expression and proportion of regulatory T cells (CD4+CD25+CD127lo). Effector function of HBV-specific T cells was examined by comparing granzyme B (GZMB) and transforming growth factor beta (TGFβ) production in undepleted PBMCs and Treg-depleted PBMCs after 7 days in vitro stimulation with HBV envelope protein overlapping peptides (Part 2). Over a median follow-up of 5 years, smoking was associated with lower probability of SC (aHR 0.70, 95% CI 0.57-0.87). PD-1 expression was increased in CD4+ T cells, CD8+ T cells and CD20+ B cells among smokers compared to non-smokers and positively correlated with pack years (all p < 0.05). Treg depletion led to partial functional recovery of HBV-specific T cells, with significantly bigger magnitude in smokers (p = 0.0451, mean difference = 4.68%) than non-smokers (p = 0.012, mean difference = 4.2%). Cigarette smoking is associated with lower chance of HBsAg seroclearance, higher PD-1 expression on lymphocytes, and impairment of effector functions of HBV-specific T cells in CHB.
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Affiliation(s)
- Tsz-Yan Kwok
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - XianHua Mao
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Guang-Sheng Ling
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Danny Ka-Ho Wong
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Fung-Yu Huang
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Mak LY, Boettler T, Gill US. HBV Biomarkers and Their Role in Guiding Treatment Decisions. Semin Liver Dis 2024; 44:474-491. [PMID: 39442530 DOI: 10.1055/a-2448-4157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Over 300 million individuals worldwide are chronically infected with hepatitis B virus and at risk for progressive liver disease. Due to the lack of a therapy that reliably achieves viral elimination and the variability of liver disease progression, treatment decisions are guided by the degree of liver disease and viral biomarkers as the viral life-cycle is well characterized and largely conserved between individuals. In contrast, the immunological landscape is much more heterogeneous and diverse and the measurement of its components is less well standardized. Due to the lack of a universal and easily measurable set of biomarkers, clinical practice guidelines remain controversial, aiming for a balance between simplifying treatment decisions by reducing biomarker requirements and using all available biomarkers to avoid overtreatment of patients with low risk for disease progression. While approved therapies such as nucleos(t)ide analogs improve patient outcomes, the inability to achieve a complete cure highlights the need for novel therapies. Since no treatment candidate has demonstrated universal efficacy, biomarkers will remain important for treatment stratification. Here, we summarize the current knowledge on virological and immunological biomarkers with a specific focus on how they might be beneficial in guiding treatment decisions in chronic hepatitis B.
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Affiliation(s)
- Lung-Yi Mak
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tobias Boettler
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Huang JP, Yeh CM, Gong YW, Tsai MH, Lin YT, Tsai CK, Liu CJ. Risk and impact of cytomegalovirus infection in lymphoma patients treated with bendamustine. Ann Hematol 2024; 103:4099-4109. [PMID: 39158713 DOI: 10.1007/s00277-024-05839-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 06/06/2024] [Indexed: 08/20/2024]
Abstract
Bendamustine is used to treat lymphoma with excellent efficacy but is known for its immunosuppressive effect. Cytomegalovirus (CMV) reactivation after bendamustine use has been reported. We aim to address the impact of CMV infection in lymphoma patients treated with bendamustine-containing regimens. We retrospectively analyzed lymphoma patients at Taipei Veterans General Hospital in Taiwan between September 1, 2010, and April 30, 2022. Clinically significant CMV infection (CS-CMVi) was defined as the first CMV reactivation after bendamustine use necessitating CMV therapy. Patients' baseline characteristics and laboratory data were recorded. The primary endpoint of the study was CS-CMVi. A time-dependent covariate Cox regression model was used to estimate the risk factors of CS-CMVi and mortality. A total of 211 lymphoma patients treated with bendamustine were enrolled. Twenty-seven (12.8%) had CS-CMVi. The cumulative incidence was 10.1 per 100 person-years during the three-year follow-up period. In the multivariate analysis, lines of therapy before bendamustine ≥ 1 (95% CI 1.10-24.76), serum albumin < 3.5 g/dL (95% CI 2.63-52.93), and liver disease (95% CI 1.51-28.61) were risk factors for CS-CMVi. In conclusion, CS-CMVi (95% confidence interval [CI] 1.23-10.73) was one of the major independent risk factors of mortality. Lines of therapy before bendamustine ≥ 1, hypoalbuminemia, and liver disease were risk factors for CS-CMVi in lymphoma patients treated with bendamustine.
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Affiliation(s)
- Jen-Pei Huang
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Chiu-Mei Yeh
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Public Health, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ya-Wen Gong
- Department of Nursing, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Ming-Hsuan Tsai
- Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Yi-Tsung Lin
- Institute of Emergency and Critical Care Medicine, National Yang-Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan
| | - Chun-Kuang Tsai
- Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist, Taipei, 112201, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan.
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan.
- Division of Hematology, Taipei Veterans General Hospital, No. 201 Shipai Road, Sec. 2, Taipei, 11217, Taiwan.
| | - Chia-Jen Liu
- Institute of Emergency and Critical Care Medicine, National Yang-Ming Chiao Tung University, No. 155, Section 2, Linong Street, Beitou District, Taipei, 112201, Taiwan.
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
- Division of Transfusion Medicine, Taipei Veterans General Hospital, No. 201 Shipai Road, Sec. 2, Taipei, 11217, Taiwan.
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Lee I, Lee A, Shin S, Kumar S, Nam MH, Kang KW, Kim BS, Cho SD, Kim H, Han S, Park SH, Seo S, Jun HS. Use of a platform with lens-free shadow imaging technology to monitor natural killer cell activity. Biosens Bioelectron 2024; 261:116512. [PMID: 38908292 DOI: 10.1016/j.bios.2024.116512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024]
Abstract
Natural killer (NK) cells are a crucial component of the innate immune system. This study introduces Cellytics NK, a novel platform for rapid and precise measurement of NK cell activity. This platform combines an NK-specific activation stimulator cocktail (ASC) and lens-free shadow imaging technology (LSIT), using optoelectronic components. LSIT captures digital hologram images of resting and ASC-activated NK cells, while an algorithm evaluates cell size and cytoplasmic complexity using shadow parameters. The combined shadow parameter derived from the peak-to-peak distance and width standard deviation rapidly distinguishes active NK cells from inactive NK cells at the single-cell level within 30 s. Here, the feasibility of the system was demonstrated by assessing NK cells from healthy donors and immunocompromised cancer patients, demonstrating a significant difference in the innate immunity index (I3). Cancer patients showed a lower I3 value (161%) than healthy donors (326%). I3 was strongly correlated with NK cell activity measured using various markers such as interferon-gamma, tumor necrosis factor-alpha, perforin, granzyme B, and CD107a. This technology holds promise for advancing immune functional assays, offering rapid and accurate on-site analysis of NK cells, a crucial innate immune cell, with its compact and cost-effective optoelectronic setup, especially in the post-COVID-19 era.
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Affiliation(s)
- Inha Lee
- Department of Biotechnology and Bioinformatics, Korea University, Sejong, 30019, Republic of Korea
| | - Ahyeon Lee
- Department of Electronics and Information Engineering, Korea University, Sejong, 30019, Republic of Korea
| | - Sanghoon Shin
- Department of Electronics and Information Engineering, Korea University, Sejong, 30019, Republic of Korea
| | - Samir Kumar
- Department of Electronics and Information Engineering, Korea University, Sejong, 30019, Republic of Korea
| | - Myung-Hyun Nam
- Department of Laboratory Medicine, Anam Hospital, Korea University College of Medicine, Seoul, 02841, Republic of Korea
| | - Ka-Won Kang
- Department of Hematology, Anam Hospital, Korea University College of Medicine, Seoul, 02841, Republic of Korea
| | - Byung Soo Kim
- Department of Hematology, Anam Hospital, Korea University College of Medicine, Seoul, 02841, Republic of Korea
| | - Sung-Dong Cho
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Hawon Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Sunmi Han
- Metaimmunetech Inc., Sejong, 30019, Republic of Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea
| | - Sungkyu Seo
- Department of Electronics and Information Engineering, Korea University, Sejong, 30019, Republic of Korea; Metaimmunetech Inc., Sejong, 30019, Republic of Korea.
| | - Hyun Sik Jun
- Department of Biotechnology and Bioinformatics, Korea University, Sejong, 30019, Republic of Korea; Metaimmunetech Inc., Sejong, 30019, Republic of Korea.
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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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Sun B, da Costa KA, Alrubayyi A, Kokici J, Fisher-Pearson N, Hussain N, D’Anna S, Piermatteo L, Salpini R, Svicher V, Kucykowicz S, Ghosh I, Burns F, Kinloch S, Simoes P, Bhagani S, Kennedy PTF, Maini MK, Bashford-Rogers R, Gill US, Peppa D. HIV/HBV coinfection remodels the immune landscape and natural killer cell ADCC functional responses. Hepatology 2024; 80:649-663. [PMID: 38687604 PMCID: PMC11782918 DOI: 10.1097/hep.0000000000000877] [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: 11/10/2023] [Accepted: 01/23/2024] [Indexed: 05/02/2024]
Abstract
BACKGROUND AND AIMS HBV and HIV coinfection is a common occurrence globally, with significant morbidity and mortality. Both viruses lead to immune dysregulation including changes in natural killer (NK) cells, a key component of antiviral defense and a promising target for HBV cure strategies. Here we used high-throughput single-cell analysis to explore the immune cell landscape in people with HBV mono-infection and HIV/HBV coinfection, on antiviral therapy, with emphasis on identifying the distinctive characteristics of NK cell subsets that can be therapeutically harnessed. APPROACH AND RESULTS Our data show striking differences in the transcriptional programs of NK cells. HIV/HBV coinfection was characterized by an over-representation of adaptive, KLRC2 -expressing NK cells, including a higher abundance of a chemokine-enriched ( CCL3/CCL4 ) adaptive cluster. The NK cell remodeling in HIV/HBV coinfection was reflected in enriched activation pathways, including CD3ζ phosphorylation and ZAP-70 translocation that can mediate stronger antibody-dependent cellular cytotoxicity responses and a bias toward chemokine/cytokine signaling. By contrast, HBV mono-infection imposed a stronger cytotoxic profile on NK cells and a more prominent signature of "exhaustion" with higher circulating levels of HBsAg. Phenotypic alterations in the NK cell pool in coinfection were consistent with increased "adaptiveness" and better capacity for antibody-dependent cellular cytotoxicity compared to HBV mono-infection. Overall, an adaptive NK cell signature correlated inversely with circulating levels of HBsAg and HBV-RNA in our cohort. CONCLUSIONS This study provides new insights into the differential signature and functional profile of NK cells in HBV and HIV/HBV coinfection, highlighting pathways that can be manipulated to tailor NK cell-focused approaches to advance HBV cure strategies in different patient groups.
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Affiliation(s)
- Bo Sun
- Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom
| | - Kelly A.S. da Costa
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Jonida Kokici
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Noshin Hussain
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Stefano D’Anna
- University of Rome Tor Vergata, Department of Experimental Medicine, Rome, Italy
| | | | - Romina Salpini
- University of Rome Tor Vergata, Department of Experimental Medicine, Rome, Italy
| | | | - Stephanie Kucykowicz
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Indrajit Ghosh
- Mortimer Market Centre, Department of HIV, CNWL NHS Trust, London, United Kingdom
| | - Fiona Burns
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
- Institute for Global Health, University College London, UK
| | - Sabine Kinloch
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
| | - Pedro Simoes
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
| | - Sanjay Bhagani
- Division of Infection and Immunity, University College London, London, United Kingdom
- Department of HIV Medicine, Royal Free Hospital NHS Foundation Trust, UK
| | | | - Mala K Maini
- Division of Infection and Immunity, University College London, London, United Kingdom
| | | | - Upkar S Gill
- Barts Liver Centre, Barts & The London School of Medicine & Dentistry, QMUL
| | - Dimitra Peppa
- Division of Infection and Immunity, University College London, London, United Kingdom
- Mortimer Market Centre, Department of HIV, CNWL NHS Trust, London, United Kingdom
- The Ian Charleson Day Centre, Royal Free Hospital NHS Foundation Trust, UK
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9
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Sabag B, Puthenveetil A, Levy M, Joseph N, Doniger T, Yaron O, Karako-Lampert S, Lazar I, Awwad F, Ashkenazi S, Barda-Saad M. Dysfunctional natural killer cells can be reprogrammed to regain anti-tumor activity. EMBO J 2024; 43:2552-2581. [PMID: 38637625 PMCID: PMC11217363 DOI: 10.1038/s44318-024-00094-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 04/20/2024] Open
Abstract
Natural killer (NK) cells are critical to the innate immune system, as they recognize antigens without prior sensitization, and contribute to the control and clearance of viral infections and cancer. However, a significant proportion of NK cells in mice and humans do not express classical inhibitory receptors during their education process and are rendered naturally "anergic", i.e., exhibiting reduced effector functions. The molecular events leading to NK cell anergy as well as their relation to those underlying NK cell exhaustion that arises from overstimulation in chronic conditions, remain unknown. Here, we characterize the "anergic" phenotype and demonstrate functional, transcriptional, and phenotypic similarities to the "exhausted" state in tumor-infiltrating NK cells. Furthermore, we identify zinc finger transcription factor Egr2 and diacylglycerol kinase DGKα as common negative regulators controlling NK cell dysfunction. Finally, experiments in a 3D organotypic spheroid culture model and an in vivo tumor model suggest that a nanoparticle-based delivery platform can reprogram these dysfunctional natural killer cell populations in their native microenvironment. This approach may become clinically relevant for the development of novel anti-tumor immunotherapeutic strategies.
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Affiliation(s)
- Batel Sabag
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Abhishek Puthenveetil
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Moria Levy
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Noah Joseph
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Tirtza Doniger
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Orly Yaron
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Sarit Karako-Lampert
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Itay Lazar
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Fatima Awwad
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Shahar Ashkenazi
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel
| | - Mira Barda-Saad
- The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 5290002, Israel.
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10
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Roe K. Immunoregulatory natural killer cells. Clin Chim Acta 2024; 558:117896. [PMID: 38583553 DOI: 10.1016/j.cca.2024.117896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/09/2024]
Abstract
This review discusses a broader scope of functional roles for NK cells. Despite the well-known cytolytic and inflammatory roles of NK cells against tumors and pathogenic diseases, extensive evidence demonstrates certain subsets of NK cells have defacto immunoregulatory effects and have a role in inducing anergy or lysis of antigen-activated T cells and regulating several autoimmune diseases. Furthermore, recent evidence suggests certain subsets of immunoregulatory NK cells can cause anergy or lysis of antigen-activated T cells to regulate hyperinflammatory diseases, including multisystem inflammatory syndrome. Several pathogens induce T cell and NK cell exhaustion and/or suppression, which impair the immune system's control of the replication speed of virulent pathogens and tumors and result in extensive antigens and antigen-antibody immune complexes, potentially inducing to some extent a Type III hypersensitivity immune reaction. The Type III hypersensitivity immune reaction induces immune cell secretion of proteinases, which can cleave specific proteins to create autoantigens which activate T cells to initiate autoimmune and/or hyperinflammatory diseases. Furthermore, pathogen induced NK cell exhaustion and/or suppression will inhibit NK cells which would have induced the anergy or lysis of activated T cells to regulate autoimmune and hyperinflammatory diseases. Autoimmune and hyperinflammatory diseases can be consequences of the dual lymphocyte exhaustion and/or suppression effects during infections, by creating autoimmune and/or hyperinflammatory diseases, while also impairing immunoregulatory lymphocytes which otherwise would have regulated these diseases.
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Affiliation(s)
- Kevin Roe
- Retired USPTO, San Jose, CA, United States of America.
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11
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Ma H, Yan QZ, Ma JR, Li DF, Yang JL. Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies. World J Gastroenterol 2024; 30:1295-1312. [PMID: 38596493 PMCID: PMC11000084 DOI: 10.3748/wjg.v30.i10.1295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 12/25/2023] [Accepted: 01/24/2024] [Indexed: 03/14/2024] Open
Abstract
Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation's delicate balance, spanning innate and adaptive immunity. Viral factors' disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation's impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.
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Affiliation(s)
- Hui Ma
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Qing-Zhu Yan
- Department of Ultrasound Medicine, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Jing-Ru Ma
- Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Dong-Fu Li
- Digestive Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Jun-Ling Yang
- Department of Respiratory and Critical Care Medicine, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
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12
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Wang Z, Liu N, Yang Y, Tu Z. The novel mechanism facilitating chronic hepatitis B infection: immunometabolism and epigenetic modification reprogramming. Front Immunol 2024; 15:1349867. [PMID: 38288308 PMCID: PMC10822934 DOI: 10.3389/fimmu.2024.1349867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/02/2024] [Indexed: 01/31/2024] Open
Abstract
Hepatitis B Virus (HBV) infections pose a global public health challenge. Despite extensive research on this disease, the intricate mechanisms underlying persistent HBV infection require further in-depth elucidation. Recent studies have revealed the pivotal roles of immunometabolism and epigenetic reprogramming in chronic HBV infection. Immunometabolism have identified as the process, which link cell metabolic status with innate immunity functions in response to HBV infection, ultimately contributing to the immune system's inability to resolve Chronic Hepatitis B (CHB). Within hepatocytes, HBV replication leads to a stable viral covalently closed circular DNA (cccDNA) minichromosome located in the nucleus, and epigenetic modifications in cccDNA enable persistence of infection. Additionally, the accumulation or depletion of metabolites not only directly affects the function and homeostasis of immune cells but also serves as a substrate for regulating epigenetic modifications, subsequently influencing the expression of antiviral immune genes and facilitating the occurrence of sustained HBV infection. The interaction between immunometabolism and epigenetic modifications has led to a new research field, known as metabolic epigenomics, which may form a mutually reinforcing relationship with CHB. Herein, we review the recent studies on immunometabolism and epigenetic reprogramming in CHB infection and discuss the potential mechanisms of persistent HBV infection. A deeper understanding of these mechanisms will offer novel insights and targets for intervention strategies against chronic HBV infection, thereby providing new hope for the treatment of related diseases.
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Affiliation(s)
- Zhengmin Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Nan Liu
- Institute of Epigenetic Medicine, First Hospital of Jilin University, Changchun, China
| | - Yang Yang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhengkun Tu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
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13
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Letafati A, Ardekani OS, Naderisemiromi M, Norouzi M, Shafiei M, Nik S, Mozhgani SH. Unraveling the dynamic mechanisms of natural killer cells in viral infections: insights and implications. Virol J 2024; 21:18. [PMID: 38216935 PMCID: PMC10785350 DOI: 10.1186/s12985-024-02287-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 01/04/2024] [Indexed: 01/14/2024] Open
Abstract
Viruses pose a constant threat to human well-being, necessitating the immune system to develop robust defenses. Natural killer (NK) cells, which play a crucial role in the immune system, have become recognized as vital participants in protecting the body against viral infections. These remarkable innate immune cells possess the unique ability to directly recognize and eliminate infected cells, thereby contributing to the early control and containment of viral pathogens. However, recent research has uncovered an intriguing phenomenon: the alteration of NK cells during viral infections. In addition to their well-established role in antiviral defense, NK cells undergo dynamic changes in their phenotype, function, and regulatory mechanisms upon encountering viral pathogens. These alterations can significantly impact the effectiveness of NK cell responses during viral infections. This review explores the multifaceted role of NK cells in antiviral immunity, highlighting their conventional effector functions as well as the emerging concept of NK cell alteration in the context of viral infections. Understanding the intricate interplay between NK cells and viral infections is crucial for advancing our knowledge of antiviral immune responses and could offer valuable information for the creation of innovative therapeutic approaches to combat viral diseases.
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Affiliation(s)
- Arash Letafati
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Omid Salahi Ardekani
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | - Mina Naderisemiromi
- Department of Immunology, Faculty of Medicine and Health, The University of Manchester, Manchester, UK
| | - Mehdi Norouzi
- Department of Virology, Faculty of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran
| | | | - Soheil Nik
- School of Medicine, Alborz University of Medical Sciences, Karaj, Alborz, Iran
| | - Sayed-Hamidreza Mozhgani
- Research Center for Clinical Virology, Tehran University of Medical Science, Tehran, Iran.
- Department of Microbiology and Virology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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14
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Schefczyk S, Luo X, Liang Y, Hasenberg M, Walkenfort B, Trippler M, Schuhenn J, Sutter K, Lu M, Wedemeyer H, Schmidt HH, Broering R. Tg1.4HBV-s-rec mice, a crossbred hepatitis B virus-transgenic model, develop mild hepatitis. Sci Rep 2023; 13:22829. [PMID: 38129531 PMCID: PMC10739827 DOI: 10.1038/s41598-023-50090-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 12/15/2023] [Indexed: 12/23/2023] Open
Abstract
Hepatitis B virus (HBV)-transgenic mice exhibit competent innate immunity and are therefore an ideal model for considering intrinsic or cell-based mechanisms in HBV pathophysiology. A highly replicative model that has been little used, let alone characterized, is the Tg1.4HBV-s-rec strain derived from cross breeding of HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1-HBV]Bri44) or lack (Tg1.4HBV-s-mut) the hepatitis B surface antigen (HBsAg). Tg1.4HBV-s-rec hepatocytes secreted HBsAg, Hepatitis B extracellular antigen (HBeAg) and produced HBV virions. Transmission electron microscopy visualised viral particles (Tg1.4HBV-s-rec), nuclear capsid formations (Tg1.4HBV-s-mut and Tg1.4HBV-s-rec) and endoplasmic reticulum malformations (Alb/HBs). Viral replication in Tg1.4HBV-s-rec and Tg1.4HBV-s-mut differed in HBsAg expression and interestingly in the distribution of HBV core antigen (HBcAg) and HBV × protein. While in Tg1.4HBV-s-mut hepatocytes, the HBcAg was located in the cytoplasm, in Tg1.4HBV-s-rec hepatocytes, the HBcAg appeared in the nuclei, suggesting a more productive replication. Finally, Tg1.4HBV-s-rec mice showed symptoms of mild hepatitis, with reduced liver function and elevated serum transaminases, which appeared to be related to natural killer T cell activation. In conclusion, the study of Alb/HBs, Tg1.4HBV-s-mut and their F1 progeny provides a powerful tool to elucidate HBV pathophysiology, especially in the early HBeAg-positive phases of chronic infection and chronic hepatitis.
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Affiliation(s)
- Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
| | - Xufeng Luo
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
- Institute for Lymphoma Research, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Yaojie Liang
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
| | - Mike Hasenberg
- Electron Microscopy Unit, Imaging Center Essen, Medical Faculty, Germany Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Bernd Walkenfort
- Electron Microscopy Unit, Imaging Center Essen, Medical Faculty, Germany Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
| | - Jonas Schuhenn
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Kathrin Sutter
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hartmut H Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
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15
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Osegueda A, Polo ML, Baquero L, Urioste A, Ghiglione Y, Paz S, Poblete G, Gonzalez Polo V, Turk G, Quiroga MF, Laufer N. Markers of Natural Killer Cell Exhaustion in HIV/HCV Coinfection and Their Dynamics After HCV Clearance Mediated by Direct-Acting Antivirals. Open Forum Infect Dis 2023; 10:ofad591. [PMID: 38107019 PMCID: PMC10723816 DOI: 10.1093/ofid/ofad591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 11/20/2023] [Indexed: 12/19/2023] Open
Abstract
Background Liver fibrosis is a leading cause of morbimortality in people with HIV/hepatitis C virus (HCV). Natural killer (NK) cells are linked with amelioration of liver fibrosis; however, NK cells from individuals coinfected with HIV/HCV with cirrhosis display impaired functionality and high PD-1 expression. Here, we aimed to study PD-1, TIGIT, and Tim3 as potential exhaustion markers in NK cells from persons coinfected with HIV/HCV with mild and advanced liver fibrosis. We also evaluated the role of PD-1 expression on NK cells after HCV clearance by direct-acting antivirals (DAAs). Methods Peripheral blood mononuclear cells were isolated from individuals coinfected with HIV/HCV (N = 54; METAVIR F0/F1, n = 27; F4, evaluated by transient elastography, n = 27). In 26 participants, samples were collected before, at the end of, and 12 months after successful DAA treatment. The frequency, immunophenotype (PD-1, TIGIT, and Tim3 expression), and degranulation capacity (CD107a assay) of NK cells were determined by flow cytometry. Results Unlike PD-1, Tim3 and TIGIT were comparably expressed between persons with mild and advanced fibrosis. Degranulation capacity was diminished in NK/TIGIT+ cells in both fibrosis stages, while NK/PD-1+ cells showed a lower CD107a expression in cirrhotic cases. Twelve months after DAA treatment, those with advanced fibrosis showed an improved NK cell frequency and reduced NK/PD-1+ cell frequency but no changes in CD107a expression. In individuals with mild fibrosis, neither PD-1 nor NK cell frequency was modified, although the percentage of NK/CD107a+ cells was improved at 12 months posttreatment. Conclusions Although DAA improved exhaustion and frequency of NK cells in cirrhotic cases, functionality was reverted only in mild liver fibrosis, remarking the importance of an early DAA treatment.
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Affiliation(s)
- Ariel Osegueda
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina. Buenos Aires, Argentina
| | - Maria Laura Polo
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina. Buenos Aires, Argentina
| | - Lucia Baquero
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina
| | - Alejandra Urioste
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina. Buenos Aires, Argentina
| | - Yanina Ghiglione
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina. Buenos Aires, Argentina
| | - Silvia Paz
- Hospital Francisco Javier Muñiz, Buenos Aires, Argentina
| | | | - Virginia Gonzalez Polo
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina. Buenos Aires, Argentina
| | - Gabriela Turk
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina
| | - Maria Florencia Quiroga
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina
| | - Natalia Laufer
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Buenos Aires, Argentina
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina
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16
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Zheng P, Dou Y, Wang Q. Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity. Front Cell Infect Microbiol 2023; 13:1206720. [PMID: 37424786 PMCID: PMC10324618 DOI: 10.3389/fcimb.2023.1206720] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major global public health risk that threatens human life and health, although the number of vaccinated people has increased. The clinical outcome of HBV infection depends on the complex interplay between viral replication and the host immune response. Innate immunity plays an important role in the early stages of the disease but retains no long-term immune memory. However, HBV evades detection by the host innate immune system through stealth. Therefore, adaptive immunity involving T and B cells is crucial for controlling and clearing HBV infections that lead to liver inflammation and damage. The persistence of HBV leads to immune tolerance owing to immune cell dysfunction, T cell exhaustion, and an increase in suppressor cells and cytokines. Although significant progress has been made in HBV treatment in recent years, the balance between immune tolerance, immune activation, inflammation, and fibrosis in chronic hepatitis B remains unknown, making a functional cure difficult to achieve. Therefore, this review focuses on the important cells involved in the innate and adaptive immunity of chronic hepatitis B that target the host immune system and identifies treatment strategies.
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Affiliation(s)
- Peiyu Zheng
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Yongqing Dou
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Qinying Wang
- Department of Infectious Diseases, The First Hospital of Shanxi Medical University, Taiyuan, China
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17
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Boulay A, Trabanelli S, Boireau S, Boyer-Clavel M, Nisole S, Romero P, Jandus C, Beignon AS, Arhel NJ. Assessing the Impact of Persistent HIV Infection on Innate Lymphoid Cells Using In Vitro Models. Immunohorizons 2023; 7:243-255. [PMID: 37000496 PMCID: PMC10563434 DOI: 10.4049/immunohorizons.2300007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 03/07/2023] [Indexed: 04/01/2023] Open
Abstract
Pathogens that persist in their host induce immune dysfunctions even in the absence of detectable replication. To better understand the phenotypic and functional changes that persistent infections induce in sentinel innate immune cells, we developed human PBMC-based HIV models of persistent infection. Autologous nonactivated PBMCs were cocultured with chronically infected, acutely infected, or uninfected cells and were then analyzed by unsupervised high-dimensional flow cytometry. Using this approach, we identified prevalent patterns of innate immune dysfunctions associated with persistent HIV infections that at least in part mirror immune dysfunctions observed in patients. In one or more models of chronic infection, bystander CD16+ NK cells expressing markers of activation, such as CD94, CD45RO, CD62L, CD69, CD25, and immune checkpoints PD1, Tim3, TIGIT, NKG2A and Lag3, were significantly reduced. Conversely, helper ILC subsets expressing PDL1/PDL2 were significantly enriched in chronic infection compared with either uninfected or acute infection, suggesting that chronic HIV-1 infection was associated with an inhibitory environment for bystander ILC and NK subsets. The cell-based models of persistent infection that we describe here provide versatile tools to explore the molecular mechanisms of these immune dysfunctions and unveil the contribution of innate immunity in sustaining pathogen persistence.
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Affiliation(s)
- Aude Boulay
- Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France
| | - Sara Trabanelli
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Stéphanie Boireau
- Montpellier Ressources Imagerie, Biocampus, Université de Montpellier, CNRS, Montpellier, France
| | - Myriam Boyer-Clavel
- Montpellier Ressources Imagerie, Biocampus, Université de Montpellier, CNRS, Montpellier, France
| | - Sébastien Nisole
- Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France
| | - Pedro Romero
- Department of Oncology, University of Lausanne, Épalinges, Switzerland
| | - Camilla Jandus
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Anne-Sophie Beignon
- Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses, France
| | - Nathalie J. Arhel
- Viral Trafficking, Restriction and Innate Signaling, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France
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18
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Jin X, Bi J. Prospects for NK-based immunotherapy of chronic HBV infection. Front Immunol 2022; 13:1084109. [PMID: 36591230 PMCID: PMC9797727 DOI: 10.3389/fimmu.2022.1084109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/01/2022] [Indexed: 12/16/2022] Open
Abstract
Effective and long-term treatment is required for controlling chronic Hepatitis B Virus (HBV) infection. Natural killer (NK) cells are antiviral innate lymphocytes and represent an essential arm of current immunotherapy. In chronic HBV (CHB), NK cells display altered changes in phenotypes and functions, but preserve antiviral activity, especially for cytolytic activity. On the other hand, NK cells might also cause liver injury in the disease. NK -based immunotherapy, including adoptive NK cell therapy and NK -based checkpoint inhibition, could potentially exploit the antiviral aspect of NK cells for controlling CHB infection while preventing liver tissue damage. Here, we review recent progress in NK cell biology under the context of CHB infection, and discuss potential NK -based immunotherapy strategies for the disease.
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19
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Yoon JS, Lee CW. Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma. Exp Mol Med 2022; 54:1799-1813. [PMID: 36380016 PMCID: PMC9722691 DOI: 10.1038/s12276-022-00883-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is a complicated heterogeneous organ composed of different cells. Parenchymal cells called hepatocytes and various nonparenchymal cells, including immune cells and stromal cells, are distributed in liver lobules with hepatic architecture. They interact with each other to compose the liver microenvironment and determine its characteristics. Although the liver microenvironment maintains liver homeostasis and function under healthy conditions, it also shows proinflammatory and profibrogenic characteristics that can induce the progression of hepatitis and hepatic fibrosis, eventually changing to a protumoral microenvironment that contributes to the development of hepatocellular carcinoma (HCC). According to recent studies, phosphatases are involved in liver diseases and HCC development by regulating protein phosphorylation in intracellular signaling pathways and changing the activities and characteristics of liver cells. Therefore, this review aims to highlight the importance of protein phosphatases in HCC development and in the regulation of the cellular components in the liver microenvironment and to show their significance as therapeutic targets.
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Affiliation(s)
- Joon-Sup Yoon
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea
| | - Chang-Woo Lee
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea ,grid.264381.a0000 0001 2181 989XDepartment of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351 Republic of Korea
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20
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Haroun-Izquierdo A, Vincenti M, Netskar H, van Ooijen H, Zhang B, Bendzick L, Kanaya M, Momayyezi P, Li S, Wiiger MT, Hoel HJ, Krokeide SZ, Kremer V, Tjonnfjord G, Berggren S, Wikström K, Blomberg P, Alici E, Felices M, Önfelt B, Höglund P, Valamehr B, Ljunggren HG, Björklund A, Hammer Q, Kveberg L, Cichocki F, Miller JS, Malmberg KJ, Sohlberg E. Adaptive single-KIR +NKG2C + NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia. J Immunother Cancer 2022; 10:jitc-2022-005577. [PMID: 36319065 PMCID: PMC9628692 DOI: 10.1136/jitc-2022-005577] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML). Current treatments are hampered by variability in NK cell subset responses, a limitation which could be circumvented by specific expansion of highly potent single killer immunoglobulin-like receptor (KIR)+NKG2C+ adaptive NK cells to maximize missing-self reactivity. METHODS We developed a GMP-compliant protocol to expand adaptive NK cells from cryopreserved cells derived from select third-party superdonors, that is, donors harboring large adaptive NK cell subsets with desired KIR specificities at baseline. We studied the adaptive state of the cell product (ADAPT-NK) by flow cytometry and mass cytometry as well as cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq). We investigated the functional responses of ADAPT-NK cells against a wide range of tumor target cell lines and primary AML samples using flow cytometry and IncuCyte as well as in a mouse model of AML. RESULTS ADAPT-NK cells were >90% pure with a homogeneous expression of a single self-HLA specific KIR and expanded a median of 470-fold. The ADAPT-NK cells largely retained their adaptive transcriptional signature with activation of effector programs without signs of exhaustion. ADAPT-NK cells showed high degranulation capacity and efficient killing of HLA-C/KIR mismatched tumor cell lines as well as primary leukemic blasts from AML patients. Finally, the expanded adaptive NK cells had preserved robust antibody-dependent cellular cytotoxicity potential and combination of ADAPT-NK cells with an anti-CD16/IL-15/anti-CD33 tri-specific engager led to near-complete killing of resistant CD45dim blast subtypes. CONCLUSIONS These preclinical data demonstrate the feasibility of off-the-shelf therapy with a non-engineered, yet highly specific, NK cell population with full missing-self recognition capability.
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Affiliation(s)
- Alvaro Haroun-Izquierdo
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Marianna Vincenti
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Herman Netskar
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Hanna van Ooijen
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Bin Zhang
- University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA
| | - Laura Bendzick
- University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA
| | - Minoru Kanaya
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Pouria Momayyezi
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Shuo Li
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Merete Thune Wiiger
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Hanna Julie Hoel
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Silje Zandstra Krokeide
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Veronika Kremer
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Geir Tjonnfjord
- Department of Hematology, Oslo University Hospital and K.G. Jebsen Centre for B-cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Stéphanie Berggren
- Vecura, Karolinska Center for Cell Therapy Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden
| | - Kristina Wikström
- Vecura, Karolinska Center for Cell Therapy Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden
| | - Pontus Blomberg
- Vecura, Karolinska Center for Cell Therapy Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden
| | - Evren Alici
- Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Martin Felices
- University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA
| | - Björn Önfelt
- Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
- Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Petter Höglund
- Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | | | - Hans-Gustaf Ljunggren
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Andreas Björklund
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Quirin Hammer
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Lise Kveberg
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Frank Cichocki
- University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA
| | - Jeffrey S Miller
- University of Minnesota, Masonic Cancer Center, Minneapolis, Minnesota, USA
| | - Karl-Johan Malmberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Ebba Sohlberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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21
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Zhang J, Rousseaux N, Walzer T. Eomes and T‐bet, a dynamic duo regulating NK cell differentiation. Bioessays 2022; 44:e2100281. [DOI: 10.1002/bies.202100281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Jiang Zhang
- Department of Dermatology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA
| | - Noémi Rousseaux
- CIRI Centre International de Recherche en Infectiologie CNRS, UMR5308, ENS de Lyon Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1 Lyon France
| | - Thierry Walzer
- CIRI Centre International de Recherche en Infectiologie CNRS, UMR5308, ENS de Lyon Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1 Lyon France
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22
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Jin X, Yan ZH, Lu L, Lu S, Zhang G, Lin W. Peripheral Immune Cells Exhaustion and Functional Impairment in Patients With Chronic Hepatitis B. Front Med (Lausanne) 2021; 8:759292. [PMID: 34782855 PMCID: PMC8589627 DOI: 10.3389/fmed.2021.759292] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/17/2021] [Indexed: 12/30/2022] Open
Abstract
After infection of hepatitis B virus (HBV), the virus induces a variety of immune disorders in the host, leading to immune escape and, finally, the chronicity of the disease. This study investigated immune cell defects and functional impairment in patients with chronic hepatitis B (CHB). We analyzed the percentage, function, and phenotypes of various immune cell subpopulations in the peripheral blood along with the concentrations of cytokines in the plasma. We compared the results between patients with CHB and healthy individuals. It was found that in patients with CHB, the cell function was impaired and, there was increased expression of inhibitory receptors, such as NKG2A and PD-1 in both NK and T cells. The impairment of function was mainly in cytokine secretion, and the cytotoxicity was not significantly diminished. We also found that the proportion of dendritic cells (DC) decreased and regulatory B cells (Breg) increased in CHB. In addition, the Breg cells were negatively correlated with T cell cytokine and positively correlated with ALT and HBV viral load. Taken together, various disorders and functional impairments were found in the immune cells of peripheral blood in CHB patients, especially NK and T cells. These cells showed exhaustion and the increase of regulatory B cells may be one of the reasons for this phenomenon.
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Affiliation(s)
- Xin Jin
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Zhi-Han Yan
- Department of Hepatology, Wuxi Fifth People's Hospital, Wuxi, China
| | - Lingna Lu
- Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Shengjia Lu
- Department of Infectious Diseases, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Guoping Zhang
- Department of Clinical Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wei Lin
- Department of Otolaryngology, Tongde Hospital of Zhejiang Province, Hangzhou, China
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23
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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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24
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Foroutan M, Molania R, Pfefferle A, Behrenbruch C, Scheer S, Kallies A, Speed TP, Cursons J, Huntington ND. The Ratio of Exhausted to Resident Infiltrating Lymphocytes Is Prognostic for Colorectal Cancer Patient Outcome. Cancer Immunol Res 2021; 9:1125-1140. [PMID: 34413087 DOI: 10.1158/2326-6066.cir-21-0137] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/14/2021] [Accepted: 08/17/2021] [Indexed: 11/16/2022]
Abstract
Immunotherapy success in colorectal cancer is mainly limited to patients whose tumors exhibit high microsatellite instability (MSI). However, there is variability in treatment outcomes within this group, which is in part driven by the frequency and characteristics of tumor-infiltrating immune cells. Indeed, the presence of specific infiltrating immune-cell subsets has been shown to correlate with immunotherapy response and is in many cases prognostic of treatment outcome. Tumor-infiltrating lymphocytes (TIL) can undergo distinct differentiation programs, acquiring features of tissue-residency or exhaustion, a process during which T cells upregulate inhibitory receptors, such as PD-1, and lose functionality. Although residency and exhaustion programs of CD8+ T cells are relatively well studied, these programs have only recently been appreciated in CD4+ T cells and remain largely unknown in tumor-infiltrating natural killer (NK) cells. In this study, we used single-cell RNA sequencing (RNA-seq) data to identify signatures of residency and exhaustion in colorectal cancer-infiltrating lymphocytes, including CD8+, CD4+, and NK cells. We then tested these signatures in independent single-cell data from tumor and normal tissue-infiltrating immune cells. Furthermore, we used versions of these signatures designed for bulk RNA-seq data to explore tumor-intrinsic mutations associated with residency and exhaustion from TCGA data. Finally, using two independent transcriptomic datasets from patients with colon adenocarcinoma, we showed that combinations of these signatures, in particular combinations of NK-cell activity signatures, together with tumor-associated signatures, such as TGFβ signaling, were associated with distinct survival outcomes in patients with colon adenocarcinoma.
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Affiliation(s)
- Momeneh Foroutan
- Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
| | - Ramyar Molania
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Aline Pfefferle
- Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.,oNKo-innate Pty Ltd., Moonee Ponds, Victoria, Australia
| | - Corina Behrenbruch
- University of Melbourne Centre for Cancer Research, Parkville, Victoria, Australia
| | - Sebastian Scheer
- Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Axel Kallies
- Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia
| | - Terence P Speed
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.,School of Mathematics & Statistics, The University of Melbourne, Parkville, Victoria, Australia
| | - Joseph Cursons
- Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. .,oNKo-innate Pty Ltd., Moonee Ponds, Victoria, Australia
| | - Nicholas D Huntington
- Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. .,oNKo-innate Pty Ltd., Moonee Ponds, Victoria, Australia
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25
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Phenotypic Characterization by Single-Cell Mass Cytometry of Human Intrahepatic and Peripheral NK Cells in Patients with Hepatocellular Carcinoma. Cells 2021; 10:cells10061495. [PMID: 34198593 PMCID: PMC8231799 DOI: 10.3390/cells10061495] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/09/2021] [Accepted: 06/09/2021] [Indexed: 12/11/2022] Open
Abstract
Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56dim and CD56bright NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160+CD56dim NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49a+CD56dim NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56dim NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a+ CX3CR1+ Siglec-10+ NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56dim NK cells may be targets for immunotherapies of HCC patients.
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26
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Piersma SJ, Brizić I. Natural killer cell effector functions in antiviral defense. FEBS J 2021; 289:3982-3999. [PMID: 34125493 DOI: 10.1111/febs.16073] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/27/2021] [Accepted: 06/14/2021] [Indexed: 11/27/2022]
Abstract
Natural killer (NK) cells are innate lymphoid cells involved in the control of tumors and viral infections. They provide protection by producing cytokines and by directly lysing target cells. Both effector mechanisms have been identified to contribute to viral control, depending on the context of infection. Activation of NK cells depends on the integration of signals received by cytokine receptors and activation and inhibitory receptors recognizing ligands expressed by virus-infected cells. While the control of viral infections by NK cells is well established, the signals perceived by NK cells and how these signals integrate to mediate optimal viral control have been focus of ongoing research. Here, we discuss the current knowledge on NK cell activation and integration of signals that lead to interferon gamma production and cytotoxicity in viral infections. We review NK cell interactions with viruses, with particular focus on murine cytomegalovirus studies, which helped elucidate crucial aspects of antiviral NK cell immunity.
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Affiliation(s)
- Sytse J Piersma
- Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Ilija Brizić
- Center for Proteomics, Faculty of Medicine, University of Rijeka, Croatia
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27
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Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches. Cells 2021; 10:cells10061332. [PMID: 34071188 PMCID: PMC8227136 DOI: 10.3390/cells10061332] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/13/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.
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28
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Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression. Int J Mol Sci 2021; 22:ijms22115497. [PMID: 34071064 PMCID: PMC8197097 DOI: 10.3390/ijms22115497] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 02/07/2023] Open
Abstract
More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation and subsequently cause liver pathologies. During the initial phase of HBV infection, innate immunity is triggered leading to antiviral cytokines production, followed by activation and intrahepatic recruitment of the adaptive immune system resulting in successful virus elimination. In chronic HBV infection, significant alterations in both innate and adaptive immunity including expansion of regulatory cells, overexpression of co-inhibitory receptors, presence of abundant inflammatory mediators, and modifications in immune cell derived exosome release and function occurs, which overpower antiviral response leading to persistent viral infection and subsequent immune pathologies associated with disease progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, we discuss the current knowledge of innate and adaptive immune cells transformations that are associated with immunopathogenesis and disease outcome in CHB patients.
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