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Zhang Y, Zhang X, Han J, Guo Y, Yang F, Li F, Zhu H, Shen Z, Huang Y, Mao R, Zhang J. Downregulated VISTA enhances Th17 differentiation and aggravates inflammation in patients with acute-on-chronic liver failure. Hepatol Int 2023; 17:1000-1015. [PMID: 36944807 DOI: 10.1007/s12072-023-10505-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/22/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AND AIMS Persistent inflammatory response and immune activation are the core mechanisms underlying acute-on-chronic liver failure (ACLF). Previous studies have shown that deficiency of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) exacerbates the progression of inflammatory diseases. We aimed to clarify the role of VISTA in the pathogenesis of ACLF. METHODS Blood and liver samples were collected from healthy subjects, stable cirrhosis, and ACLF patients to characterize VISTA expression and function. An ACLF mouse model was used to ascertain potential benefits of anti-VISTA monoclonal antibody (mAb) treatment. RESULTS VISTA expression was significantly reduced in the naïve and central memory CD4+ T cells from patients with ACLF. The expression of VISTA on CD4+ T cells was associated with disease severity and prognosis. VISTA downregulation contributed to the activation and proliferation of CD4+ T cells and enhanced the differentiation of T helper 17 cells (Th17) and secretion of inflammatory cytokines through the activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Moreover, agonistic anti-VISTA mAb treatment inhibited the activation and cytokine production of CD4+ T cells and reduced mortality and liver inflammation of the ACLF mice. CONCLUSIONS The decreased expression of VISTA may facilitate development of Th17 cells and promote the progression of inflammation in ACLF patients. These findings are helpful for elucidating the pathogenesis of ACLF and for the identification of new drug targets.
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Affiliation(s)
- Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Jiajia Han
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
- Key Laboratory of Medical Molecular Virology, MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
| | - Zhongliang Shen
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China
- Key Laboratory of Medical Molecular Virology, MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China.
- Department of Hepatitis Disease, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China.
- Key Laboratory of Medical Molecular Virology, MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Room 510, Building 5, 12 Middle Wulumuqi Road, Shanghai, China.
- Key Laboratory of Medical Molecular Virology, MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
- Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, China.
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Beringer A, Miossec P. IL-17 and IL-17-producing cells and liver diseases, with focus on autoimmune liver diseases. Autoimmun Rev 2018; 17:1176-1185. [PMID: 30321671 DOI: 10.1016/j.autrev.2018.06.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/05/2018] [Indexed: 02/07/2023]
Abstract
The pro-inflammatory cytokine interleukin(IL)-17 and IL-17-producing cells are important players in the pathogenesis of many autoimmune / inflammatory diseases. More recently, they have been associated with liver diseases. This review first describes the general knowledge on IL-17 and IL-17 producing cells. The second part describes the in vitro and in vivo effects of IL-17 on liver cells and the contribution of IL-17 producing cells to liver diseases. IL-17 induces immune cell infiltration and liver damage driving to hepatic inflammation and fibrosis and contributes to autoimmune liver diseases. The circulating levels of IL-17 and the frequency of IL-17-producing cells are elevated in a variety of acute and chronic liver diseases. The last part focuses on the effects of IL-17 deletion or neutralization in various murine models. Some of these observed beneficial effects suggest that targeting the IL-17 axis could be a new therapeutic strategy to prevent chronicity and progression of various liver diseases.
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Affiliation(s)
- Audrey Beringer
- Immunogenomics and Inflammation Research Unit EA4130, University of Lyon, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit EA4130, University of Lyon, Lyon, France.
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Zhang GL, Zhang T, Zhao QY, Lin CS, Gao ZL. Th17 cells over 5.9% at admission indicate poor prognosis in patients with HBV-related acute-on-chronic liver failure. Medicine (Baltimore) 2018; 97:e12656. [PMID: 30290645 PMCID: PMC6200497 DOI: 10.1097/md.0000000000012656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Our previous study demonstrated that Th17 cells increased significantly in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). However, their prognostic role in HBV-ACLF patients remains unknown.Sixty-eight consecutive HBV-ACLF patients were enrolled in this cohort study. Th17 cells were examined using flow cytometry. Disease severity scores were assessed. ROC curves were used to evaluate the value in predicting prognosis. Survival was analyzed using Kaplan-Meier curves. Predictors of mortality were determined by regression analysis.Th17 cells were significantly higher in HBV-ACLF patients compared to patients with chronic hepatitis B and normal controls (both P < .001). Also, Th17 cells were higher in nonsurviving HBV-ACLF patients than in surviving patients (P = .014). Th17 cells were positively correlated with CLIF-Consortium ACLF (CLIF-C ACLF) score (r = 0.240, P = .048). ROC curves showed that the frequency of Th17 cells had accuracy in predicting 90-day prognosis equivalent to MELD, MELD-Na and CLIF-C ACLF scores in HBV-ACLF (P = .34, P = .26, and P = .15, respectively). More importantly, the area under the ROC curve (AUROC) increased when Th17 cells were combined with MELD, MELD-Na or CLIF-C ACLF score than using Th17 cells alone (P = .021, P = .006, and P = .023, respectively). Kaplan-Meier analysis revealed that higher Th17 cells (≥5.9%) were closely associated with poor overall survival in HBV-ACLF (P = .0086). Additionally, multivariate regression analysis showed that the frequency of Th17 cells over 5.9% was an independent predictor of mortality (OR = 0.154, P = .025).Circulating Th17 cells positively correlated with disease severity in HBV-ACLF. The frequency of Th17 cells over 5.9% could serve as a prognostic biomarker for HBV-ACLF patients.
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Affiliation(s)
- Geng-Lin Zhang
- Department of Infectious Diseases
- Guangdong Provincial Key Laboratory of Liver Disease
| | - Ting Zhang
- Department of ultrasound, The Third Affiliated Hospital of Sun-Yat-sen University
| | - Qi-Yi Zhao
- Department of Infectious Diseases
- Guangdong Provincial Key Laboratory of Liver Disease
| | - Chao-Shuang Lin
- Department of Infectious Diseases
- Guangdong Provincial Key Laboratory of Liver Disease
| | - Zhi-Liang Gao
- Department of Infectious Diseases
- Guangdong Provincial Key Laboratory of Liver Disease
- Key Laboratory of Tropical Disease Control (Sun-Yat-sen University), Ministry of Education, Guangzhou, China
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Xu C, Lu Y, Zheng X, Feng X, Yang X, Timm J, Wu J, Wang B, Lu M, Yang D, Liu J. TLR2 Expression in Peripheral CD4+ T Cells Promotes Th17 Response and Is Associated with Disease Aggravation of Hepatitis B Virus-Related Acute-On-Chronic Liver Failure. Front Immunol 2017; 8:1609. [PMID: 29218046 PMCID: PMC5703711 DOI: 10.3389/fimmu.2017.01609] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 11/07/2017] [Indexed: 12/16/2022] Open
Abstract
Th17 responses have been shown to play crucial roles in the pathogenesis of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF). The mechanism underlying the enhanced Th17 responses in these patients remains largely unclear. Here we investigated toll-like receptors (TLRs) expression in peripheral T cells and their roles in Th17 cell differentiation and disease aggravation in ACLF patients. 18 healthy subjects (HS), 20 chronic HBV-infected (CHB) patients, and 26 ACLF patients were enrolled and examined for TLRs expression in peripheral blood mononuclear cells (PBMCs). The correlations of T cell TLR2 expression with the antigen non-specific Th17 responses and disease aggravation, as well as the Th17 response to TLR2 ligand stimulation were evaluated in ACLF patients. Compared to HS and CHB patients, ACLF patients showed a distinct TLRs expression pattern in PBMCs. Significantly increased TLR2 expression in T cells was observed in ACLF patients. The TLR2 expression in CD4+ T cells was correlated with the Th17 responses and the clinical markers for disease aggravation in ACLF patients. Moreover, TLR2 ligands stimulation promoted Th17 cell differentiation and response in PBMCs of ACLF patients. These findings implicate that TLR2 signaling plays critical roles in Th17 cell differentiation and disease aggravation of HBV-related ACLF.
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Affiliation(s)
- Chunli Xu
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinping Lu
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xin Zheng
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuemei Feng
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuecheng Yang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Joerg Timm
- Institute for Virology, University Hospital, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
| | - Jun Wu
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baoju Wang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Dongliang Yang
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Liu
- Department of Infectious Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Paquissi FC. Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis. Front Immunol 2017; 8:1195. [PMID: 29033929 PMCID: PMC5626935 DOI: 10.3389/fimmu.2017.01195] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 09/11/2017] [Indexed: 12/13/2022] Open
Abstract
Cirrhosis is a common final pathway for most chronic liver diseases; representing an increasing burden worldwide and is associated with increased morbidity and mortality. Current evidence has shown that, after an initial injury, the immune response has a significant participation in the ongoing damage, and progression from chronic viral hepatitis (CVH) to cirrhosis, driving the activation and maintenance of main fibrogenic pathways. Among immune deregulations, those related to the subtype 17 of T helper lymphocytes (Th17)/interleukin-17 (IL-17) axis have been recognized as key immunopathological and prognostic elements in patients with CVH. The Th17/IL-17 axis has been found involved in several points of fibrogenesis chain from the activation of stellate cells, increased expression of profibrotic factors as TGF-β, promotion of the myofibroblastic or epithelial–mesenchymal transition, stimulation of the synthesis of collagen, and induction of imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). It also promotes the recruitment of inflammatory cells and increases the expression of proinflammatory cytokines such as IL-6 and IL-23. So, the Th17/IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment. This work aims to present the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).
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Zhao J, Fan YC, Liu XY, Zhao ZH, Li F, Wang K. Hypermethylation of the galectin-3 promoter is associated with poor prognosis of acute-on-chronic hepatitis B liver failure. Dig Liver Dis 2017; 49:664-671. [PMID: 28185839 DOI: 10.1016/j.dld.2017.01.158] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS The possible role of galectin-3 in acute-on-chronic hepatitis B liver failure (ACHBLF) remains unknown. This study aimed to determine the methylation status of the galectin-3 promoter in patients with ACHBLF and analyze its prognostic value. METHODS The methylation status of the galectin-3 promoter in patients with ACHBLF, chronic hepatitis B (CHB) and healthy controls (HCs) was determined by methylation-specific polymerase chain reaction (MSP). The galectin-3 mRNA level in peripheral blood mononuclear cells (PBMCs) was detected using real-time polymerase chain reaction (RT-PCR). RESULTS The methylation frequency of the galectin-3 promoter was significantly higher while galectin-3 mRNA was lower in ACHBLF than in CHB and HCs. Galectin-3 promoter methylation was negatively correlated with the mRNA level in ACHBLF. In addition, ACHBLF patients carrying the methylated promoter showed shorter survival time, higher 3-month mortality, and higher model for end-stage liver disease (MELD) score when compared to ACHBLF patients carrying the unmethylated promoter. Moreover, promoter methylation was a better predictor of 3-week mortality than the MELD score in ACHBLF patients. CONCLUSION Our results suggest that hypermethylation of the galectin-3 promoter might be an early biomarker for predicting disease severity and prognosis in patients with ACHBLF.
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Affiliation(s)
- Jing Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China; Institute of Hepatology, Shandong University, Jinan, China
| | - Xin-Yuan Liu
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Ze-Hua Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Feng Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China; Institute of Hepatology, Shandong University, Jinan, China.
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Fischer J, Silva TE, Soares E Silva PE, Colombo BS, Silva MC, Wildner LM, Bazzo ML, Rateke ECM, Frode TS, Mello SVD, Rosa JS, Dantas-Correa EB, Narciso-Schiavon JL, Schiavon LL. From stable disease to acute-on-chronic liver failure: Circulating cytokines are related to prognosis in different stages of cirrhosis. Cytokine 2017; 91:162-169. [PMID: 28082235 DOI: 10.1016/j.cyto.2016.12.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 11/24/2016] [Accepted: 12/21/2016] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Although both pro- and anti-inflammatory circulating cytokines are known to be elevated in liver cirrhosis, its clinical significance is not completely recognized. Our aim was to evaluate the prognostic significance of circulating cytokines interleukin (IL)-6, IL-17 and IL-10 in different stages of cirrhosis. METHODS This prospective study included two cohorts: (1) stable cirrhosis attended in the Outpatient Clinic (n=118), and (2) subjects hospitalized for acute decompensation (AD) (n=130). Thirty healthy subjects served as control group. RESULTS Patients with cirrhosis exhibited higher levels of cytokines as compared to controls. In stable cirrhosis, during a median follow-up of 17months, liver-related events occurred in 26 patients. Higher IL-10 levels and Child-Pugh B/C were independently associated with reduced event-free survival. In AD cohort, death after 90days of follow-up occurred in 39 patients and was independently associated with ascites, higher IL-6 and model for end-stage liver disease. IL-6 levels also showed higher AUROC than CRP for predicting bacterial infection in the AD cohort (0.831±0.043vs. 0.763±0.048, respectively). IL-17 decreased at third day of hospitalization only in patients who progressed to death. Higher IL-6 levels were observed in acute-on-chronic liver failure (ACLF) patients even in the absence of bacterial infection whereas IL-10 was higher only in subjects with infection-related ACLF. Higher IL-10 and IL-17 levels were associated with progression to death in ACLF. CONCLUSIONS The pattern of immune response seems to vary according to the phase of cirrhosis and is related to prognosis, from stable disease to ACLF.
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Affiliation(s)
- Josiane Fischer
- Division of Gastroenterology, Federal University of Santa Catarina, Brazil
| | | | | | | | | | | | - Maria Luiza Bazzo
- Department of Clinical Analysis, Federal University of Santa Catarina, Brazil
| | | | - Tania Silvia Frode
- Department of Clinical Analysis, Federal University of Santa Catarina, Brazil
| | | | - Júlia S Rosa
- Department of Clinical Analysis, Federal University of Santa Catarina, Brazil
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Gao S, Huan SL, Han LY, Li F, Ji XF, Li XY, Fan YC, Wang K. Overexpression of serum sST2 is associated with poor prognosis in acute-on-chronic hepatitis B liver failure. Clin Res Hepatol Gastroenterol 2015; 39:315-323. [PMID: 25481239 DOI: 10.1016/j.clinre.2014.10.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 10/08/2014] [Accepted: 10/16/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE Interleukin-33 (IL-33) and soluble ST2 (sST2) have been demonstrated to be involved in liver injury. The present study aims to evaluate serum IL-33 and sST2 level in acute-on-chronic hepatitis B liver failure (ACHBLF) and determine their predictive value for prognosis. METHODS Serum IL-33 and sST2 level in patients with ACHBLF, chronic hepatitis B (CHB) and healthy controls (HCs) were determined by enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory parameters were obtained. RESULTS Serum IL-33 was significantly higher in patients with ACHBLF (313.10±419.97pg/ml) than those with CHB (97.25±174.67pg/ml, P<0.01) and HCs (28.39±6.53pg/ml, P<0.01). Serum sST2 was significantly higher in patients with ACHBLF (1545.87±1135.70pg/ml) than those with CHB (152.55±93.28pg/ml, P<0.01) and HCs (149.27±104.90pg/ml, P<0.01). In all participants, serum IL-33 was significantly correlated with sST2 (r=0.43, P<0.01). In patients with ACHBLF, serum IL-33 was significantly correlated with alanine aminotransferase (ALT; r=0.26, P=0.04). Serum sST2 was significantly correlated with total bilirubin (TBIL; r=0.59, P<0.01), Log10 [HBV DNA] (r=-0.47, P<0.01) and model for end-stage liver diseases (MELD; r=0.28, P=0.03). Serum sST2 had an area under the receiver operating characteristic curve (AUC) of 0.81 in predicting 3-month mortality of ACHBLF. Patients with ACHBLF who had sST2 >1507pg/ml showed significantly poorer survival than those who had sST2 ≤1507pg/ml (P<0.01). Moreover, measurement of sST2 and MELD together significantly improved the diagnostic value of MELD alone (P<0.05). CONCLUSIONS Our study showed that serum IL-33 and sST2 were overexpressed in ACHBLF and sST2 might potentially serve as a prognostic marker for it.
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Affiliation(s)
- Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Shu-Ling Huan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Li-Yan Han
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Institute of Hepatology, Shandong University, Jinan 250012, Shandong, China
| | - Feng Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Xiang-Fen Ji
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Xin-You Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Institute of Hepatology, Shandong University, Jinan 250012, Shandong, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Institute of Hepatology, Shandong University, Jinan 250012, Shandong, China.
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Th17 cells in autoimmune and infectious diseases. Int J Inflam 2014; 2014:651503. [PMID: 25152827 PMCID: PMC4137509 DOI: 10.1155/2014/651503] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2014] [Accepted: 07/20/2014] [Indexed: 02/06/2023] Open
Abstract
The view of CD4 T-cell-mediated immunity as a balance between distinct lineages of Th1 and Th2 cells has changed dramatically. Identification of the IL-17 family of cytokines and of the fact that IL-23 mediates the expansion of IL-17-producing T cells uncovered a new subset of Th cells designated Th17 cells, which have emerged as a third independent T-cell subset that may play an essential role in protection against certain extracellular pathogens. Moreover, Th17 cells have been extensively analyzed because of their strong association with inflammatory disorders and autoimmune diseases. Also, they appear to be critical for controlling these disorders. Similar to Th1 and Th2 cells, Th17 cells require specific cytokines and transcription factors for their differentiation. Th17 cells have been characterized as one of the major pathogenic Th cell populations underlying the development of many autoimmune diseases, and they are enhanced and stabilized by IL-23. The characteristics of Th17 cells, cytokines, and their sources, as well as their role in infectious and autoimmune diseases, are discussed in this review.
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Kim HY, Jhun JY, Cho ML, Choi JY, Byun JK, Kim EK, Yoon SK, Bae SH, Chung BH, Yang CW. Interleukin-6 upregulates Th17 response via mTOR/STAT3 pathway in acute-on-chronic hepatitis B liver failure. J Gastroenterol 2014; 49:1264-73. [PMID: 24366287 DOI: 10.1007/s00535-013-0891-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 09/18/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Interleukin (IL)-17-producing CD4(+) T cells (Th17) have been shown to play crucial roles in the pathogenesis of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF). However, the mechanism underlying the enhanced Th17 responses in these patients remains elusive. In this study, the relevance of the IL-6/signal transducer and activator of transcription 3 (STAT3)/mammalian target of rapamycin (mTOR)/Th17 loop in HBV-associated ACLF was investigated. METHODS Eight patients with HBV-associated ACLF, eight asymptomatic chronic HBV carriers and eight healthy controls were enrolled in our study. The frequency of peripheral Th17 cells was determined by flow cytometry. IL-17 and IL-6 mRNA levels in peripheral blood mononuclear cells were quantified using quantitative real-time reverse polymerase chain reaction. The activation of STAT3 was seen upon stimulation with IL-6. Rapamycin, an mTOR inhibitor, was used for analysis of the suppressive effect on the Th17 response in vitro. RESULTS The percentage of peripheral Th17 cells significantly increased in ACLF patients. CD4(+) T cells from ACLF patients produced higher levels of IL-17 and IL-6 upon stimulation in vitro. Activation of STAT3 in response to IL-6 was elevated in ACLF patients. The IL-6-induced upregulation of IL-17 production by CD4(+) T cells could be reversed by an mTOR inhibitor through decreasing STAT3 activation. CONCLUSIONS STAT3 activation upon IL-6 stimulation contributed to the enhanced Th17 response in HBV-associated ACLF patients and mTOR regulated STAT3 phosphorylation. mTOR can be a novel target to suppress Th17-mediated liver injury in HBV-associated ACLF patients.
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Affiliation(s)
- Hee Yeon Kim
- Division of Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-040, Korea
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Liang XS, Li CZ, Zhou Y, Yin W, Liu YY, Fan WH. Changes in circulating Foxp3 + regulatory T cells and interleukin-17-producing T helper cells during HBV-related acute-on-chronic liver failure. World J Gastroenterol 2014; 20:8558-8571. [PMID: 25024610 PMCID: PMC4093705 DOI: 10.3748/wjg.v20.i26.8558] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Revised: 12/31/2013] [Accepted: 04/09/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To longitudinally investigate cytokine gene expression and protein levels in Th17 and Treg cells, to observe T-cell phenotypes during hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACHBLF) and to analyze changes in Th17 and Treg phenotypes during disease progression.
METHODS: We measured the expression of seven Th17/Treg differentiation-related genes and serum concentrations of the corresponding cytokines in 18 ACHBLF, 18 chronic hepatitis B (CHB) disease controls and 10 healthy controls (HCs) by real-time quantitative PCR and enzyme linked immunosorbent assay. Peripheral Th17 and Treg cell frequencies were analyzed by flow cytometry.
RESULTS: From the onset of ACHBLF, patients presented with a conductive Th17 differentiation cytokine environment accompanied by high Th17 frequency and high serum IL-17 levels, which were sustained throughout the disease course. The Treg-related cytokine IL-2 and Foxp3 were also up-regulated from disease onset, and Foxp3 gene expression showed a gradually increasing trend during ACHBLF. The circular phenotype of Treg and Th17 cells showed changes from the onset of ACHGLF. At disease onset, Th17 frequency increased significantly compared with both CHB and HCs, but Treg cell frequency decreased significantly compared with CHB. During the ACHBLF event, Th17 frequency remained higher compared with HCs, but decreased sharply from the peak point to the recovery point; Treg cell frequency increased gradually during the ACHBLF event. Treg and Th17 cell counts correlated with ACHBLF development; in all patients, serum IL-17 levels significantly correlated with patient serum ALT levels. In survivors, Th17 frequency at the onset point and the Treg to Th17 ratio at the peak point correlated with the patient’s model for end stage liver disease (MELD) plus sodium (MELD-Na) score. The Treg to Th17 ratio and the Th17 frequency at onset were significant predictors of patient survival. Low Treg/Th17 cell ratios at the onset predicted poor survival. Survivors exhibited an initial decrease in the circulating Treg/Th17 ratio from the onset to the peak time, and subsequently displayed a continuous increase.
CONCLUSION: Treg and Th17 cells showed changes in genes, protein levels and T cell phenotypes during ACHBLF events. An increased Treg/Th17 ratio was associated with the survival of ACHBLF patients.
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Loggi E, Gamal N, Bihl F, Bernardi M, Andreone P. Adaptive response in hepatitis B virus infection. J Viral Hepat 2014; 21:305-313. [PMID: 24674098 DOI: 10.1111/jvh.12255] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a major cause of acute and chronic liver inflammation worldwide. The immune response against the virus represents a key factor in determining infection outcome, in terms of both viral clearance and the perpetuation of liver damage. Significant advances have recently been achieved regarding the functions of antiviral CD8+ T cells, leading to a better understanding of their abnormalities during chronic infection as well as the pathways to be manipulated to reverse the immune impairment of chronic infection. In this review, we aimed to analyse the patterns of adaptive immunity that develop during acute infection and the profiles in chronic infection. In addition to CD8+ T cells, which are the best-described subset to date, we reviewed and commented on the direct and indirect roles of CD4+ T cells and B cells.
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Affiliation(s)
- E Loggi
- Institute for Research in Biomedicine, Bellinzona, Switzerland; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Sun XF, Gu L, Deng WS, Xu Q. Impaired balance of T helper 17/T regulatory cells in carbon tetrachloride-induced liver fibrosis in mice. World J Gastroenterol 2014; 20:2062-2070. [PMID: 24616573 PMCID: PMC3934476 DOI: 10.3748/wjg.v20.i8.2062] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 11/01/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of T helper (Th) 17/T regulatory (Treg) cells on hepatic fibrosis in mice and its possible mechanism.
METHODS: Hepatic fibrosis was induced by intraperitoneal injection of carbon tetrachloride. Hepatic pathological changes were observed by hematoxylin and eosin staining; the protein levels of interleukin (IL)-6, transforming growth factor (TGF)-β and α-smooth muscle actin (SMA) in liver tissue were determined by Western blotting; and the frequency of Th17 and Treg cells in the liver was estimated by flow cytometry. In addition, hepatic stellate cells were isolated from healthy mouse liver and co-cultured with Th17 or Treg cells. Immunofluorescence staining and Western blotting were performed to determine the change in HSC activation.
RESULTS: In the model group, there were different degrees of fibroplasia, degeneration and necrosis. The protein levels of IL-6, TGF-β and α-SMA in liver tissue were significantly higher than those in the control group at 12 wk (P < 0.05). Compared with the control group, the frequency of Th17 cells in the model group was increased but the frequency of Treg cells decreased gradually. Furthermore, at 4, 8 and 12 wk, there were significant differences in the number of Th17 cells (0.52% ± 0.16%, 1.46% ± 0.24%, and 2.60% ± 0.41%, respectively, P < 0.05) and Treg cells (2.99% ± 0.40%, 2.16% ± 0.50%, and 1.49% ± 0.34%, respectively, P < 0.05). In vitro, Th17 cells promoted, whereas Treg cells inhibited the expression of α-SMA, both in a dose-dependent manner, compared with the control group.
CONCLUSION: Th17/Treg imbalance exists in mice with liver fibrosis, which potentially promotes liver fibrosis via HSC activation.
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Li L, Liu M, Cheng LW, Gao XY, Fu JJ, Kong G, Feng X, Pan XC. HBcAg-specific IL-21-producing CD4+ T cells are associated with relative viral control in patients with chronic hepatitis B. Scand J Immunol 2014; 78:439-46. [PMID: 23957859 DOI: 10.1111/sji.12099] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 08/05/2013] [Indexed: 12/29/2022]
Abstract
Function exhaustion of specific cytotoxic CD8+ T cell in chronic virus infection partly results from the low levels of CD4 help, but the mechanisms by which CD4 help T cell required to control hepatitis B virus infection are not well understood. In this study, we investigated the role of interleukin-21-producing CD4+ T cell response in viral control of hepatitis B virus infection. HBcAg-specific interleukin-21-producing CD4+ T cells in blood were detected in patients with hepatitis B virus infection. Patients with acute hepatitis B had greater HBcAg-specific interleukin-21-producing CD4+ T cells in blood compared with chronic hepatitis B patients, and there was no statistical significance between immune active chronic hepatitis B patients and inactive healthy carrier patients for these cells, whereas frequencies of these cells negatively correlated with HBV DNA levels but positively correlated with HBc18-27-specific IFN-γ-producing CD8+ T cells. Moreover, interleukin-21 sustained HBc18-27-specific CD8+ T cells in vitro, and interleukin-21 production by HBcAg-specific IL-21-producing CD4+ T cells of acute hepatitis B patients enhanced IFN-γ and perforin expression by CD8+ T cells from chronic hepatitis B patients. Our results demonstrate that HBcAg-specific interleukin-21-producing CD4+ T cell responses might contribute to viral control by sustaining CD8+ T cell antiviral function.
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Affiliation(s)
- L Li
- Department of Infectious Disease, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China
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Ye H, Wang LY, Zhao J, Wang K. Increased CD163 expression is associated with acute-on-chronic hepatitis B liver failure. World J Gastroenterol 2013; 19:2818-2825. [PMID: 23687420 PMCID: PMC3653157 DOI: 10.3748/wjg.v19.i18.2818] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 03/14/2013] [Accepted: 03/23/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To assess CD163 expression in plasma and peripheral blood and analyze its association with disease in acute-on-chronic hepatitis B liver failure (ACHBLF) patients. METHODS A retrospective study was conducted from January 1, 2011 to January 1, 2012. Forty patients with ACHBLF (mean age 44.48 ± 12.28 years, range 18-69 years), 40 patients with chronic hepatitis B (CHB) (mean age 39.45 ± 12.22 years, range 21-57 years) and 20 age- and sex-matched healthy controls (mean age 38.35 ± 11.97 years, range 28-60 years) were included in this study. Flow cytometry was used to analyze the frequency of CD163+ peripheral blood mononuclear cells (PBMCs) and surface protein expression of CD163. Real-time transcription-polymerase chain reaction was performed to assess relative CD163 mRNA levels in PBMCs. Plasma soluble CD163 (sCD163) levels were measured by enzyme-linked immunosorbent assay. Clinical variables were also recorded. Comparisons between groups were analyzed by Kruskal-Wallis H test and Mann-Whitney U test. Statistical analyses were performed using SPSS 15.0 software and a P value < 0.05 was considered statistically significant. RESULTS Flow cytometry showed that the population of CD163+ PBMCs was significantly greater in ACHBLF patients than in CHB patients and healthy controls (47.9645% ± 17.1542%, 32.0975% ± 11.0215% vs 17.9460% ± 6.3618%, P < 0.0001). However, there were no significant differences in mean fluorescence intensity of CD163+ PBMCs within the three groups (27.4975 ± 11.3731, 25.8140 ± 10.0649 vs 20.5050 ± 6.2437, P = 0.0514). CD163 mRNA expression in ACHBLF patients was significantly increased compared with CHB patients and healthy controls (1.41 × 10⁻² ± 2.18 × 10⁻², 5.10 × 10⁻³ ± 3.61 × 10⁻³ vs 37.0 × 10⁻⁴ ± 3.55 × 10⁻⁴, P = 0.02). Plasma sCD163 levels in patients with ACHBLF were significantly increased compared with CHB patients and healthy controls (4706.2175 ± 1681.1096 ng/mL, 1089.7160 ± 736.8395 ng/mL vs 435.9562 ± 440.8329 ng/mL, P < 0.0001). In ACHBLF patients, plasma sCD163 levels were significantly positively associated with model for end-stage liver disease scores (r = 0.5075, P = 0.008), hepatitis B virus-DNA (r = 0.6827, P < 0.0001), and negatively associated with prothrombin activity (r = -0.3348, P = 0.0347), but had no correlation with total bilirubin (r = 0.2551, P = 0.1122). Furthermore, sCD163 was obviously elevated in non-surviving patients compared with surviving patients with ACHBLF (5344.9080 ± 1589.5199 ng/mL vs 3641.7333 ± 1264.5228 ng/mL, P = 0.0321). CONCLUSION CD163 and sCD163 may be related to disease severity and prognosis in ACHBLF patients.
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MESH Headings
- Acute Disease
- Adolescent
- Adult
- Aged
- Antigens, CD/blood
- Antigens, CD/genetics
- Antigens, Differentiation, Myelomonocytic/blood
- Antigens, Differentiation, Myelomonocytic/genetics
- Biomarkers/blood
- Female
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/immunology
- Humans
- Liver Failure/blood
- Liver Failure/diagnosis
- Liver Failure/immunology
- Liver Failure/virology
- Male
- Middle Aged
- Prognosis
- RNA, Messenger/blood
- Receptors, Cell Surface/blood
- Receptors, Cell Surface/genetics
- Retrospective Studies
- Severity of Illness Index
- Up-Regulation
- Young Adult
- CD163 Antigen
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Xue ZM, Yao DM. Th17 cells and liver diseases. Shijie Huaren Xiaohua Zazhi 2013; 21:1185-1190. [DOI: 10.11569/wcjd.v21.i13.1185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, it has been demonstrated that T helper cells 17 (Th17) are closely related to the occurrence and development of many kinds of liver diseases such as viral hepatitis, autoimmune liver diseases and fatty liver diseases. Th17 cells are a new CD4+ T cell subset, which can interact with Th1, Th2 and Treg cells. There exists complex antagonistic or collaborative relationship among these cells. Understanding the role of Th17 cells in liver diseases will help explore the pathogenesis and treatment of these diseases.
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Wang B, Zhao XP, Fan YC, Zhang JJ, Zhao J, Wang K. IL-17A but not IL-22 suppresses the replication of hepatitis B virus mediated by over-expression of MxA and OAS mRNA in the HepG2.2.15 cell line. Antiviral Res 2013; 97:285-292. [PMID: 23274784 DOI: 10.1016/j.antiviral.2012.12.018] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 12/14/2012] [Accepted: 12/17/2012] [Indexed: 02/08/2023]
Abstract
Interleukin-17A (IL-17A) and interleukin-22 (IL-22), mainly secreted by interleukin-17-producing T help cells (Th17), are pleiotropic cytokines that regulate the biological responses of several target cells, including hepatocytes. Th17 frequency was reported to negatively correlate with plasma hepatitis B virus (HBV) DNA load in patients with HBV infection. Several studies have indicated that cytokines, such as IL-6 and IL-4, are involved in the noncytopathic suppression of HBV replication. We therefore hypothesized that IL-17A and IL-22 might have a potent suppressive effect on HBV replication. In our present study, we analyzed the suppressive effect of IL-17A and IL-22 on HBV replication in the hepatocellular carcinoma cell line HepG2.2.15. IL-17A did not inhibit the proliferation of HepG2.2.15 cells. It decreased the levels of HBV s antigen (HBsAg) and HBV e antigen (HBeAg) in culture medium and the levels of intracellular HBV DNA. By contrast, blockage of IL-17 receptor (IL-17R) increased the levels of HBsAg and extracellular HBV DNA in culture medium and the levels of intracellular HBV DNA. The expression of antiviral proteins, including myxovirus resistance A (MxA) and oligoadenylate synthetase (OAS), was enhanced by IL-17A. IL-22 and anti-human IL-22 receptor (IL-22R) antibody did not change any indexes. We demonstrated that IL-17A effectively suppressed HBV replication in a noncytopathic manner and the over-expression of MxA and OAS mRNA was involved in the suppression of HBV replication by IL-17A.
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Affiliation(s)
- Bing Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Wenhuaxi Road 107#, Jinan 250012, China
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Yang B, Wang Y, Zhao C, Yan W, Che H, Shen C, Zhao M. Increased Th17 cells and interleukin-17 contribute to immune activation and disease aggravation in patients with chronic hepatitis B virus infection. Immunol Lett 2012; 149:41-9. [PMID: 23237940 DOI: 10.1016/j.imlet.2012.12.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 11/28/2012] [Accepted: 12/01/2012] [Indexed: 12/19/2022]
Abstract
T helper17 (Th17) cells have been demonstrated to participate in the pathogenesis of hepatitis B virus (HBV) associated liver damage. However, the contribution of Th17 cells to immune activation and disease aggravation in patients with HBV infection is not fully clear. In this study, we investigated the Th17 cells frequencies and interleukin-17 (IL-17) mRNA expressions in peripheral blood mononuclear cells (PBMCs), intrahepatic IL-17-positive cells accumulation, as well as serum IL-17 levels in asymptomatic chronic HBV carriers (AsC), and patients with chronic hepatitis B (CHB) and HBV related acute-on-chronic liver failure (ACLF). Furthermore, the dynamic changes of Th17 cells frequencies and IL-17 concentration in different prognostic ACLF patients were observed. As result, the intrahepatic and peripheral Th17 cells and serum IL-17 concentration were both significantly higher in CHB and HBV related ACLF patients than that in AsC and normal control groups, and increased gradually with immune inflammation aggravation from AsC, CHB to ACLF. Moreover, in ACLF patients, peripheral Th17 cells frequencies were positively correlated with international normalized ratio (INR) and model of end-stage liver disease (MELD) score. Especially the survival patients had an initially lower Th17 cells frequencies and IL-17 levels which gradually decreased following condition improvement as compared with higher baseline level followed by gradually increasing trend in the non-survivals. In conclusion, Th17 cells can be contributed to the immune activation and disease aggravation in patients with chronic HBV infection. This may places Th17 cells as a potential blocking target for controlling CHB and ACLF.
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Affiliation(s)
- Bo Yang
- Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China
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