|
1
|
Rao J, Ye D, Ren A, He W, Zhang X, Chen P, Jian Q, Fu Z, Deng R, Hu Y, Gao Y, Ma Y. Macrophage Evolution during Progression of Hepatitis Virus B-Related Acute-on-Chronic Liver Failure. J Innate Immun 2024; 17:29-43. [PMID: 39637841 PMCID: PMC11753795 DOI: 10.1159/000542946] [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: 05/23/2024] [Accepted: 11/19/2024] [Indexed: 12/07/2024] Open
Abstract
INTRODUCTION Hepatitis B virus (HBV)-related liver diseases, including hepatitis, cirrhosis, and liver failure, seriously threaten human lives and health worldwide. Innate and adaptive immune cells are all thought to participate in HBV-related diseases. However, there is a lack of information on the comprehensive landscape of the immune microenvironment. METHODS In this study, single-cell ribonucleic acid sequencing was performed on liver samples obtained from patients diagnosed with hepatitis, cirrhosis, and acute-on-chronic liver failure, which were caused by HBV. Trajectory analysis was performed to analyze the evolution of cell subsets, and branch expression analysis modeling was applied to visualize the changes in gene expression during evolution. RESULTS Finally, there was a significant increase in adaptive immune cells in the hepatitis and cirrhosis groups, whereas more innate immune cells were observed in the liver failure group. Furthermore, we found that monocytes underwent remarkable transcriptomic changes into FABP5+ macrophages, promoting the degranulation and chemotaxis of neutrophils through RESISTIN signaling, and LGMN+ macrophages, with the sequential activation of antigen presentation and defense to pathogens through SPP1 signaling. CONCLUSION Macrophages were revealed as central to the progression of acute-on-chronic liver failure as they regulated the activation or inhibition of other immune cells, which could help in developing an effective novel therapy.
Collapse
Affiliation(s)
- Jiawei Rao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Dongmei Ye
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Ao Ren
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Wenjin He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Xuzhi Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Pengrui Chen
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Qian Jian
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Zongli Fu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Ronghai Deng
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Yixin Hu
- State Key Laboratory of Oncology in South China, Department of Ultrasound Sun Yat-Sen University Cancer Center, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China
| | - Yifang Gao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Yi Ma
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China
- Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
- Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| |
Collapse
|
|
2
|
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.
Collapse
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
| |
Collapse
|
|
3
|
Yang Zhou J. Innate immunity and early liver inflammation. Front Immunol 2023; 14:1175147. [PMID: 37205101 PMCID: PMC10187146 DOI: 10.3389/fimmu.2023.1175147] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/30/2023] [Indexed: 05/21/2023] Open
Abstract
The innate system constitutes a first-line defence mechanism against pathogens. 80% of the blood supply entering the human liver arrives from the splanchnic circulation through the portal vein, so it is constantly exposed to immunologically active substances and pathogens from the gastrointestinal tract. Rapid neutralization of pathogens and toxins is an essential function of the liver, but so too is avoidance of harmful and unnecessary immune reactions. This delicate balance of reactivity and tolerance is orchestrated by a diverse repertoire of hepatic immune cells. In particular, the human liver is enriched in many innate immune cell subsets, including Kupffer cells (KCs), innate lymphoid cells (ILCs) like Natural Killer (NK) cells and ILC-like unconventional T cells - namely Natural Killer T cells (NKT), γδ T cells and Mucosal-associated Invariant T cells (MAIT). These cells reside in the liver in a memory-effector state, so they respond quickly to trigger appropriate responses. The contribution of aberrant innate immunity to inflammatory liver diseases is now being better understood. In particular, we are beginning to understand how specific innate immune subsets trigger chronic liver inflammation, which ultimately results in hepatic fibrosis. In this review, we consider the roles of specific innate immune cell subsets in early inflammation in human liver disease.
Collapse
Affiliation(s)
- Jordi Yang Zhou
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
- Leibniz Institute for Immunotherapy, Regensburg, Germany
- *Correspondence: Jordi Yang Zhou,
| |
Collapse
|
|
4
|
Cao W, Lu H, Zhang L, Wang S, Deng W, Jiang T, Lin Y, Yang L, Bi X, Lu Y, Zhang L, Shen G, Liu R, Chang M, Wu S, Gao Y, Hao H, Xu M, Chen X, Hu L, Xie Y, Li M. Functional molecular expression of nature killer cells correlated to HBsAg clearance in HBeAg-positive chronic hepatitis B patients during PEG-IFN α-2a therapy. Front Immunol 2022; 13:1067362. [PMID: 36479104 PMCID: PMC9720173 DOI: 10.3389/fimmu.2022.1067362] [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: 10/11/2022] [Accepted: 11/02/2022] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE To explore whether the frequencies and functional molecules expression of Natural Killer cells (NK cells) are related to hepatitis B surface antigen (HBsAg) disappearance in hepatitis B e envelope antigen (HBeAg)-positive patients with chronic hepatitis B (CHB) throughout peginterferon alpha-2a (PEG-IFN α-2a) treatment. METHODS In this prospective research, HBeAg-positive patients with CHB received PEG-IFN α-2a treatment, completing 4-year follow-up. After PEG-IFN α-2a treatment, undetectable HBV DNA, HBsAg loss, and HBeAg disappearance were defined as functional cure. Proportions of NK, CD56dim, CD56bright, NKp46+, NKp46dim, NKp46high, and interferon alpha receptor 2 (IFNAR2)+ NK cells, and the mean fluorescence intensity (MFI) of NK cell surface receptors IFNAR2 and NKp46 were detected. RESULTS 66 patients were enrolled into the study in which 17 patients obtained functional cure. At baseline, hepatitis B virus desoxyribose nucleic acid (HBV DNA) titer in patients with functional cure was remarkably lower than that in Non-functional cure group. Compared with baseline, HBV DNA levels, HBsAg levels, and HBeAg levels significantly declined at week 12 and 24 of therapy in patients with functional cure. At baseline, the negative correlation between CD56bright NK% and HBV DNA and the negative correlation between CD56dim NK% and HBV DNA was showed; CD56bright NK% and IFNAR2 MFI in patients with functional cure were remarkably higher than those in patients without functional cure. After therapy, CD56bright NK% and NKp46high NK% in patients with functional cure were higher than those in patients without functional cure. In Functional cure group, after 24 weeks of treatment NK%, CD56bright NK%, IFNAR2 MFI weakly increased, and NKp46high NK% and NKp46 MFI significantly increased, meanwhile, CD56dim NK% and NKp46dim NK% decreased. Only NKp46 MFI increased after therapy in patients without functional cure. CONCLUSION The lower HBV DNA load and the higher CD56bright NK% before therapy, and the higher the post-treatment CD56bright NK%, IFNAR2 MFI, NKp46high NK%, the easier to achieve functional cure.
Collapse
Affiliation(s)
- Weihua Cao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Infectious Diseases, Miyun Teaching Hospital, Capital Medical University, Beijing, China
| | - Huihui Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Obstetrics and Gynecology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Luxue Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Infectious Disease Department, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shiyu Wang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Hongxiao Hao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoxue Chen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| |
Collapse
|
|
5
|
Wang J, Hou H, Mao L, Wang F, Yu J, Luo Y, Lin Q, Sun Z. TIGIT Signaling Pathway Regulates Natural Killer Cell Function in Chronic Hepatitis B Virus Infection. Front Med (Lausanne) 2022; 8:816474. [PMID: 35265633 PMCID: PMC8898961 DOI: 10.3389/fmed.2021.816474] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 12/29/2021] [Indexed: 12/24/2022] Open
Abstract
Background and Objective Persistent infection of hepatitis B virus (HBV) and liver damage in immune active chronic hepatitis B (CHB) could be partly due to the overreaction of natural killer (NK) cells, including pro-inflammatory cytokine secretion and cytotoxicity. An immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine–based inhibitory motif (ITIM) domain (TIGIT) is specifically expressed in NK cells. This study aims to investigate the role of the TIGIT signaling pathway in regulating NK cell functions in patients with CHB. Method We comparatively assessed the expression of TIGIT in NK cells of patients with immune active CHB (CHB-IA), carriers of immune control chronic HBV (CHB-IC), and healthy controls (HCs), and then explored mechanisms of the TIGIT signaling pathway in regulating NK cell-mediated liver injury by different molecular assessments. Result The expression of TIGIT in NK cells was enhanced in CHB-IC but was reduced in CHB-IA compared with the HC group. In patients with CHB-IA, the expression of TIGIT was inversely correlated with intensity of the liver damage. Moreover, TIGIT-NK cells show higher IFN-γ secretion capability, degranulation activity, and cytotoxicity but lower apoptosis than TIGIT+ NK cells. Blockade of the TIGIT pathway with anti-TIGIT antibody increased NK cell function, while activation of the TIGIT pathway with TIGIT Fc and CD155 Fc chimera protein down-regulated NK cell function. Conclusion Our data showed that the TIGIT signaling pathway participates in NK cell impairment, which could be used as a new therapeutic target to protect patients with chronic HBV infection from severe liver injury.
Collapse
Affiliation(s)
- Juan Wang
- Department of Blood Transfusion, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyan Hou
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Lie Mao
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Wang
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yu
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Luo
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qun Lin
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ziyong Sun
- Department of Laboratory Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
6
|
Association of PD-L1 gene polymorphisms and circulating sPD-L1 levels with HBV infection susceptibility and related liver disease progression. Gene 2022; 806:145935. [PMID: 34478821 DOI: 10.1016/j.gene.2021.145935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/08/2023]
Abstract
Soluble molecules of programmed death ligand 1 (sPD-L1) are known to modulate T-cell depletion, an important mechanism of hepatitis B virus (HBV) persistence and liver disease progression. In addition, PD-L1 polymorphisms in the 3'-UTR can influence PD-L1 expression and have been associated with cancer risk, although not definitively. The purpose of this study was to investigate the association of PD-L1 polymorphisms and circulating levels of sPD-L1 in HBV infection and live disease progression. In this study, five hundred fifty-one HBV infected patients of the three clinically well-defined subgroups chronic hepatitis B (CHB, n = 186), liver cirrhosis (LC, n = 142) and hepatocellular carcinoma (HCC, n = 223) and 240 healthy individuals (HC) were enrolled. PD-L1 polymorphisms (rs2297136 and rs4143815) were genotyped by in-house validated ARMS assays. Logistic regression models were applied in order to determine the association of PD-L1 polymorphisms with HBV infection as well as with progression of related liver diseases. Plasma sPD-L1 levels were quantified by ELISA assays. The PD-L1 rs2297136 AA genotype was associated with HBV infection susceptibility (HBV vs. HC: OR = 1.6; 95%CI = 1.1-2.3; p = 0.0087) and disease progression (LC vs. CHB: OR = 1.8; 95%CI = 1.1-2.9; p = 0.018). Whereas, the rs2297136 GG genotype was a protective factor for HCC development. Plasma sPD-L1 levels were significantly high in HBV patients (p < 0.0001) and higher in the LC followed by CHB and HCC groups. High sPD-L1 levels correlated with increased liver enzymes and with advanced liver disease progression (Child-pugh C > B > A, p < 0.0001) and BCLC classification (BCLC D > C > B > A, p = 0.031). We could, for the first time, conclude that PD-L1 rs2297136 polymorphism and plasma sPD-L1 protein levels associate with HBV infection and HBV-related liver disease progression.
Collapse
|
|
7
|
Philips CA, Ahamed R, Abduljaleel JK, Rajesh S, Augustine P. Critical Updates on Chronic Hepatitis B Virus Infection in 2021. Cureus 2021; 13:e19152. [PMID: 34733599 PMCID: PMC8557099 DOI: 10.7759/cureus.19152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global healthcare burden in the form of chronic liver disease, cirrhosis, liver failure and liver cancer. There is no definite cure for the virus and even though extensive vaccination programs have reduced the burden of liver disease in the future population, treatment options to eradicate the virus from the host are still lacking. In this review, we discuss in detail current updates on the structure and applied biology of the virus in the host, examine updates to current treatment and explore novel and state-of-the-art therapeutics in the pipeline for management of chronic HBV. Furthermore, we also specifically review clinical updates on HBV-related acute on chronic liver failure (ACLF). Current treatments for chronic HBV infection have seen important updates in the form of considerations for treating patients in the immune tolerant phase and some clarity on end points for treatment and decisions on finite therapy with nucleos(t)ide inhibitors. Ongoing cutting-edge research on HBV biology has helped us identify novel target areas in the life cycle of the virus for application of new therapeutics. Due to improvements in the area of genomics, the hope for therapeutic vaccines, vector-based treatments and focused management aimed at targeting host integration of the virus and thereby a total cure could become a reality in the near future. Newer clinical prognostic tools have improved our understanding of timing of specific treatment options for the catastrophic syndrome of ACLF secondary to reactivation of HBV. In this review, we discuss in detail pertinent updates regarding virus biology and novel therapeutic targets with special focus on the appraisal of prognostic scores and treatment options in HBV-related ACLF.
Collapse
Affiliation(s)
- Cyriac A Philips
- Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, IND
| | - Rizwan Ahamed
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Jinsha K Abduljaleel
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Sasidharan Rajesh
- Diagnostic and Interventional Radiology, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Philip Augustine
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| |
Collapse
|
|
8
|
Du Y, Anastasiou OE, Strunz B, Scheuten J, Bremer B, Kraft A, Kleinsimglinhaus K, Todt D, Broering R, Hardtke-Wolenski M, Wu J, Yang D, Dittmer U, Lu M, Cornberg M, Björkström NK, Khera T, Wedemeyer H. The impact of hepatitis B surface antigen on natural killer cells in patients with chronic hepatitis B virus infection. Liver Int 2021; 41:2046-2058. [PMID: 33794040 DOI: 10.1111/liv.14885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/28/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB). METHODS Eighty CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes. RESULTS Compared to the healthy controls, a reshaping of NK cell pool towards more CD56bright NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/mL) displayed an activated phenotype with increased expression of activation makers CD38, granzyme B and proliferation marker Ki-67 while presenting with defective functional responses (MIP-1β, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age. CONCLUSIONS The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance.
Collapse
Affiliation(s)
- Yanqin Du
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Olympia E Anastasiou
- Institute for Virology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Benedikt Strunz
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Janina Scheuten
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anke Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Center for Individualized Infection Medicine (CIIM), Hannover, Germany.,Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Karolina Kleinsimglinhaus
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Ruth Broering
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Matthias Hardtke-Wolenski
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ulf Dittmer
- Institute for Virology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Mengji Lu
- Institute for Virology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Center for Individualized Infection Medicine (CIIM), Hannover, Germany.,Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany.,German Center for Infection Research (DZIF), Braunschweig, Germany.,Cluster of Excellence Resolving Infection Susceptibility (RESIST:EXC), Hannover Medical School, Hannover, Germany
| | - Niklas K Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Tanvi Khera
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Braunschweig, Germany
| |
Collapse
|
|
9
|
Ochayon DE, Waggoner SN. The Effect of Unconventional Cytokine Combinations on NK-Cell Responses to Viral Infection. Front Immunol 2021; 12:645850. [PMID: 33815404 PMCID: PMC8017335 DOI: 10.3389/fimmu.2021.645850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 03/01/2021] [Indexed: 12/30/2022] Open
Abstract
Cytokines are soluble and membrane-bound factors that dictate immune responses. Dogmatically, cytokines are divided into families that promote type 1 cell-mediated immune responses (e.g., IL-12) or type 2 humoral responses (e.g., IL-4), each capable of antagonizing the opposing family of cytokines. The discovery of additional families of cytokines (e.g., IL-17) has added complexity to this model, but it was the realization that immune responses frequently comprise mixtures of different types of cytokines that dismantled this black-and-white paradigm. In some cases, one type of response may dominate these mixed milieus in disease pathogenesis and thereby present a clear therapeutic target. Alternatively, synergistic or blended cytokine responses may obfuscate the origins of disease and perplex clinical decision making. Most immune cells express receptors for many types of cytokines and can mediate a myriad of functions important for tolerance, immunity, tissue damage, and repair. In this review, we will describe the unconventional effects of a variety of cytokines on the activity of a prototypical type 1 effector, the natural killer (NK) cell, and discuss how this may impact the contributions of these cells to health and disease.
Collapse
Affiliation(s)
- David E. Ochayon
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Stephen N. Waggoner
- Center for Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| |
Collapse
|
|
10
|
The Characteristics of Natural Killer Cells in Chronic Hepatitis B Patients Who Received PEGylated-Interferon versus Entecavir Therapy. BIOMED RESEARCH INTERNATIONAL 2021; 2021:2178143. [PMID: 33575322 PMCID: PMC7857883 DOI: 10.1155/2021/2178143] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 11/17/2020] [Accepted: 12/31/2020] [Indexed: 12/14/2022]
Abstract
Background To explore the role of natural killer (NK) cells in the process of hepatitis B virus (HBV) clearance and whether their phenotype is related to antiviral treatment outcome in chronic hepatitis B (CHB) patients. Method We performed a single-center prospective cohort study to analyze changes of NK cells at weeks 12 and 24 from baseline in CHB patients who received PEGylated-interferon- (PEG-IFN-) α-2a versus entecavir. The frequencies of NK, CD56bright, CD56dim, IFNAR2+, NKp46+, NKp46bright, and NKp46dim NK cells and mean fluorescence intensity (MFI) of receptors NKp46 and IFNAR2 on the surface of NK cells were measured. Subgroup analyses were performed by comparing treatment responders versus nonresponders with aforementioned parameters in each group. Results In PEG-IFN-α-treated patients, posttreatment CD56bright NK cell frequency increased, but CD56dim NK cell frequency decreased. Additionally, receptor NKp46 and IFNAR2 expression enhanced. In entecavir-treated patients, although NK cell frequency increased, CD56bright and CD56dim NK cell frequencies and IFNAR2 expression did not differ between baseline and posttreatment. In subgroup analyses, posttreatment CD56bright NK cell frequency and IFNAR2 expression significantly increased in PEG-IFN-α responders from baseline, while changes were absent in PEG-IFN-α nonresponders and entecavir treatment responders. Among patients with HBV viremia after entecavir therapy, NK cell frequency significantly increased, whereas NKp46bright and IFNAR2+ NK frequency and IFNAR2 MFI significantly decreased at 12 and 24 weeks from baseline. Conclusions In CHB patients, PEG-IFN-α treatment significantly enhanced NK cell frequency and function when compared to entacavir. Positive treatment responses to either interferon or entecavir were associated with NK cell function improvement. This trial is registered with clinical trial registration no. NCT03208998.
Collapse
|
|
11
|
Natural killer frequency determines natural killer cytotoxicity directly in accentuated zones and indirectly in "moderate-to-normal frequency" segment. Cent Eur J Immunol 2021; 45:315-324. [PMID: 33437184 DOI: 10.5114/ceji.2020.101263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 07/10/2018] [Indexed: 11/17/2022] Open
Abstract
Natural killer (NK) frequency and NK cytotoxicity (NKc) are key determining factors of a clinical outcome. In our previous study, we showed the prognostic clinical significance of immune parameters when they are beyond the optimal range (accentuated). In this study, we attempted to explain the disparity of accentuated but physiologically and immunologically normal NK parameters that might serve as negative clinical prognostics indications of failed pregnancies. We have analyzed NK%, NKc levels, and their reciprocal correlation in 2,804 patients with reproductive failures. In the entire clinical population, NK% correlates with NKc. Interestingly, we found this relationship to be strongly dependent on NK level's status. NK%-NKc correlation was the strongest (r = 0.2021, p < 0.0001) in a patient group with high NK% (> 17.5%). Patients with NK% between 15-17.5% manifested lower but still significant correlation NK%-NKc (r = 0.1213, p = 0.0155). Additionally, significant correlation (r = 0.2689, p < < 0.0001) between NK% and NKc was observed in a group of patients with NK levels < 7% (1.7-7%). While patients' groups with NK% (7-15%) did not reveal NK%-NKc association. This led us to hypothesize that the qualitative-quantitative status of NK population is responsible for their cytotoxic activity. Consistent with our hypothesis, the "balanced zone" NK% is tightly controlled, and thus does not correlate directly with NKc. In contrast, the "accentuated zones" of NK% escape this control and directly affecting NKc. Demonstrated phenomena supports our idea about the clinical significance of immune accentuation and explains its novel physiological role.
Collapse
|
|
12
|
Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer. Cell Mol Immunol 2020; 18:57-72. [PMID: 33041339 DOI: 10.1038/s41423-020-00561-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is a lymphoid organ with unique immunological properties, particularly, its predominant innate immune system. The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases, including hepatotropic virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, and liver cancer, which are major health problems globally. In the past decade, with the discovery of liver-resident natural killer cells, the importance of innate lymphocytes with tissue residency has gradually become the focus of research. In this review, we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics, including NK cells, ILC1/2/3s, NKT cells, γδ T cells, and MAIT cells, and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer. A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.
Collapse
|
|
13
|
Gu Y, Lian Y, Zheng Q, Huang Z, Gu L, Bi Y, Li J, Huang Y, Wu Y, Chen L, Huang Y. Association among cytokine profiles of innate and adaptive immune responses and clinical-virological features in untreated patients with chronic hepatitis B. BMC Infect Dis 2020; 20:509. [PMID: 32664850 PMCID: PMC7362653 DOI: 10.1186/s12879-020-05233-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 07/07/2020] [Indexed: 02/07/2023] Open
Abstract
Background Complete clearance of intracellular viruses depends on effector cells of innate and adaptive immune systems. This study aimed to identify the relationships among antiviral cytokines produced by natural killer (NK) and T cells and clinical-virological characteristics in untreated chronic hepatitis B (CHB) patients. Methods We measured antiviral cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) produced by T, NK and natural killer T (NKT) cells, respectively, in a cohort with chronic hepatitis B virus (HBV) infection (CHB). We also correlated these cytokines with clinical-virological characteristics using a linear regression model. Results levels of IFN-γ+ and TNF-α+ CD4+ and CD8+ T cells were significantly higher in immune active (IA) phase than in other phases. Immune tolerant (IT) patients showed the lowest expression of IFN-γ by NK and NKT cells, and TNF-α by NK cells. IFN-γ+, TNF-α+ and IL-2+ CD4+ and CD8+ T cells frequencies were similar between IA and gray zone (GZ) phases. Principal component analysis based on cytokines confirmed that most IT patients significantly differed from inactive carriers (IC) and IA patients, while GZ patients were widely scattered. Multivariate analysis showed both T and NK cells producing IFN-γ and TNF-α, but not IL-2, had significant association with serum alanine aminotransferase (ALT). Moreover, IFN-γ+ NKT cells were associated with HBV DNA, while IFN-γ+ CD4+ and CD8+ T cells were correlated with age. Conclusion HBV clinical phases are characterized by distinct cytokine signatures, which showed relationship to viral features in these untreated CHB patients.
Collapse
Affiliation(s)
- Yurong Gu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Qiaolan Zheng
- Journal Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Zexuan Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Lin Gu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yanhua Bi
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Jing Li
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yanlin Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Yuankai Wu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China
| | - Lubiao Chen
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China.
| | - Yuehua Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China. .,Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tian He Rd, Guangzhou, 510630, China.
| |
Collapse
|
|
14
|
Immunopathogenesis of HBV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:71-107. [DOI: 10.1007/978-981-13-9151-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
15
|
Fisicaro P, Rossi M, Vecchi A, Acerbi G, Barili V, Laccabue D, Montali I, Zecca A, Penna A, Missale G, Ferrari C, Boni C. The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy. Int J Mol Sci 2019; 20:ijms20205080. [PMID: 31614928 PMCID: PMC6834135 DOI: 10.3390/ijms20205080] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/09/2019] [Accepted: 10/10/2019] [Indexed: 12/12/2022] Open
Abstract
Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines and by exerting cytotoxic functions against virus-infected cells. However, in patients with chronic hepatitis B, NK cells have been described to be more pathogenic than protective with preserved cytolytic activity but with a poor capacity to produce anti-viral cytokines. In addition, NK cells can exert a regulatory activity and possibly suppress adaptive immune responses in the setting of persistent viral infections. Consequently, a potential drawback of NK-cell targeted modulatory interventions is that they can potentiate the suppressive NK cell effect on virus-specific T cells, which further causes impairment of exhausted anti-viral T cell functions. Thus, clinically useful NK-cell modulatory strategies should be not only suited to improve positive anti-viral NK cell functions but also to abrogate T cell suppression by NK cell-mediated T cell killing. This review outlines the main NK cell features with a particular focus on CHB infection. It describes different mechanisms involved in NK-T cell interplay as well as how NK cells can have positive anti-viral effector functions and negative suppressive effects on T cells activity. This review discusses how modulation of their balance can have potential therapeutic implications.
Collapse
Affiliation(s)
- Paola Fisicaro
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Marzia Rossi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Andrea Vecchi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Greta Acerbi
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Valeria Barili
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Diletta Laccabue
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Ilaria Montali
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Alessandra Zecca
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Amalia Penna
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| | - Gabriele Missale
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Carlo Ferrari
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.
| | - Carolina Boni
- Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda-Ospedaliero-Universitaria di Parma, 43126 Parma, Italy.
| |
Collapse
|
|
16
|
Polo ML, Ghiglione YA, Salido JP, Urioste A, Poblete G, Sisto AE, Martinez A, Rolón MJ, Ojeda DS, Cahn PE, Turk GJ, Laufer NL. Liver cirrhosis in HIV/HCV-coinfected individuals is related to NK cell dysfunction and exhaustion, but not to an impaired NK cell modulation by CD4 + T-cells. J Int AIDS Soc 2019; 22:e25375. [PMID: 31536177 PMCID: PMC6752153 DOI: 10.1002/jia2.25375] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 07/24/2019] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION HIV worsens HCV-related liver disease by accelerating fibrosis progression; however, progression rates are extremely variable among HIV/HCV-coinfected individuals. NK cells are associated with modulation of liver fibrosis and are profoundly altered during HCV and HIV infections. CD4+ T-cells modulate NK cell function, and are also affected by HIV infection. Here, we aim to characterize the association of hepatic fibrosis with both the phenotype and function of peripheral NK cells and their regulation by CD4+ T-cells, in HIV/HCV-coinfected individuals. METHODS Thirty-four HIV/HCV-coinfected individuals with minimal (n = 16) and advanced (n = 18) fibrosis (METAVIR F0/F1 and F4 scores respectively) and 20 healthy volunteers were enrolled. PBMC were obtained from peripheral blood samples and NK and CD4+ T-cells were isolated and analysed. NK cell phenotype (CD25, CD69, Nkp46, NKG2D, PD-1), degranulation (CD107a) and IFN-γ and TNF-α production, as well as CD4+ T-cell activation (CD69, CD25 and CD38) were measured by flow cytometry. CD4+ T-cell conditioned medium (CM) derived from F0/F1 or F4 individuals was assessed for IL-2 levels by ELISA. Modulation of NK cell functionality by these CMs was also analysed. RESULTS When comparing to NK cells from individuals with minimal fibrosis, degranulation and cytokine secretion by NK cells from subjects with F4 scores was significantly impaired, while PD-1 expression was augmented. On the one hand, neither the expression of activation markers nor IL-2 secretion was distinctly induced in CD4+ T-cells from subjects with F0/F1 or F4 METAVIR scores. Finally, NK cell degranulation and cytokine secretion were not differentially modulated by CD4+ T-cell CM, whether CD4+ T-cells derived from subjects with minimal or advanced fibrosis. CONCLUSIONS Low levels of NK and CD4+ T-cells in HIV/HCV-coinfected individuals with advanced liver fibrosis have been previously described. Here, we show that advanced liver fibrosis in coinfected individuals is associated to a defective function of NK cells and an increased expression of the exhaustion/senescence marker PD-1. This NK signature could not be attributed to changes in the ability of CD4+ T-cells to modulate NK cell function.
Collapse
Affiliation(s)
- María L Polo
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
| | - Yanina A Ghiglione
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
| | - Jimena P Salido
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
| | - Alejandra Urioste
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
| | - Gabriela Poblete
- Infectious Diseases UnitHospital General de Agudos “Dr. JA Fernández”Buenos AiresArgentina
| | - Alicia E Sisto
- Infectious Diseases UnitHospital General de Agudos “Dr. JA Fernández”Buenos AiresArgentina
| | - Ana Martinez
- Gastroenterology UnitHospital General de Agudos “Dr. JA Fernández”Buenos AiresArgentina
| | - María J Rolón
- Infectious Diseases UnitHospital General de Agudos “Dr. JA Fernández”Buenos AiresArgentina
| | - Diego S Ojeda
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
| | | | - Gabriela J Turk
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
| | - Natalia L Laufer
- CONICET‐Universidad de Buenos AiresInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS)Buenos AiresArgentina
- Infectious Diseases UnitHospital General de Agudos “Dr. JA Fernández”Buenos AiresArgentina
| |
Collapse
|
|
17
|
Wijaya RS, Read SA, Schibeci S, Eslam M, Azardaryany MK, El-Khobar K, van der Poorten D, Lin R, Yuen L, Lam V, George J, Douglas MW, Ahlenstiel G. KLRG1+ natural killer cells exert a novel antifibrotic function in chronic hepatitis B. J Hepatol 2019; 71:252-264. [PMID: 30905683 DOI: 10.1016/j.jhep.2019.03.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 03/06/2019] [Accepted: 03/07/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Natural killer (NK) cells are known to exert strong antiviral activity. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is expressed by terminally differentiated NK cells and KLRG1-expressing lymphocytes are known to expand following chronic viral infections. We aimed to elucidate the previously unknown role of KLRG1 in the pathogenesis of chronic hepatitis B (CHB). METHODS KLRG1+ NK cells were taken from the blood and liver of healthy individuals and patients with CHB. The phenotype and function of these cells was assessed using flow cytometry and in vitro stimulation. RESULTS Patients with CHB had a higher frequency of KLRG1+ NK cells compared to healthy controls (blood 13.4 vs. 2.3%, p <0.0001 and liver 23.4 vs. 2.6%, p <0.01). KLRG1+ NK cells were less responsive to K562 and cytokine stimulation, but demonstrated enhanced cytotoxicity (9.0 vs. 4.8%, p <0.05) and IFN-γ release (8.0 vs. 1.5%, p <0.05) via antibody dependent cellular cytotoxicity compared to their KLRG1- counterparts. KLRG1+ NK cells possessed a mature phenotype, demonstrating stronger cytolytic activity and IFN-γ secretion against hepatic stellate cells (HSCs) than KLRG1- NK cells. Moreover, KLRG1+ NK cells more effectively induced primary HSC apoptosis in a TRAIL-dependent manner. Increased KLRG1+ NK cell frequency in the liver and blood was associated with lower fibrosis stage (F0/F1) in patients with CHB. Finally, the expression of CD44, degranulation and IFN-γ production were all increased in KLRG1+ NK cells following stimulation with osteopontin, the CD44 ligand, suggesting that HSC-derived osteopontin may cause KLRG1+ NK cell activation. CONCLUSIONS KLRG1+ NK cells likely play an antifibrotic role during the natural course of CHB infection. Harnessing this antifibrotic function may provide a novel therapeutic approach to treat liver fibrosis in patients with CHB. LAY SUMMARY Individuals that are chronically infected with hepatitis B virus (HBV) possess an increased number of immune cells, called natural killer (NK) cells expressing the surface marker KLRG1 in the blood and liver. Here, we demonstrate that these specific NK cells are able to kill activated stellate cells in the liver. Because activated stellate cells contribute to liver scarring, i.e. fibrosis, and subsequent liver dysfunction in individuals with chronic HBV infection, KLRG1+ NK cells are a novel immune cell type that can limit liver scarring.
Collapse
Affiliation(s)
- Ratna S Wijaya
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia
| | - Scott A Read
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia
| | - Stephen Schibeci
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia
| | - Mohammed Eslam
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia
| | - Mahmoud K Azardaryany
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia
| | - Korri El-Khobar
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia
| | | | - Rita Lin
- Westmead Hospital, University of Sydney, NSW, Australia
| | - Lawrence Yuen
- Westmead Hospital, University of Sydney, NSW, Australia; Discipline of Surgery, University of Sydney, Australia
| | - Vincent Lam
- Westmead Hospital, University of Sydney, NSW, Australia; Discipline of Surgery, University of Sydney, Australia
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Westmead Hospital, University of Sydney, NSW, Australia
| | - Mark W Douglas
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Westmead Hospital, University of Sydney, NSW, Australia; Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead NSW 2145, Australia
| | - Golo Ahlenstiel
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148, Australia; Blacktown Hospital, Blacktown, NSW 2148, Australia.
| |
Collapse
|
|
18
|
Chen Y, Hao X, Sun R, Wei H, Tian Z. Natural Killer Cell-Derived Interferon-Gamma Promotes Hepatocellular Carcinoma Through the Epithelial Cell Adhesion Molecule-Epithelial-to-Mesenchymal Transition Axis in Hepatitis B Virus Transgenic Mice. Hepatology 2019; 69:1735-1750. [PMID: 30329167 DOI: 10.1002/hep.30317] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 10/09/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) is a major risk factor for development of hepatocellular carcinoma (HCC), at least partially due to dysfunctional anti-HBV adaptive immunity; however, the role of innate immune response to HBV in this process is not well understood. In this study, low-dose polyinosinic:polycytidylic acid (poly [I:C]), a natural killer (NK) cell activator (3 μg/g body weight, twice/week for 8 weeks), induced HCC in HBV transgenic (HBs-Tg) mice, with an incidence of 100% after 6 months, while HBs-Tg mice without treatment only had HCC with an incidence of 16.7%. In HBs-Tg mice, poly (I:C) induced liver inflammation with markedly increased infiltrating lymphocytes, along with the concurrently increased apoptosis and proliferation of hepatocytes, leading to the accelerated epithelial-to-mesenchymal transition (EMT) of hepatocytes shown by increased expression of the typical transcriptional factors (Slug, Twist, and mothers against decapentaplegic-interacting protein 1) and phenotypic proteins (vimentin and chemokine [C-X-C motif] receptor 4). The EMT and tumorigenesis in this model depended on the presence of NK cells because depletion of these cells significantly reduced the HCC rate to 28.6%. Further, intrahepatic NK cells highly expressed interferon-gamma (IFN-γ), anti-IFN-γ neutralizing monoclonal antibody might obviously alleviate the hepatitis, and hepatocyte-specific IFN-γ overexpression promoted HCC. Moreover, IFN-γ deficiency in HBs-Tg mice prevented HCC occurring, though hepatic NK cells existed and could be activated, suggesting the critical role of IFN-γ in NK cell-mediated tumorigenesis. In an in vitro experiment, IFN-γ up-regulated epithelial cell adhesion molecule (EpCAM) expression through phosphorylated signal transducer and activator of transcription (p-STAT1) pathway, which was followed by EMT, and p-STAT1 inhibitor might absolutely abolish the expression of EpCAM and EMT in HBV surface antigen-positive hepatocytes. Conclusion: This work demonstrates that NK cell-derived IFN-γ promotes HCC through the EpCAM-EMT axis in HBs-Tg mice, revealing the importance of innate immunity in pathogenesis of HBV-associated HCC.
Collapse
Affiliation(s)
- Yongyan Chen
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, and Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Xiaolei Hao
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, and Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Rui Sun
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, and Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, and Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, and Institute of Immunology, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
19
|
Stojanovic B, Milovanovic J, Arsenijevic A, Stojanovic B, Strazic Geljic I, Arsenijevic N, Jonjic S, Lukic ML, Milovanovic M. Galectin-3 Deficiency Facilitates TNF-α-Dependent Hepatocyte Death and Liver Inflammation in MCMV Infection. Front Microbiol 2019; 10:185. [PMID: 30800112 PMCID: PMC6376859 DOI: 10.3389/fmicb.2019.00185] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/23/2019] [Indexed: 12/12/2022] Open
Abstract
Galectin-3 (Gal-3) has a role in multiple inflammatory pathways. Various, opposite roles of Gal-3 in liver diseases have been described but there are no data about the role of Gal-3 in development of hepatitis induced with cytomegalovirus infection. In this study we aimed to clarify the role of Gal-3 in murine cytomegalovirus (MCMV)-induced hepatitis by using Gal-3-deficient (Gal-3 KO) mice. Here we provide the evidence that Gal-3 has the protective role in MCMV-induced hepatitis. Enhanced hepatitis manifested by more inflammatory and necrotic foci and serum level of ALT, enhanced apoptosis and necroptosis of hepatocytes and enhanced viral replication were detected in MCMV-infected Gal-3 deficient mice. NK cells does not contribute to more severe liver damage in MCMV-infected Gal-3 KO mice. Enhanced expression of TNF-α in the hepatocytes of Gal-3 KO mice after MCMV infection, abrogated hepatocyte death, and attenuated inflammation in the livers of Gal-3 KO mice after TNF-α blockade suggest that TNF-α plays the role in enhanced disease in Gal-3 deficient animals. Treatment with recombinant Gal-3 reduces inflammation and especially necrosis of hepatocytes in the livers of MCMV-infected Gal-3 KO mice. Our data highlight the protective role of Gal-3 in MCMV-induced hepatitis by attenuation of TNF-α-mediated death of hepatocytes.
Collapse
Affiliation(s)
- Bojana Stojanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Faculty of Medical Sciences, Institute of Pathophysiology, University of Kragujevac, Kragujevac, Serbia
| | - Jelena Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia.,Faculty of Medical Sciences, Institute of Histology, University of Kragujevac, Kragujevac, Serbia
| | - Aleksandar Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Bojan Stojanovic
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Ivana Strazic Geljic
- Department for Histology and Embryology, Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Stipan Jonjic
- Department for Histology and Embryology, Center for Proteomics, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Miodrag L Lukic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Marija Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| |
Collapse
|
|
20
|
NK cells in liver homeostasis and viral hepatitis. SCIENCE CHINA-LIFE SCIENCES 2018; 61:1477-1485. [PMID: 30421296 DOI: 10.1007/s11427-018-9407-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 08/15/2018] [Indexed: 12/11/2022]
Abstract
As an important member of the innate immune system, natural killer (NK) cells are well known for their rapid and efficient immune responses against infectious agents and tumors. NK cells are widely distributed throughout the body and are particularly enriched within the liver, where they display unique phenotypic and functional properties, playing important roles in various liver diseases. Herein, we present an overview of liver NK cell properties with regard to phenotype, function, and subset composition at steady state, and we also summarize the complex reciprocal interactions between liver NK cells and other cell types within the local environment of the liver. We also provide an overview of recent advances demonstrating the roles of NK cells in viral hepatitis, including a discussion of NK cell altered states and their beneficial versus harmful effects during hepatitis B virus and hepatitis C virus infection.
Collapse
|
|
21
|
Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice. J Virol 2018; 92:JVI.01083-18. [PMID: 30111561 DOI: 10.1128/jvi.01083-18] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 08/07/2018] [Indexed: 01/22/2023] Open
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe hepatic injury in humans. However, the mechanism(s) causing this damage is poorly characterized. CCHFV produces an acute disease, including liver damage, in mice lacking type I interferon (IFN-I) signaling due to either STAT-1 gene deletion or disruption of the IFN-I receptor 1 gene. Here, we explored CCHFV-induced liver pathogenesis in mice using an antibody to disrupt IFN-I signaling. When IFN-I blockade was induced within 24 h postexposure to CCHFV, mice developed severe disease with greater than 95% mortality by 6 days postexposure. In addition, we observed increased proinflammatory cytokines, chemoattractants, and liver enzymes in these mice. Extensive liver damage was evident by 4 days postexposure and was characterized by hepatocyte necrosis and the loss of CLEC4F-positive Kupffer cells. Similar experiments in CCHFV-exposed NOD-SCID-γ (NSG), Rag2-deficient, and perforin-deficient mice also demonstrated liver injury, suggesting that cytotoxic immune cells are dispensable for hepatic damage. Some apoptotic liver cells contained viral RNA, while other apoptotic liver cells were negative, suggesting that cell death occurred by both intrinsic and extrinsic mechanisms. Protein and transcriptional analysis of livers revealed that activation of tumor necrosis factor superfamily members occurred by day 4 postexposure, implicating these molecules as factors in liver cell death. These data provide insights into CCHFV-induced hepatic injury and demonstrate the utility of antibody-mediated IFN-I blockade in the study of CCHFV pathogenesis in mice.IMPORTANCE CCHFV is an important human pathogen that is both endemic and emerging throughout Asia, Africa, and Europe. A common feature of acute disease is liver injury ranging from mild to fulminant hepatic failure. The processes through which CCHFV induces severe liver injury are unclear, mostly due to the limitations of existing small-animal systems. The only small-animal model in which CCHFV consistently produces severe liver damage is mice lacking IFN-I signaling. In this study, we used antibody-mediated blockade of IFN-I signaling in mice to study CCHFV liver pathogenesis in various transgenic mouse systems. We found that liver injury did not depend on cytotoxic immune cells and observed extensive activation of death receptor signaling pathways in the liver during acute disease. Furthermore, acute CCHFV infection resulted in a nearly complete loss of Kupffer cells. Our model system provides insight into both the molecular and the cellular features of CCHFV hepatic injury.
Collapse
|
|
22
|
Tang J, Wu ZY, Dai RJ, Ma J, Gong GZ. Hepatitis B virus-persistent infection and innate immunity defect: Cell-related or virus-related? World J Clin Cases 2018; 6:233-241. [PMID: 30211203 PMCID: PMC6134278 DOI: 10.12998/wjcc.v6.i9.233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/31/2018] [Accepted: 08/07/2018] [Indexed: 02/05/2023] Open
Abstract
The outcomes of hepatitis B virus (HBV) infection are closely related to the age at which infection was acquired. Infection acquired in adult life tends to be self-limited, in contrast to perinatal acquirement, for which chronic persistence of the HBV is a general outcome. Innate immunity plays an indispensable role in early virus infection, facilitating virus clearance. However, it has been reported that HBV is under-recognized and poorly eliminated by the innate immune system in the early stages of infection, possibly explaining the long-lasting persistence of viremia afterwards. Furthermore, due to the existence of covalently closed circular DNA, chronic HBV clearance is very difficult, even when patients are given interferon-α and nucleotide/nucleoside analogs for antiviral therapy. The mechanism by which HBV evades innate immune recognition and establishes persistent infection remains a subject of debate. Besides, some researchers are becoming more interested in how to eradicate chronic HBV infection by restoring or boosting innate immunity. This review aimed to summarize the current knowledge on how intrahepatocyte signaling pathways and innate immune cells act after the onset of HBV infection and how these actions are related to the persistence of HBV. We anticipate the insights presented herein to be helpful for future development of novel immune therapeutic strategies to fight HBV infection.
Collapse
Affiliation(s)
- Jian Tang
- Department of Infectious Disease, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Zhen-Yu Wu
- Department of Infectious Disease, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Rong-Juan Dai
- Department of Infectious Disease, the First Affiliated Hospital of University of South China, Hengyang 421001, Hunan Province, China
| | - Jing Ma
- Department of Infectious Disease, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Guo-Zhong Gong
- Department of Infectious Disease, the Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| |
Collapse
|
|
23
|
Mf Akbar S, Al-Mahtab M, I Khan S. Nature of Host Immunity during Hepatitis B Virus Infection and designing Immune Therapy. Euroasian J Hepatogastroenterol 2018; 8:42-46. [PMID: 29963460 PMCID: PMC6024052 DOI: 10.5005/jp-journals-10018-1256] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/14/2018] [Indexed: 12/23/2022] Open
Abstract
Hepatitis B virus (HBV) infections represent one of the major public health problems in global context. More than 2 billion people in the world have been infected with this virus at some point of time in their life and millions are chronically infected, indicating that chronic HBV-infected subjects remain as a living source of HBV transmission. The public health impact of this is tremendous. Considerable numbers of chronic HBV-infected individuals would eventually develop progressive liver diseases and their complications like hepatic failure, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Epidemiological studies have suggested that about 0.6 to 1.2 million people die annually from HBV-related liver diseases. These figures about death due to HBV and sufferings from HBV-related diseases indicate a notion of medical emergencies about HBV. In addition to these, the impact of HBV on health care delivery system moves beyond these numbers of HBV-related patients and HB-related deaths. This is because significant insights have already been developed about epidemiology, virology, and pathogenesis of HBV. Also, an effective and widely used preventive vaccine is available against HBV. In addition to these, antiviral drugs against HBV have been developed from early 1980s and several such drugs are now available commercially in the open market around the worldwide. Unfortunately, the ongoing therapeutic regimens could not stand the test of time and new insights about HBV pathogenesis are required for the development of new, novel, and evidence-based therapies for chronic HBV infections. How to cite this article: Akbar SMF, Al-Mahtab M, Khan SI. Nature of Host Immunity during Hepatitis B Virus Infection and designing Immune Therapy. Euroasian J Hepato-Gastroenterol 2018;8(1):42-46.
Collapse
Affiliation(s)
- Sheikh Mf Akbar
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan and Miyakawa Memorial Research Foundation, Tokyo Japan
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Sakirul I Khan
- Department of Anatomy and Embryology, Graduate School of Medicine, Ehime University, Ehime, Japan
| |
Collapse
|
|
24
|
Zheng M, Sun H, Tian Z. Natural killer cells in liver diseases. Front Med 2018; 12:269-279. [PMID: 29675689 DOI: 10.1007/s11684-018-0621-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 12/06/2017] [Indexed: 12/12/2022]
Abstract
The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct "killer" functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.
Collapse
Affiliation(s)
- Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
| | - Haoyu Sun
- Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China
| | - Zhigang Tian
- Institute of Immunology, Key Laboratory of Innate Immunity and Chronic Disease of Chinese Academy of Sciences, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China
| |
Collapse
|
|
25
|
Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol 2018; 326:52-59. [PMID: 28860007 DOI: 10.1016/j.cellimm.2017.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 08/02/2017] [Accepted: 08/04/2017] [Indexed: 02/07/2023]
|
|
26
|
Association between IRF1 Gene Expression and Liver Enzymes in HBV-infected Liver Transplant Recipients with and without Experience of Rejection. Int J Organ Transplant Med 2018; 9:68-74. [PMID: 30834090 PMCID: PMC6390982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Liver function indices and anti-viral immune regulatory markers can both improve graft outcomes, which lead to better post-transplantation management and increase the possibility of surveillance in liver transplant recipients with chronic hepatitis B virus (HBV) infection. OBJECTIVE To determine the association between the interferon regulatory factor 1 (IRF1) mRNA levels and liver enzymes in HBV-infected liver transplant recipients with and without experience of rejection. METHODS A total of 46 chronic HBV-infected patients who had undergone liver transplant surgery was divided into 2 groups of recipients "with rejection" and "without rejection.". Blood samples were collected form each patient on days 1, 4, and 7 post-transplantation. A SYBER GREEN real-time PCR was used to evaluate the expression level of IRF1 in liver recipients. Liver enzyme activities were also measured in all patients. RESULTS The expression of IRF1 in the patients with rejection was up-regulated at all 3 follow-up days compared with those without rejection. The serum levels of ALT and AST were more than normal levels at 3 follow-up times in both study groups. Significant differences were found in IRF1 gene expression levels and also serum ALT levels between those with and without rejection after 7 days post-transplantation. CONCLUSION The IRF1 expression and serum ALT levels were increased significantly in patient with rejection compared to those without rejection. IRF1, an inflammatory factor, may also intensify induction of inflammatory pathways in engrafted liver and promote liver inflammation and injuries leading to liver enzymes elevation in patients with graft rejection.
Collapse
|
|
27
|
Keawvichit R, Khowawisetsut L, Lertjuthaporn S, Tangnararatchakit K, Apiwattanakul N, Yoksan S, Chuansumrit A, Chokephaibulkit K, Ansari AA, Onlamoon N, Pattanapanyasat K. Differences in activation and tissue homing markers of natural killer cell subsets during acute dengue infection. Immunology 2017; 153:455-465. [PMID: 29105052 DOI: 10.1111/imm.12858] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 10/27/2017] [Accepted: 10/29/2017] [Indexed: 12/25/2022] Open
Abstract
Dengue virus (DENV) infection is considered one of the most important mosquito-borne diseases. It causes a spectrum of illness that could be due to qualitative and/or quantitative difference(s) of the natural killer (NK) cell responses during acute DENV infection. This view prompted us to perform a detailed phenotypic comparative characterization of NK cell subsets from DENV-infected patients with dengue fever (DF), patients with dengue haemorrhagic fever (DHF) and healthy controls. The activation/differentiation molecules, CD69 and CD57 and a variety of tissue homing molecules were analysed on the CD56hi CD16- and CD56lo CD16+ NK cells. Although there was no increase in the frequency of the total NK cells during DENV infection compared with the healthy individuals, there was a significant increase in the frequency of the CD56hi CD16- subset and the frequency of CD69 expression by both NK cell subsets during the febrile phase of infection. We also found an increase in the frequencies of cells expressing CD69 and CD57 in the CD56lo CD16+ subset compared with those in the CD56hi CD16- subset. Moreover, although the CD56lo CD16+ subset contained a high frequency of cells expressing skin-homing markers, the CD56hi CD16- subset contained a high frequency of cells expressing bone marrow and lymph node trafficking markers. Interestingly, no differences of these NK cell subsets were noted in samples from patients with DF versus those with DHF. These findings suggest that activation and differentiation and the patterns of tissue homing molecules of the two major NK cell subsets are different and that these might play a critical role in the immune response against acute DENV infection.
Collapse
Affiliation(s)
- Rassamon Keawvichit
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ladawan Khowawisetsut
- Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sakaorat Lertjuthaporn
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.,Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kanchana Tangnararatchakit
- Department of Paediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Nopporn Apiwattanakul
- Department of Paediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Sutee Yoksan
- Centre for Vaccine Development, Institute of Molecular Biosciences, Mahidol University, Nakorn Pathom, Thailand
| | - Ampaiwan Chuansumrit
- Department of Paediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Kulkanya Chokephaibulkit
- Department of Paediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Aftab A Ansari
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Nattawat Onlamoon
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kovit Pattanapanyasat
- Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
28
|
Ortega-Prieto AM, Dorner M. Immune Evasion Strategies during Chronic Hepatitis B and C Virus Infection. Vaccines (Basel) 2017; 5:E24. [PMID: 28862649 PMCID: PMC5620555 DOI: 10.3390/vaccines5030024] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 08/25/2017] [Accepted: 08/30/2017] [Indexed: 12/15/2022] Open
Abstract
Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are a major global healthcare problem with more than 240 million and 70 million infected, respectively. Both viruses persist within the liver and result in progressive liver disease, resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma. Strikingly, this pathogenesis is largely driven by immune responses, unable to clear an established infection, rather than by the viral pathogens themselves. Even though disease progression is very similar in both infections, HBV and HCV have evolved distinct mechanisms, by which they ensure persistence within the host. Whereas HCV utilizes a cloak-and-dagger approach, disguising itself as a lipid-like particle and immediately crippling essential pattern-recognition pathways, HBV has long been considered a "stealth" virus, due to the complete absence of innate immune responses during infection. Recent developments and access to improved model systems, however, revealed that even though it is among the smallest human-tropic viruses, HBV may, in addition to evading host responses, employ subtle immune evasion mechanisms directed at ensuring viral persistence in the absence of host responses. In this review, we compare the different strategies of both viruses to ensure viral persistence by actively interfering with viral recognition and innate immune responses.
Collapse
Affiliation(s)
| | - Marcus Dorner
- Section of Virology, Department of Medicine, Imperial College London, London W2 1PG, UK.
| |
Collapse
|
|
29
|
Increased level and interferon-γ production of circulating natural killer cells in patients with scrub typhus. PLoS Negl Trop Dis 2017; 11:e0005815. [PMID: 28750012 PMCID: PMC5549767 DOI: 10.1371/journal.pntd.0005815] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 08/08/2017] [Accepted: 07/19/2017] [Indexed: 12/27/2022] Open
Abstract
Background Natural killer (NK) cells are essential immune cells against several pathogens. Not much is known regarding the roll of NK cells in Orientia tsutsugamushi infection. Thus, this study aims to determine the level, function, and clinical relevance of NK cells in patients with scrub typhus. Methodology/Principal findings This study enrolled fifty-six scrub typhus patients and 56 health controls (HCs). The patients were divided into subgroups according to their disease severity. A flow cytometry measured NK cell level and function in peripheral blood. Circulating NK cell levels and CD69 expressions were significantly increased in scrub typhus patients. Increased NK cell levels reflected disease severity. In scrub typhus patients, tests showed their NK cells produced higher amounts of interferon (IFN)-γ after stimulation with interleukin (IL)-12 and IL-18 relative to those of HCs. Meanwhile, between scrub typhus patients and HCs, the cytotoxicity and degranulation of NK cells against K562 were comparable. CD69 expressions were recovered to the normal levels in the remission phase. Conclusions This study shows that circulating NK cells are activated and numerically increased, and they produced more IFN-γ in scrub typhus patients. Orientia tsutsugamushi is an obligate intracellular bacterium. It primarily invades endothelial cells, macrophages, monocytes, and dendritic cells. Plasma concentrations of interferon (IFN)-γ, several cytokines and chemokines, which are known to recruit natural killer (NK) cells and T cells, were found to be increased in scrub typhus patients. NK cells are known as essential immune cells against several pathogens. In murine models of Rickettsial infection, the clearance of bacteria was found to be significantly associated with NK cell activity. Not much is known regarding NK cells’ role in O. tsutsugamushi infection in humans. This study is very possibly the first to measure NK cells’ level and function of in scrub typhus patients, or to examine NK cell levels’ clinical relevance. This study’s results demonstrate that circulating NK cells are activated and numerically increased in scrub typhus patients. Notably, increased production IFN-γ by NK cells of scrub typhus patients suggests their contribution to enhancement of intracellular bacterial killing in infected antigen presenting cells. Moreover, disease severity corresponded to increased NK cell levels. These findings importantly suggest that NK cells play a role in protecting the host against O. tsutsugamushi infection.
Collapse
|
|
30
|
Ji W, Chen J, Mi Y, Wang G, Xu X, Wang W. Role of natural killer cells in liver transplantation treatment of liver cancer. Exp Ther Med 2017; 14:2380-2384. [PMID: 28962171 DOI: 10.3892/etm.2017.4748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 02/10/2017] [Indexed: 02/07/2023] Open
Abstract
Liver cancer caused by diet or life style is a significant public health problem. Liver transplantation (LT) is a commonly used method of treatment for the liver cancer. The present study aimed to determine whether assessing the net state of natural killer (NK) cell function following LT distinguishes patients at risk for transplantation rejection. A total of 53 patients were involved; all underwent LT for hepatocellular carcinoma with (n=13) or without (n=40) transplantation rejection. The density of interferon-γ (IFN-γ) in blood serum was examined and patients were divided into two groups: Higher (H) and lower (L), on the basis of IFN-γ density. The percentage of NK cells and their producing cytokines was detected using fluorescence-activated cell sorting in peripheral blood and liver samples. As evaluation indexes of liver function, aspartate transaminase (AST) and alanine transaminase (ALT) were detected in blood serum. NK cell activation of the H-group was observed to be higher than the L-group, specifically the expression of NK group 2D, cluster of differentiation 69 and IFN-γ were higher than the L-group. The H-group exhibited a higher level of AST and ALT, which indicates the potential for acute transplantation rejection. The results of the present study indicate that NK cells and NK-derived IFN-γ serve an important function in regulating the rejection of LT and tumor metastasis in response to LT.
Collapse
Affiliation(s)
- Wenbin Ji
- Department of Radiology, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Jin Chen
- Department of Radiology, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Yuche Mi
- Department of Radiology, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Guiliang Wang
- Department of Radiology, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Xinjiang Xu
- Department of Radiology, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| | - Weizheng Wang
- Department of Vascular Surgery, Taizhou Hospital of Wenzhou Medical University, Taizhou, Zhejiang 317000, P.R. China
| |
Collapse
|
|
31
|
Wang Y, Wang W, Shen C, Wang Y, Jiao M, Yu W, Yin H, Shang X, Liang Q, Zhao C. NKG2D modulates aggravation of liver inflammation by activating NK cells in HBV infection. Sci Rep 2017; 7:88. [PMID: 28273905 PMCID: PMC5427972 DOI: 10.1038/s41598-017-00221-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 02/14/2017] [Indexed: 12/19/2022] Open
Abstract
Hepatitis B virus (HBV) infection is thought to be an immune-mediated liver disease. The mechanisms underlying natural killer (NK) cell group 2D receptor (NKG2D) that activates NK cells and participates in anti-HBV immunity and immunopathology has not been thoroughly elucidated. Peripheral NKG2D+ and IFN-γ+ NK cells frequencies and intrahepatic NKG2D and IFN-γ mRNA and protein expressions were determined in HBV-infected patients. Levels of NKG2D and IFN-γ mRNA and protein in NK cells, co-cultured with HBV-replicating HepG2 cells with or without NKG2D blockade, were analyzed. Serum and supernatant IFN-γ, TNF-α, perforin and granzyme B were measured. In results, peripheral NKG2D+ and IFN-γ+ NK cells frequencies, intrahepatic NKG2D and IFN-γ mRNA and protein levels, and serum IFN-γ, TNF-α, perforin and granzyme B levels were all highest in HBV-related acute-on-chronic liver failure group, followed by chronic hepatitis B and chronic HBV carrier groups. In vitro, NKG2D and IFN-γ mRNA and protein levels were higher in NK cells with IFN-α stimulation than without stimulation. Supernatant IFN-γ, TNF-α, perforin and granzyme B levels were increased under co-culture or IFN-α stimulating conditions, but were partially blocked by NKG2DmAb. In conclusion, NKG2D regulates immune inflammation and anti-viral response partly through activation of NK cells during HBV infection.
Collapse
Affiliation(s)
- Yadong Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Wei Wang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chuan Shen
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Wang
- Department of Scientific Research, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Mingjing Jiao
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Weiyan Yu
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hongzhu Yin
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaobo Shang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qianfei Liang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
| | - Caiyan Zhao
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.
| |
Collapse
|
|
32
|
Sriram U, Hill BL, Cenna JM, Gofman L, Fernandes NC, Haldar B, Potula R. Impaired Subset Progression and Polyfunctionality of T Cells in Mice Exposed to Methamphetamine during Chronic LCMV Infection. PLoS One 2016; 11:e0164966. [PMID: 27760221 PMCID: PMC5070876 DOI: 10.1371/journal.pone.0164966] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 10/04/2016] [Indexed: 01/23/2023] Open
Abstract
Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host’s innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStone™ to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection. Furthermore, we have studied in detail the effects of METH on splenic T cell functions, such as cytokine production and degranulation, and how they regulate each other. We used the Probability State Modeling (PSM) program to visualize the differentiation of effector/memory T cell subsets during LCMV infection and analyze the effects of METH on T cell subset progression. We recently demonstrated that METH increased PD-1 expression on T cells during viral infection. In this study, we further analyzed the impact of PD-1 expression on T cell functional markers as well as its expression in the effector/memory subsets. Overall, our study indicates that analyzing polyfunctionality of T cells can provide additional insight into T cell effector functions. Analysis of T cell heterogeneity is important to highlight changes in the evolution of memory/effector functions during chronic viral infections. Our study also highlights the impact of METH on PD-1 expression and its consequences on T cell responses.
Collapse
Affiliation(s)
- Uma Sriram
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, United States of America
| | - Beth L. Hill
- Verity Software House, Topsham, Maine, United States of America
| | - Jonathan M. Cenna
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, United States of America
| | - Larisa Gofman
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, United States of America
| | - Nicole C. Fernandes
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, United States of America
| | - Bijayesh Haldar
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, United States of America
| | - Raghava Potula
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, United States of America
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States of America
- * E-mail:
| |
Collapse
|
|
33
|
Akbar SMF, Al-Mahtab M, Khan MSI, Raihan R, Shrestha A. Immune therapy for hepatitis B. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:335. [PMID: 27761439 DOI: 10.21037/atm.2016.08.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Although several antiviral drugs are now available for treatment of patients with chronic hepatitis B (CHB), sustained off-treatment clinical responses and containment of CHB-related complications are not achieved in majority of CHB patients by antiviral therapy. In addition, use of these drugs is endowed with substantial long term risk of viral resistance and drug toxicity. The infinite treatment regimens of antiviral drugs for CHB patients are also costly and usually unbearable by most patients of developing and resource-constrained countries. Taken together, there is a pressing need to develop new and innovative therapeutic approaches for CHB patients. Immune therapy seems to be an alternate therapeutic approach for CHB patients because impaired or distorted or diminished immune responses have been detected in most of these patients. Also, investigators have shown that restoration or induction of proper types of immune responses may have therapeutic implications in CHB. Various immunomodulatory agents have been used to treat patients with CHB around the world and the outcomes of these clinical trials show that the properties of immune modulators and nature and designing of immune therapeutic regimens seem to be highly relevant in the context of treatment of CHB patients. In this review, the general properties and specific features of immune therapy for CHB have been discussed for developing the guidelines of effective regimens of immune therapy for CHB.
Collapse
Affiliation(s)
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Sakilur Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Ruksana Raihan
- Department of Virology, AIMST University, Semeling, Bedong, Kedah, Malaysia
| | - Ananta Shrestha
- Department of Hepatology, The Liver Clinic, Liver Foundation, Kathmandu, Nepal
| |
Collapse
|
|
34
|
Zhang QF, Shao JY, Yin WW, Xia Y, Chen L, Wang X, Hu HD, Hu P, Ren H, Zhang DZ. Altered Immune Profiles of Natural Killer Cells in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0160171. [PMID: 27513564 PMCID: PMC4981347 DOI: 10.1371/journal.pone.0160171] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 07/14/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells are the main effective component of the innate immune system that responds to chronic hepatitis B (CHB) infection. Although numerous studies have reported the immune profiles of NK cells in CHB patients, they are limited by inconsistent results. Thus, we performed a meta-analysis to characterize reliably the immune profiles of NK cells after CHB infection, specifically frequency, phenotype, and function. METHODS A literature search of the computer databases MEDLINE, PUBMED, EMBASE, and Cochrane Center Register of Controlled Trails was performed and 19 studies were selected. The standard mean difference (SMD) and 95% confidence interval (CI) of each continuous variable was estimated with a fixed effects model when I2 < 50% for the test for heterogeneity, or the random effects model otherwise. Publication bias was evaluated using Begg's and Egger's tests. RESULTS The meta-analysis of publications that reported frequency of peripheral NK cells showed that NK cell levels in CHB patients were significantly lower compared with that of healthy controls. A higher frequency of CD56bright NK subsets was found in CHB patients, but the CD56dim NK subsets of CHB patients and healthy controls were similar. CHB patients before and after antiviral therapy with nucleotide analogues (NUCs) showed no statistical difference in NK frequency. The activating receptors were upregulated, whereas inhibitory receptors were comparable in the peripheral NK cells of CHB individuals and healthy controls. NK cells of CHB patients displayed higher cytotoxic potency as evidenced by CD107a protein levels and conserved potency to produce interferon-gamma (IFNγ), compared with their healthy counterparts. CONCLUSION Our results revealed that CHB patients had a lower frequency of NK cells compared with healthy individuals not treatable with antiviral NUC therapy. With an activating phenotype, NK cells in CHB patients showed better cytotoxic potency and conserved IFNγ production.
Collapse
Affiliation(s)
- Qiong-Fang Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Jian-Ying Shao
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Wen-Wei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Yang Xia
- Department of Urinary Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqiong, China
| | - Ling Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Xing Wang
- Department of Orthopedic Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqiong, China
| | - Huai-Dong Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
| | - Da-Zhi Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China
- * E-mail:
| |
Collapse
|
|
35
|
Zhang E, Kosinska A, Lu M, Yan H, Roggendorf M. Current status of immunomodulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: Search for the "magic bullet" to kill cccDNA. Antiviral Res 2015; 123:193-203. [PMID: 26476376 DOI: 10.1016/j.antiviral.2015.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/09/2015] [Accepted: 10/09/2015] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B (CHB) is currently treated with IFN-α and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus-specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis".
Collapse
Affiliation(s)
- Ejuan Zhang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Anna Kosinska
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Huimin Yan
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Michael Roggendorf
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
| |
Collapse
|