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Li S, Liu J, Wu J, Zheng X. Immunological Mechanisms and Effects of Bacterial Infections in Acute-on-Chronic Liver Failure. Cells 2025; 14:718. [PMID: 40422221 DOI: 10.3390/cells14100718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 05/09/2025] [Accepted: 05/10/2025] [Indexed: 05/28/2025] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by high morbidity and mortality rates. Bacterial infection is a frequent precipitating factor and complication in ACLF patients, significantly worsening patient outcomes. Elucidating the mechanisms underlying bacterial infections and their impact on ACLF pathophysiology is crucial for developing effective therapies to reduce infection rates and mortality. Current research highlights that immune suppression in ACLF increases susceptibility to bacterial infections, which in turn exacerbate immune dysfunction. However, a comprehensive review summarizing the emerging mechanisms underlying this immunosuppression is currently lacking. This review aims to provide an overview of the latest research, focusing on alterations in the immune responses of innate immune cells-including monocytes, macrophages, and neutrophils-as well as adaptive immune cells such as T and B lymphocytes during the onset and progression of bacterial infections in ACLF. In addition, recent advances in immunomodulatory therapies, including stem cell-based interventions, will also be discussed.
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Affiliation(s)
- Sumeng Li
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jing Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jun Wu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xin Zheng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
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Yao J, Ji Y, Liu T, Bai J, Wang H, Yao R, Wang J, Zhou X. Single-Cell RNA Sequencing Shows T-Cell Exhaustion Landscape in the Peripheral Blood of Patients with Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure. Gut Liver 2024; 18:520-530. [PMID: 37317515 PMCID: PMC11096905 DOI: 10.5009/gnl220449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 06/16/2023] Open
Abstract
Background/Aims The occurrence and development of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is closely related to the immune pathway. We explored the heterogeneity of peripheral blood T cell subsets and the characteristics of exhausted T lymphocytes, in an attempt to identify potential therapeutic target molecules for immune dysfunction in ACLF patients. Methods A total of 83,577 T cells from HBV-ACLF patients and healthy controls were screened for heterogeneity by single-cell RNA sequencing. In addition, exhausted T-lymphocyte subsets were screened to analyze their gene expression profiles, and their developmental trajectories were investigated. Subsequently, the expression of exhausted T cells and their capacity in secreting cytokines (interleukin 2, interferon γ, and tumor necrosis factor α) were validated by flow cytometry. Results A total of eight stable clusters were identified, among which CD4+ TIGIT+ subset and CD8+ LAG-3+ subset, with high expression of exhaust genes, were significantly higher in the HBV-ACLF patients than in normal controls. As shown by pseudotime analysis, T cells experienced a transition from naïve T cells to effector T cells and then exhausted T cells. Flow cytometry confirmed that the CD4+TIGIT+ subset and CD8+LAG-3+ subset in the peripheral blood of the ACLF patients were significantly higher than those in the healthy controls. Moreover, in vitro cultured CD8+LAG-3+ T cells were significantly fewer capable of secreting cytokines than CD8+LAG-3- subset. Conclusions Peripheral blood T cells are heterogeneous in HBV-ACLF. The exhausted T cells markedly increase during the pathogenesis of ACLF, suggesting that T-cell exhaustion is involved in the immune dysfunction of HBV-ACLF patients.
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Affiliation(s)
- Jia Yao
- Department of Gastroenterology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Taiyuan, China
- Hepatobiliary and Pancreatic Surgery and Liver Transplant Center, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yaqiu Ji
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Medical University, Taiyuan, China
| | - Tian Liu
- Department of Gastroenterology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Taiyuan, China
| | - Jinjia Bai
- Department of Gastroenterology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Taiyuan, China
| | - Han Wang
- Department of Gastroenterology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Taiyuan, China
| | - Ruoyu Yao
- Department of Gastroenterology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Taiyuan, China
| | - Juan Wang
- Department of Gastroenterology, Third Hospital of Shanxi Medical University (Shanxi Bethune Hospital), Taiyuan, China
| | - Xiaoshuang Zhou
- Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, China
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The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing. J Immunol Res 2022; 2022:5091275. [PMID: 36387424 PMCID: PMC9646330 DOI: 10.1155/2022/5091275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 09/14/2022] [Accepted: 10/11/2022] [Indexed: 01/24/2023] Open
Abstract
Acute-on-chronic liver failure (ACLF) is a complex clinical syndrome, and patients often have high short-term mortality. It occurs with intense systemic inflammation, often accompanied by a proinflammatory event (such as infection or alcoholic hepatitis), and is closely related to single or multiple organ failure. Liver inflammation begins when innate immune cells (such as Kupffer cells (KCs)) are activated by binding of pathogen-associated molecular patterns (PAMPs) from pathogenic microorganisms or damage-associated molecular patterns (DAMPs) of host origin to their pattern recognition receptors (PRRs). Activated KCs can secrete inflammatory factors as well as chemokines and recruit bone marrow-derived cells such as neutrophils and monocytes to the liver to enhance the inflammatory process. Bacterial translocation may contribute to ACLF when there are no obvious precipitating events. Immunometabolism plays an important role in the process (including mitochondrial dysfunction, amino acid metabolism, and lipid metabolism). The late stage of ACLF is mainly characterized by immunosuppression. In this process, the dysfunction of monocyte and macrophage is reflected in the downregulation of HLA-DR and upregulation of MER tyrosine kinase (MERTK), which weakens the antigen presentation function and reduces the secretion of inflammatory cytokines. We also describe the specific function of bacterial translocation and the gut-liver axis in the process of ACLF. Finally, we also describe the transcriptomics in HBV-ACLF and the recent progress of single-cell RNA sequencing as well as its potential application in the study of ACLF in the future, in order to gain a deeper understanding of ACLF in terms of single-cell gene expression.
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Zhan Q, Xu JH, Yu YY, Lo KK E, Felicianna, El-Nezami H, Zeng Z. Human immune repertoire in hepatitis B virus infection. World J Gastroenterol 2021; 27:3790-3801. [PMID: 34321844 PMCID: PMC8291018 DOI: 10.3748/wjg.v27.i25.3790] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/08/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a public health threat that affects 257 million people worldwide and can progress to liver cirrhosis, liver failure, and hepatocellular carcinoma. The HBV antigen- induced adaptive immune response plays an important role in HBV clearance. Immune repertoire sequencing (IRS) has been used to investigate the molecular mechanisms behind the immune system, find novel ways to treat HBV infection, and evaluate the genetic responses and immune characteristics of individuals infected by HBV or immunized by HBV vaccine. This review summarizes the human immune repertoire analysis methodology, and the application of the IRS in the prediction of HBV infection progression, treatment, and vaccination.
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Affiliation(s)
- Qiao Zhan
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Jing-Hang Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Yan-Yan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Emily Lo KK
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Felicianna
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Hani El-Nezami
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
- Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
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Zhou X, Li Y, Ji Y, Liu T, Zhao N, He J, Yao J. PD-1 Involvement in Peripheral Blood CD8 + T Lymphocyte Dysfunction in Patients with Acute-on-chronic Liver Failure. J Clin Transl Hepatol 2021; 9:283-290. [PMID: 34221914 PMCID: PMC8237147 DOI: 10.14218/jcth.2020.00142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/09/2021] [Accepted: 03/07/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIMS Programmed cell death-1 (PD-1) plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood. This study aimed to explore the role of PD-1 in CD8+ T lymphocyte dysfunction in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS Thirty patients with HBV-ACLF and 30 healthy controls (HCs) were recruited. The differences in the numbers and functions of CD8+ T lymphocytes, PD-1 and glucose transporter-1 (Glut1) expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed. In vitro, the CD8+ T lymphocytes from HCs were cultured (HC group) and the CD8+ T lymphocytes from ACLF patients were cultured with PD-L1-IgG (ACLF+PD-1 group) or IgG (ACLF group). The numbers and functions of CD8+ T lymphocytes, PD-1 expression, glycogen uptake capacity, and Glut1, hexokinase-2 (HK2), and pyruvate kinase (PKM2) expression were analyzed among the HC group, ACLF group and ACLF+ PD-1group. RESULTS The absolute numbers of CD8+ T lymphocytes in the peripheral blood from patients with HBV-ACLF were lower than in the HCs (p<0.001). The expression of PD-1 in peripheral blood CD8+ T lymphocytes was lower in HCs than in patients with HBV-ACLF (p=0.021). Compared with HCs, PD-1 expression was increased (p=0.021) and Glut1 expression was decreased (p=0.016) in CD8+ T lymphocytes from the HBV-ACLF group. In vitro, glycogen uptake and functions of ACLF CD8+ T lymphocytes were significantly lower than that in HCs (p=0.017; all p<0.001). When PD-1/PD-L1 was activated, the glycogen uptake rate and expression levels of Glut1, HK2, and PKM2 showed a decreasing trend (ACLF+PD-1 group compared to ACLF group , all p<0.05). The functions of CD8+ T lymphocytes in the ACLF+PD-1 group [using biomarkers of Ki67, CD69, IL-2, interferon-gamma, and tumor necrosis factor-alpha- were lower than in the ACLF group (all p<0.05). CONCLUSIONS CD8+ T lymphocyte dysfunction is observed in patients with HBV-ACLF. PD-1-induced T lymphocyte dysfunction might involve glycolysis inhibition.
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Affiliation(s)
- Xiaoshuang Zhou
- Department of Nephrology, Shanxi Provincial People’s Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yidong Li
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yaqiu Ji
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Tian Liu
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ninghui Zhao
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
- Correspondence to: Jia Yao and Ninghui Zhao, Department of Gastroenterology, Shanxi Baiqiuen Hospital, Shanxi Medical University, No. 99 Longcheng Street, Taiyuan, Shanxi 030001, China. ORCID: https://orcid.org/0000-0003-2210-7717 (JY), https://orcid.org/0000-0002-9715-9303 (NZ). Tel/Fax: +86-199-3491-1619, E-mail: (JY) and (NZ); Jiefeng He, Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China. ORCID: https://orcid.org/0000-0003-2958-0232. E-mail:
| | - Jiefeng He
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
- Correspondence to: Jia Yao and Ninghui Zhao, Department of Gastroenterology, Shanxi Baiqiuen Hospital, Shanxi Medical University, No. 99 Longcheng Street, Taiyuan, Shanxi 030001, China. ORCID: https://orcid.org/0000-0003-2210-7717 (JY), https://orcid.org/0000-0002-9715-9303 (NZ). Tel/Fax: +86-199-3491-1619, E-mail: (JY) and (NZ); Jiefeng He, Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China. ORCID: https://orcid.org/0000-0003-2958-0232. E-mail:
| | - Jia Yao
- Department of Gastroenterology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi, China
- Institute of Liver Disease and Organ Transplantation, Shanxi Medical University, Taiyuan, Shanxi, China
- Correspondence to: Jia Yao and Ninghui Zhao, Department of Gastroenterology, Shanxi Baiqiuen Hospital, Shanxi Medical University, No. 99 Longcheng Street, Taiyuan, Shanxi 030001, China. ORCID: https://orcid.org/0000-0003-2210-7717 (JY), https://orcid.org/0000-0002-9715-9303 (NZ). Tel/Fax: +86-199-3491-1619, E-mail: (JY) and (NZ); Jiefeng He, Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China. ORCID: https://orcid.org/0000-0003-2958-0232. E-mail:
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Yang L, Zhang Q, Song J, Wang W, Jin Z. Interleukin-35 Suppresses CD8 + T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure. Dig Dis Sci 2020; 65:3614-3623. [PMID: 31974915 DOI: 10.1007/s10620-020-06077-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/13/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Interleukin (IL)-35 is a newly indentified cytokine and induces immunotolerance via suppression of CD8+ T cell activity in chronic viral hepatitis. AIMS To investigate the modulatory function of IL-35 to CD8+ T cells in viral hepatitis-induced acute-on-chronic liver failure (ACLF). METHODS Fifty-five ACLF patients and 21 healthy controls were enrolled. Serum IL-35 concentration was measured by ELISA. Absolute accounts for T cells, immune checkpoint molecules, and cytotoxic molecules in CD8+ T cells were measured by flow cytometry and real-time PCR, respectively. Direct and indirect contact co-culture systems between CD8+ T cells and HepG2 cells were set up. The regulatory function of IL-35 to CD8+ T cells was assessed by measuring lactate dehydrogenase expression and cytokine production. RESULTS Serum IL-35 concentration was elevated in ACLF patients and positively correlated with total bilirubin, but negatively correlated with prothrombin time activity. Peripheral CD8+ T cells showed exhausted phenotype in ACLF patients, which manifested as up-regulation of programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) but down-regulation of perforin, granzyme B, and FasL. Recombinant IL-35 stimulation dampened cytotoxicity and interferon-γ production in both direct and indirect contact co-culture systems. This process was accompanied by elevation of PD-1, CTLA-4, and LAG3, as well as reduction of perforin, granzyme B, and FasL in CD8+ T cells. CONCLUSION Elevated IL-35 suppressed both cytolytic and non-cytolytic activity of CD8+ T cells in ACLF patients.
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Affiliation(s)
- Lanlan Yang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Qian Zhang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Jie Song
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Wudong Wang
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China
| | - Zhenjing Jin
- Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, No. 218 Ziqiang St, Nanguan District, Changchun, 130041, Jilin Province, China.
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Shi W, Wang Y, Zhang C, Jin H, Zeng Z, Wei L, Tian Y, Zhang D, Sun G. Isolation and purification of immune cells from the liver. Int Immunopharmacol 2020; 85:106632. [PMID: 32470880 DOI: 10.1016/j.intimp.2020.106632] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 01/27/2023]
Abstract
Isolating and purifying liver immune cells are crucial for observing the changes in intrahepatic immune responses during the development of liver diseases and exploring the potential immunological mechanisms. Therefore, the aim of this study was to provide an optimal protocol for isolating immune cells with a high yield and less damage. We compared mechanical dissection and collagenase digestion, and the results were represented by the proportion of lymphocytes, Kupffer cells and neutrophils. The apoptosis rates of liver immune cells resulted by different isolation protocols were compared by Annexin V-staining using flow cytometric analysis. Our data indicated that the enzymatic digestion in vitro was more efficient than the mechanical dissection in vitro with a suitable collagenase IV concentration of 0.01%, and the purification of liver immune cells by a one-step density gradient centrifugation in 33% Percoll had the definite advantage of a higher proportion of the target cells. We also provided evidence that enzymatic digestion in vitro method was superior to collagenase digestion in situ for liver T lymphocytes, NK cells and NKT cells isolation and purification. This protocol was also validated in human liver samples. In conclusion, we developed an optimal protocol for isolating and purifying immune cells from mouse and human liver samples in vitro by 0.01% collagenase IV and 33% Percoll density gradient centrifugation with the advantages of higher cell yields and viability. This method provides a basis for further studying liver immune cells and liver immunity with a wide range of applications.
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Affiliation(s)
- Wen Shi
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Yaning Wang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Chunpan Zhang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Hua Jin
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Zhigui Zeng
- Department of Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lin Wei
- Department of Liver Transplantation Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yue Tian
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China
| | - Dong Zhang
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
| | - Guangyong Sun
- Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Beijing Clinical Research Institute, Beijing 100050, China; Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing 100050, China; National Clinical Research Center for Digestive Diseases, Beijing 100050, China.
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Shen G, Sun S, Huang J, Deng H, Xu Y, Wang Z, Tang X, Gong X. Dynamic changes of T cell receptor repertoires in patients with hepatitis B virus-related acute-on-chronic liver failure. Hepatol Int 2019; 14:47-56. [PMID: 31872330 DOI: 10.1007/s12072-019-10008-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 11/27/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS T cell-mediated immune injury plays a critical role in the pathogenesis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). Given the high short-term mortality and crucial role of T cells in the disease progression, it is necessary to investigate the dynamics of T cell clones during HBV-ACLF. The aim of this study was to longitudinally investigate dynamic changes in the composition and perturbation of T cell receptor β (TCRβ) chain repertoires and to determine whether TCR repertoire characteristics were associated with HBV-ACLF patient outcomes. METHODS Peripheral blood mononuclear cells (PBMCs) were collected at two time points from 5 HBV-ACLF patients. Global CD4+ and CD8+ T cells were sorted using magnetic beads. TCRβ complementarity-determining region 3 was analyzed by unbiased high-throughput sequencing. RESULTS During HBV-ACLF, there was a significant decrease in the diversity of T cell repertoires and an increase in proportion of the most 100 abundant clonotypes of CD8 T cells but not CD4. Decreased CD8 repertoire diversity was positively correlated with the reduction of the Model for End-Stage Liver Disease (MELD) score. CONCLUSIONS There was significant clonal expansion in CD8 but not in CD4 T cell repertoires in HBV-ACLF patients during disease progression. Patients with greater clonal expansions in CD8 T cell repertoires may have better outcomes. CD8 TCRβ repertoire diversity may serve as a potential predictive marker for disease outcome.
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Affiliation(s)
- Guojun Shen
- Hepatology Unit, The Third People's Hospital of Jiujiang City, No. 408, Shili Road, Jiujiang, 332000, Jiangxi, China
| | - Shuilin Sun
- Department of Infectious Diseases, The Second Affiliated Hospital of Nanchang University, No.1, Minde Road, Nanchang, Jiangxi, China
| | - Jie Huang
- Hepatology Unit, The Third People's Hospital of Jiujiang City, No. 408, Shili Road, Jiujiang, 332000, Jiangxi, China
| | - Haohui Deng
- Department of Infectious Diseases, Guangzhou Eight People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ying Xu
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhanhui Wang
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiong Tang
- Hepatology Unit, The Third People's Hospital of Jiujiang City, No. 408, Shili Road, Jiujiang, 332000, Jiangxi, China
| | - Xiaodong Gong
- Hepatology Unit, The Third People's Hospital of Jiujiang City, No. 408, Shili Road, Jiujiang, 332000, Jiangxi, China.
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Wang YM, Li K, Dou XG, Bai H, Zhao XP, Ma X, Li LJ, Chen ZS, Huang YC. Treatment of AECHB and Severe Hepatitis (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498915 DOI: 10.1007/978-94-024-1603-9_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the general treatment and immune principles and internal management for AECHB and HBV ACLF, including ICU monitoring, general supportive medications/nutrition/nursing, immune therapy, artificial liver supportive systems, hepatocyte/stem cell, and liver transplant, management for special populations, frequently clinical complications and the utilization of Chinese traditional medicines.
Early clinical indicators of severe hepatitis B include acratia, gastrointestinal symptoms, a daily increase in serum bilirubin >1 mg/dL, toxic intestinal paralysis, bleeding tendency and mild mind anomaly or character change, and the presence of other diseases inducing severe hepatitis. Laboratory indicators include T-Bil, PTA, cholinesterase, pre-albumin and albumin. The roles of immune indicators (such as IL-6, TNF-α, and fgl2), gene polymorphisms, HBV genotypes, and gene mutations as early clinical indicators. Intensive Care Unit monitor patients with severe hepatitis include intracranial pressure, infection, blood dynamics, respiratory function, renal function, blood coagulation function, nutritional status and blood purification process. Nursing care should not only include routine care, but psychological and special care (complications). Nutrition support and nursing care should be maintained throughout treatment for severe hepatitis. Common methods of evaluating nutritional status include direct human body measurement, creatinine height index (CHI) and subject global assessment of nutrition (SGA). Malnourished patients should receive enteral or parenteral nutrition support. Immune therapies for severe hepatitis include promoting hepatocyte regeneration (e.g. with glucagon, hepatocyte growth factor and prostaglandin E1), glucocorticoid suppressive therapy, and targeting molecular blocking. Corticosteroid treatment should be early and sufficient, and adverse drug reactions monitored. Treatments currently being investigated are those targeting Toll-like receptors, NK cell/NK cell receptors, macrophage/immune coagulation system, CTLA-4/PD-1 and stem cell transplantation. In addition to conventional drugs and radioiodine, corticosteroids and artificial liver treatment can also be considered for severe hepatitis patients with hyperthyreosis. Patients with gestational severe hepatitis require preventive therapy for fetal growth restriction, and it is necessary to choose the timing and method of fetal delivery. For patients with both diabetes and severe hepatitis, insulin is preferred to oral antidiabetic agents to control blood glucose concentration. Liver toxicity of corticosteroids and immune suppressors should be monitored during treatment for severe hepatitis in patients with connective tissue diseases including SLE, RA and sicca syndrome. Patient with connective tissue diseases should preferably be started after the antiviral treatment with nucleos(t)ide analogues. An artificial liver can improve patients’ liver function; remove endotoxins, blood ammonia and other toxins; correct amino acid metabolism and coagulation disorders; and reverse internal environment imbalances. Non-bioartificial livers are suitable for patients with early and middle stage severe hepatitis; for late-stage patients waiting for liver transplantation; and for transplanted patients with rejection reaction or transplant failure. The type of artificial liver should be determined by each patient’s condition and previous treatment purpose, and patients should be closely monitored for adverse reactions and complications. Bio- and hybrid artificial livers are still under development. MELD score is the international standard for choosing liver transplantation. Surgical methods mainly include the in situ classic type and the piggyback type; transplantation includes no liver prophase, no liver phase or new liver phase. Preoperative preparation, management of intraoperative and postoperative complications and postoperative long-term treatment are keys to success. Severe hepatitis belongs to the categories of “acute jaundice”, “scourge jaundice”, and “hot liver” in traditional Chinese medicine. Treatment methods include Chinese traditional medicines, acupuncture and acupoint injection, external application of drugs, umbilical compress therapy, drip, blow nose therapy, earpins, and clysis. Dietary care is also an important part of traditional Chinese medicine treatment.
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Ning Q. Main Complications of AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498917 DOI: 10.1007/978-94-024-1603-9_2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Qin Ning
- Department of Infectious Disease, Tongji Hospital, Wuhan, China
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Davies R, Hammenfors D, Bergum B, Jakobsen K, Solheim M, Vogelsang P, Brun JG, Bryceson Y, Jonsson R, Appel S. Patients with Primary Sjögren's Syndrome Have Alterations in Absolute Quantities of Specific Peripheral Leucocyte Populations. Scand J Immunol 2017; 86:491-502. [PMID: 29072325 DOI: 10.1111/sji.12622] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 10/17/2017] [Indexed: 12/26/2022]
Abstract
An accurate dissection of peripheral blood enumeration is lacking in primary Sjögren's syndrome (pSS). The purpose of this study was to quantify different leucocyte populations in peripheral blood of patients with pSS. Numbers of specific leucocyte subsets were determined in 86 pSS patients and 74 healthy donors quantifying 21 distinct subtypes by flow cytometry. Subgroups of pSS patients were stratified based on presence of extraglandular manifestations (EGMs) and SSA/SSB autoantibodies. Overall, pSS patients manifested decreased lymphocyte subpopulations compared to healthy donors. Such decreases were more pronounced in SSA/SSB positive patients and patients with EGM. Granulocyte and monocyte subpopulations were increased in pSS patients compared to healthy donors, with the greatest increases in SSA/SSB positive patients. Unsupervised hierarchal clustering based on cell quantities was used to further subgroup the pSS patients into four clusters. One of the clusters characterized by higher concentrations of NKT cells, CD56hi NK cells, CD20+ CD38- B cells and CD8+ CD38- T cells was associated with weaker clinical symptoms than the other clusters, possibly marking a milder disease phenotype. In conclusion, our analyses indicate significant alterations in the cellular profiles of peripheral blood leucocytes in patients with pSS and may help to stratify the patients according to disease severity.
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Affiliation(s)
- R Davies
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - D Hammenfors
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
| | - B Bergum
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - K Jakobsen
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - M Solheim
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - P Vogelsang
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - J G Brun
- Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Y Bryceson
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Medicine, Centre for Infectious Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - R Jonsson
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
| | - S Appel
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway
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Willemse SB, Jansen L, de Niet A, Sinnige MJ, Takkenberg RB, Verheij J, Kootstra NA, Reesink HW. Intrahepatic IP-10 mRNA and plasma IP-10 levels as response marker for HBeAg-positive chronic hepatitis B patients treated with peginterferon and adefovir. Antiviral Res 2016; 131:148-55. [PMID: 27155352 DOI: 10.1016/j.antiviral.2016.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 04/27/2016] [Accepted: 05/03/2016] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Interferon-y-inducible protein-10 (IP-10), also called CXCL10, is produced by different types of cells such as monocytes, neutrophils and hepatocytes. IP-10 functions as an inflammatory cytokine, which after binding to its receptor CXCR3, expressed on T-lymphocytes, leads to immune activation. We aimed to establish if IP-10 expression in liver tissue and in plasma of chronic hepatitis B (CHB) patients correlated with each other and further to investigate if IP-10 levels before and during therapy with peginterferon and adefovir could predict treatment outcome in CHB patients. PATIENTS AND METHODS A total of 86 CHB patients (41 HBeAg-positive and 45 HBeAg-negative) received combination therapy of peginterferon and adefovir for 48 weeks. Combined Response (CR) (HBeAg-negativity, HBV-DNA ≤ 2000 IU/mL, ALT normalization) and non-response (NR) were assessed at Week 72. Plasma IP-10 levels were measured at baseline and during treatment at Day 3 (D3) and Week 1 (W1). Pre-treatment liver biopsies from 40 of 86 patients were obtained and stored in liquid nitrogen for the analysis of intrahepatic IP-10 mRNA expression. RESULTS CR was achieved in 14/41 HBeAg-positive and 17/45 HBeAg-negative patients. Mean baseline plasma IP-10 levels were significantly higher in HBeAg-positive patients with CR than NR (3.20 vs 3.00 log pg/mL p = 0.03); but not in HBeAg-negative patients. Baseline IP-10 levels correlated with ALT-levels in HBeAg-positive and -negative patients (both p < 0.001), and with a decline of HBsAg-levels of ≥0.5 log IU/mL at Week 12 in HBeAg-positive patients (p = 0.001). Plasma IP-10 levels were associated with intrahepatic IP-10 mRNA expression, however, more strongly in HBeAg-positive (R = 0.79, p < 0.001) than in HBeAg-negative patients (R = 0.53, p = 0.011). IP-10 levels only correlated with HAI-scores in HBeAg-positive patients (R = 0.40 p = 0.025). Mean plasma IP-10 levels of both HBeAg-positive and -negative patients increased significantly at D3 compared to baseline (+0.30 log pg/mL p = 0.003), to then decline subsequently at W1 to a level still significantly higher than baseline (+0.14 log pg/mL p < 0.001). The increase of IP-10 was significantly higher in HBeAg-positive patients with NR than in those with CR (+0.35 versus +0.11 log pg/mL p = 0.003). CONCLUSIONS Baseline plasma IP-10 levels and IP-10 mRNA expression in the liver are correlated with each other, suggesting that plasma IP-10 reflects intrahepatic immune activation. Higher IP-10 levels at baseline seem to be associated with CR in HBeAg-positive patients treated with peginterferon and adefovir, but not in HBeAg-negative patients.
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Affiliation(s)
- S B Willemse
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands.
| | - L Jansen
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
| | - A de Niet
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
| | - M J Sinnige
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands; Department of Experimental Immunology, Academic Medical Center, The Netherlands
| | - R B Takkenberg
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
| | - J Verheij
- Department of Pathology, Academic Medical Center, The Netherlands
| | - N A Kootstra
- Department of Experimental Immunology, Academic Medical Center, The Netherlands
| | - H W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, The Netherlands
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