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Yang L, Zheng SG. Role of regulatory T cells in inflammatory liver diseases. Autoimmun Rev 2025; 24:103806. [PMID: 40139456 DOI: 10.1016/j.autrev.2025.103806] [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: 07/08/2024] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 03/29/2025]
Abstract
The liver is the human body's largest digestive gland, which can participate in digestion, metabolism, excretion, detoxification and immunity. Chronic liver diseases such as metabolic dysfunction-associated fatty liver disease (MAFLD) or viral hepatitis involve ongoing inflammation and resulting liver fibrosis may ultimately lead to the development of hepatobiliary cancers (HCC). Inflammation is the coordinated reaction of different liver cell types to cell signals and death of inflammation, which are linked to injury pathways within the liver or external agents from the gut-liver axis and the circulation. Regulatory T (Treg) cells play a crucial role in controlling inflammation and are essential for maintaining immune tolerance and balance. In this review, we highlight the recent discoveries related to the function of immune systems in liver inflammation and discuss the role of Treg cells in the different liver diseases (including MAFLD, autoimmune hepatitis and others).
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Affiliation(s)
- Linjie Yang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China
| | - Song Guo Zheng
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523808, China; Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China; State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 201600, China.
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Kakh M, Doroudchi M, Talepoor A. Induction of Regulatory T Cells After Virus Infection and Vaccination. Immunology 2025. [PMID: 40329764 DOI: 10.1111/imm.13927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/04/2025] [Accepted: 03/17/2025] [Indexed: 05/08/2025] Open
Abstract
Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines. Trial Registration: ClinicalTrials.gov identifier: NCT04357444.
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Affiliation(s)
- MansourehKarimi Kakh
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - AtefeGhamar Talepoor
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhang X, Yang F, Han L, Su Q, Gao Y, Wu R, Wang D, Li W, Zheng K, Liu F, Ran J. Identification of pivotal genes and crucial pathways in liver fibrosis through WGCNA analysis. Technol Health Care 2025; 33:431-448. [PMID: 39177628 DOI: 10.3233/thc-241142] [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] [Indexed: 08/24/2024]
Abstract
BACKGROUND Liver fibrosis is a progressive liver disease with increasing incidence, yet its underlying pathogenic mechanisms remain incompletely understood. OBJECTIVE : This study aims to explore potential therapeutic targets for liver fibrosis using weighted gene co-expression network analysis (WGCNA) and experimental validation. METHODS We retrieved the microarray data (GSE174099) from the GEO database and performed differential expression analysis and WGCNA to identify co-expression modules associated with liver fibrosis. A module with the highest correlation to liver fibrosis was selected for further analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to investigate the biological functions and signaling pathways of the identified genes. Protein-protein interaction (PPI) networks were constructed using the STRING database. The correlation between core genes and immune cells was analyzed with the CIBERSORT algorithm. Additionally, pathological and molecular biology experiments were performed to validate the expression levels of core genes in liver tissue, including HE and Masson staining, immunohistochemistry, RT-qPCR, and Western blotting. RESULTS We identified a total of 86 intersecting genes from the differential expression analysis and WGCNA. GO enrichment analysis revealed that these genes were involved in processes such as cellular response to cAMP, collagen-containing extracellular matrix, and G protein-coupled receptor binding. KEGG pathway analysis highlighted the involvement of these genes in pathways like Cell Adhesion Molecules and the PI3K-Akt signaling pathway. Using Cytoscape software, we identified four core genes: Cftr, Cldn4, Map2, and Spp1. Pathological examinations showed that the experimental group exhibited significant fibrous tissue proliferation compared to the control group. Immunohistochemistry, RT-qPCR, and Western blotting analyses confirmed that these core genes were significantly upregulated in the experimental group (P< 0.05). CONCLUSION This study identified four key genes (Cftr, Cldn4, Map2, Spp1) that are significantly associated with liver fibrosis. These genes are upregulated in liver fibrosis and could potentially as biomarkers for diagnosis and targets for therapeutic interventions.
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Affiliation(s)
- Xibing Zhang
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Fuli Yang
- Department of Pathology, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Lei Han
- Department of Hepatobiliary Surgery, Changzhi People's Hospital, Changzhi, Shanxi, China
| | - Qiuming Su
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Yang Gao
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Ruichao Wu
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Duo Wang
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Wang Li
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Kepu Zheng
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Fang Liu
- Department of Endocrinology, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
| | - Jianghua Ran
- Department of Hepatopancreatobiliary and Vascular Surgery, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Yunnan, China
- Yunnan Organ Transplantation Research Institute, The Affiliated Calmette Hospital of Kunming Medical University, The First People's Hospital of Kunming, Kunming, Yunnan, China
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Garbuglia AR, Pauciullo S, Zulian V, Del Porto P. Update on Hepatitis C Vaccine: Results and Challenges. Viruses 2024; 16:1337. [PMID: 39205311 PMCID: PMC11359353 DOI: 10.3390/v16081337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/15/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Therapy against the Hepatitis C virus (HCV) has significantly improved with the introduction of direct-acting antiviral drugs (DAAs), achieving over 95% sustained virological response (SVR). Despite this, the development of an effective anti-HCV vaccine remains a critical challenge due to the low number of patients treated with DAAs and the occurrence of HCV reinfections in high-risk groups. Current vaccine strategies aim to stimulate either B-cell or T-cell responses. Vaccines based on E1 and E2 proteins can elicit broad cross-neutralizing antibodies against all major HCV genotypes, though with varying efficiencies and without full protection against infection. In humans, the neutralizing antibodies induced by such vaccines mainly target the AR3 region, but their levels are generally insufficient for broad neutralization. Various HCV proteins expressed through different viral vectors have been utilized to elicit T cell immune responses, showing sustained expansion of HCV-specific effector memory T cells and improved proliferation and polyfunctionality of memory T cells over time. However, despite these advancements, the frequency and effectiveness of T-cell responses remain limited.
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Affiliation(s)
- Anna Rosa Garbuglia
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.)
| | - Silvia Pauciullo
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.)
| | - Verdiana Zulian
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani” (IRCCS), 00149 Rome, Italy; (S.P.); (V.Z.)
| | - Paola Del Porto
- Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome, 00100 Rome, Italy;
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Abdelaziz AI, Abdelsameea E, Abdel-Samiee M, Ghanem SE, Wahdan SA, Elsherbiny DA, Zakaria Z, Azab SS. Effect of immunogenetics polymorphism and expression on direct-acting antiviral drug response in chronic hepatitis C. Clin Exp Med 2024; 24:184. [PMID: 39117877 PMCID: PMC11310263 DOI: 10.1007/s10238-024-01432-x] [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: 04/10/2024] [Accepted: 07/09/2024] [Indexed: 08/10/2024]
Abstract
The prevalence of HCV infection in Egypt has decreased following the introduction of direct-acting antiviral therapy. However, treatment response is influenced by various factors, particularly host immunogenetics such as IL-28B and FOXP3 polymorphisms. The current study examined the impact of SNPs in the FOXP3 gene promoter region on HCV-infected Egyptian patients, along with SNPs in the IL28B gene.This study involved 99 HCV patients who achieved SVR12 after a 12 week DAA treatment while 63 HCV patients experienced treatment failure. IL28B rs12979860 SNP was identified using real-time PCR, while IL28B rs8099917, FOXP3 rs3761548, and rs2232365 SNPs were analyzed using RFLP-PCR. Serum levels of IL28B and FOXP3 were quantified using ELISA technique in representative samples from both groups. The IL28B rs12979860 T > C (P = 0.013) and FOXP3 rs2232365 A > G polymorphisms (P = 0.008) were found to significantly increase the risk of non-response. Responders had higher IL28B serum levels (P = 0.046) and lower FOXP3 levels (P < 0.001) compared to non-responders. Regression analysis showed an association between IL28B rs12979860 and FOXP3 rs2232365 with treatment response, independent of age and gender. A predictive model was developed with 76.2% sensitivity and 91.9% specificity for estimating DAAs response in HCV patients.Our findings confirmed the IL28B rs12979860 T > C and FOXP3 rs2232365 A > G polymorphisms significantly affect DAA treatment response in HCV Egyptian patients. Lower levels of IL-28B along with higher levels of FOXP3 are linked to poor response. Our results may lead to new insights into DAA responsiveness contributing to personalized medicine and improving therapeutic decision-making for HCV patients.
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Affiliation(s)
- Aya Ismail Abdelaziz
- Department of Research and Development, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Mohamed Abdel-Samiee
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Samar E Ghanem
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Sara A Wahdan
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Doaa A Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt
| | - Zeinab Zakaria
- Department of Research and Development, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt
| | - Samar S Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
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Loffredo LF, Savage TM, Ringham OR, Arpaia N. Treg-tissue cell interactions in repair and regeneration. J Exp Med 2024; 221:e20231244. [PMID: 38668758 PMCID: PMC11046849 DOI: 10.1084/jem.20231244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/22/2024] [Accepted: 04/11/2024] [Indexed: 04/29/2024] Open
Abstract
Regulatory T (Treg) cells are classically known for their critical immunosuppressive functions that support peripheral tolerance. More recent work has demonstrated that Treg cells produce pro-repair mediators independent of their immunosuppressive function, a process that is critical to repair and regeneration in response to numerous tissue insults. These factors act on resident parenchymal and structural cells to initiate repair in a tissue-specific context. This review examines interactions between Treg cells and tissue-resident non-immune cells-in the context of tissue repair, fibrosis, and cancer-and discusses areas for future exploration.
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Affiliation(s)
- Lucas F. Loffredo
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Thomas M. Savage
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Olivia R. Ringham
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
| | - Nicholas Arpaia
- Department of Microbiology and Immunology, Columbia University, New York, NY, USA
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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Liu W, Zeng X, Wang X, Hu Y, Chen L, Luo N, Ouyang D, Rao T. 2,3,5,4'- tetrahydroxystilbene-2-O-β-D- glucopyranoside (TSG)-Driven immune response in the hepatotoxicity of Polygonum multiflorum. JOURNAL OF ETHNOPHARMACOLOGY 2024; 326:117865. [PMID: 38369066 DOI: 10.1016/j.jep.2024.117865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 01/31/2024] [Accepted: 02/03/2024] [Indexed: 02/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG) as the primary constituent of Polygonum multiflorum Thumb. (PM) possesses anti-oxidative, antihypercholesterolemic, anti-tumor and many more biological activities. The root of PM has been used as a tonic medicine for thousands of years. However, cases of PM-induced liver injury are occasionally reported, and considered to be related to the host immune status. AIM OF THE STUDY The primary toxic elements and specific mechanisms PM causing liver damage are still not thoroughly clear. Our study aimed to investigate the influences of TSG on the immune response in idiosyncratic hepatotoxicity of PM. MATERIALS AND METHODS The male C57BL/6 mice were treated with different doses of TSG and the alterations in liver histology, serum liver enzyme levels, proportions of T cells and cytokines secretion were evaluated by hematoxylin and eosin (HE), RNA sequencing, quantitative real time polymerase chain reaction (qRT-PCR), Flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA), respectively. Then, primary spleen cells from drug-naive mice were isolated and cultured with TSG in vitro. T cell subsets proliferation and cytokines secretion after treated with TSG were assessed by CCK8, FCM and ELISA. In addition, mice were pre-treated with anti-CD25 for depleting regulatory T cells (Tregs), and then administered with TSG. Liver functions and immunological alterations were analyzed to evaluate liver injury. RESULTS Data showed that TSG induced liver damage, and immune cells infiltration in the liver tissues. FCM results showed that TSG could activate CD4+T and CD8+T in the liver. Results further confirmed that TSG notably up-regulated the levels of inflammatory cytokines including TNF-α, IFN-γ, IL-18, perforin and granzyme B in the liver tissues. Furthermore, based on transcriptomics profiles, some immune system-related pathways including leukocyte activation involved in inflammatory response, leukocyte cell-cell adhesion, regulation of interleukin-1 beta production, mononuclear cell migration, antigen processing and presentation were altered in TSG treated mice. CD8+T/CD4+T cells were also stimulated by TSG in vitro. Interestingly, increased proportion of Tregs was observed after TSG treatment in vitro and in vivo. Foxp3 and TGF-β1 mRNA expressions were up-regulated in the liver tissues. Depletion of Tregs moderately enhanced TSG induced the secretion of inflammatory cytokines in serum. CONCLUSIONS Our findings showed that TSG could trigger CD4+T and CD8+T cells proliferation, promote cytokines secretion, which revealed that adaptive immune response associated with the mild liver injury cause by TSG administration. Regulatory T cells (Tregs) mainly sustain immunological tolerance, and in this study, the progression of TSG induced liver injury was limited by Tregs. The results of our investigations allow us to preliminarily understand the mechanisms of PM related idiosyncratic hepatotoxicity.
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Affiliation(s)
- Wenhui Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan Province, 410078, China; Department of Clinical Laboratory, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Province, 541001, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan Province, 410078, China
| | - Xiangchang Zeng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan Province, 410078, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan Province, 410078, China; Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, Hunan Province, 410221, China
| | - Xinfeng Wang
- Department of Human Anatomy, College of Basic Medicine, Guilin Medical University, Guilin, Guangxi Province, 541199, China
| | - Yuwei Hu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan Province, 410078, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan Province, 410078, China
| | - Lulu Chen
- Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, Hunan Province, 410221, China
| | - Naixiang Luo
- Department of Immunology, College of Basic Medicine, Guilin Medical University, Guilin, Guangxi Province, 541199, China.
| | - Dongsheng Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan Province, 410078, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan Province, 410078, China; Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, Hunan Province, 410221, China.
| | - Tai Rao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan Province, 410078, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan Province, 410078, China.
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Ajith A, Merimi M, Arki MK, Hossein-khannazer N, Najar M, Vosough M, Sokal EM, Najimi M. Immune regulation and therapeutic application of T regulatory cells in liver diseases. Front Immunol 2024; 15:1371089. [PMID: 38571964 PMCID: PMC10987744 DOI: 10.3389/fimmu.2024.1371089] [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: 01/16/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024] Open
Abstract
CD4+ CD25+ FOXP3+ T regulatory cells (Tregs) are a subset of the immunomodulatory cell population that can inhibit both innate and adaptive immunity by various regulatory mechanisms. In hepatic microenvironment, proliferation, plasticity, migration, and function of Tregs are interrelated to the remaining immune cells and their secreted cytokines and chemokines. In normal conditions, Tregs protect the liver from inflammatory and auto-immune responses, while disruption of this crosstalk between Tregs and other immune cells may result in the progression of chronic liver diseases and the development of hepatic malignancy. In this review, we analyze the deviance of this protective nature of Tregs in response to chronic inflammation and its involvement in inducing liver fibrosis, cirrhosis, and hepatocellular carcinoma. We will also provide a detailed emphasis on the relevance of Tregs as an effective immunotherapeutic option for autoimmune diseases, liver transplantation, and chronic liver diseases including liver cancer.
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Affiliation(s)
- Ananya Ajith
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Makram Merimi
- Genetics and Immune Cell Therapy Unit, LBBES Laboratory, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Najar
- Osteoarthritis Research Unit, Department of Medicine, University of Montreal Hospital Research Center (CRCHUM), Montreal, QC, Canada
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Centre, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Huddinge, Sweden
| | - Etienne Marc Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Jiang T, Xiang X, Wang X, Han Z, Cheng C, Zhu Y, Yang Z, Liang Y. Role of regulatory T cells in pathogenesis and therapeutics of primary biliary cholangitis and primary sclerosing cholangitis. REGULATORY T CELLS AND AUTOIMMUNE DISEASES 2024:433-452. [DOI: 10.1016/b978-0-443-13947-5.00014-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Bai Q, Li R, He X, Hong X, Yan Y, Zhao Z, Lin H, Tacke F, Engelmann C, Hu T. Single-cell landscape of immune cells during the progression from HBV infection to HBV cirrhosis and HBV-associated hepatocellular carcinoma. Front Immunol 2023; 14:1320414. [PMID: 38116005 PMCID: PMC10729758 DOI: 10.3389/fimmu.2023.1320414] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023] Open
Abstract
Introduction Immune cells play crucial roles in the development of chronic hepatitis B virus (HBV) infection, leading to cirrhosis and hepatocellular carcinoma (HCC). However, their functions at different disease stages are not fully understood. Methods In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the human liver immune microenvironment at different disease stages. We analyzed scRNA-seq data from 118,455 immune cells obtained from livers of six healthy individuals, four patients with HBV infection, five patients with HBV cirrhosis, and three patients with HBV-associated HCC. Results Our results showed an accumulation of scar-associated macrophages during disease progression, and we identified two relevant immune subsets, Macrophage-CD9/IL18 and macrophage-CD9/IFI6. Macrophage-CD9/IL18 expanded from HBV infection to cirrhosis, while macrophage-CD9/IFI6 expanded from cirrhosis to HCC. We verified the existence of Macrophage-CD9/IFI6 using multiplex immunofluorescence staining. We also found an increase in cytotoxic NK Cell-GNLY during progression from cirrhosis to HCC. Additionally, the proportion of CD4 T cell-TNFAIP3, CD8 T cell-TNF (effector CD8 T cells), and CD8 T cell-CD53 increased, while the proportion of Treg cells decreased from HBV infection to cirrhosis. The proportion of Treg and CD8 T cell-LAG3 (Exhausted CD8 T cell) enhanced, while the proportion of CD8 T cell-TNF (effector CD8 T cells) decreased from cirrhosis to HCC. Furthermore, GSEA enrichment analyses revealed that MAPK, ERBB, and P53 signaling pathways in myeloid cells were gradually inhibited from HBV infection to cirrhosis and HCC. Discussion Our study provides important insights into changes in the hepatic immune environment during the progression of HBV-related liver disease, which may help improve the management of HBV-infected liver diseases.
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Affiliation(s)
- Qingquan Bai
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Runyang Li
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Xiao He
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xiaoting Hong
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Ying Yan
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Zhengyang Zhao
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
| | - Han Lin
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health - Charité - Universitätsmedizin Berlin, Berlin, Germany
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Tianhui Hu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, China
- Shenzhen Research Institute of Xiamen University, Shenzhen, China
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12
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Lowe KO, Tanase CE, Maghami S, Fisher LE, Ghaemmaghami AM. Inflammatory Network of Liver Fibrosis and How It Can Be Targeted Therapeutically. IMMUNO 2023; 3:375-408. [DOI: 10.3390/immuno3040023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Liver fibrosis is a complex, dynamic process associated with a broad spectrum of chronic liver diseases and acute liver failure, characterised by the dysregulated intrahepatic production of extracellular matrix proteins replacing functional liver cells with scar tissue. Fibrosis progresses due to an interrelated cycle of hepatocellular injury, triggering a persistent wound-healing response. The accumulation of scar tissue and chronic inflammation can eventually lead to cirrhosis and hepatocellular carcinoma. Currently, no therapies exist to directly treat or reverse liver fibrosis; hence, it remains a substantial global disease burden. A better understanding of the intricate inflammatory network that drives the initiation and maintenance of liver fibrosis to enable the rationale design of new intervention strategies is required. This review clarifies the most current understanding of the hepatic fibrosis cellular network with a focus on the role of regulatory T cells, and a possible trajectory for T cell immunotherapy in fibrosis treatment. Despite good progress in elucidating the role of the immune system in liver fibrosis, future work to better define the function of different immune cells and their mediators at different fibrotic stages is needed, which will enhance the development of new therapies.
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Affiliation(s)
- Kirstin O. Lowe
- School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
| | | | - Susan Maghami
- Hull York Medical School, University of York, York YO10 5DD, UK
| | - Leanne E. Fisher
- School of Life Sciences, University of Nottingham, Nottingham NG7 2RD, UK
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13
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Wang L, Li D, Zhu Z, Liao Y, Wu J, Liu Y, Yang R, Dai H, Wu Z, Sun X. Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression. Pharmacol Res 2023; 195:106886. [PMID: 37591326 DOI: 10.1016/j.phrs.2023.106886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/30/2023] [Accepted: 08/08/2023] [Indexed: 08/19/2023]
Abstract
Liver fibrosis can occur in many chronic liver diseases, and no effective treatments are available due to the poorly characterized molecular pathogenesis. Semaphorin 4D (Sema4D) has immune functions and serves important roles in T cell priming. Here, we found that Sema4D was highly expressed in fibrotic liver, and the expression of Sema4D increased with hepatic stellate cells (HSCs) activation. Knockout of Sema4D alleviated liver fibrosis. Mechanistically, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism. Further investigation demonstrated that retinoic acid receptor α (RARA), an important nuclear receptor of retinoic acid, was reduced by Sema4D knockout during liver fibrogenesis. Sema4D knockout-mediated suppression of liver fibrosis was partly mediated by regulating the balance of Th1, Th2, Th17, and T-bet+Treg cells via inhibiting AOX1/RARA. Thus, targeting Sema4D may hold promise as a potential therapeutic approach for treating liver fibrosis.
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Affiliation(s)
- Lifu Wang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Dinghao Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China
| | - Zifeng Zhu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China
| | - Yao Liao
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Ji Wu
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Yuheng Liu
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou 511436, China
| | - Ruibing Yang
- Guangzhou KingMed Diagnostic Laboratory Group Co Ltd, Guangzhou 510310, China
| | - Hanqiao Dai
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhongdao Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China.
| | - Xi Sun
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou 510080, China; Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou 510080, China.
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14
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Kleczka A, Mazur B, Tomaszek K, Gabriel A, Dzik R, Kabała-Dzik A. Association of NK Cells with the Severity of Fibrosis in Patients with Chronic Hepatitis C. Diagnostics (Basel) 2023; 13:2187. [PMID: 37443584 DOI: 10.3390/diagnostics13132187] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/19/2023] [Accepted: 06/21/2023] [Indexed: 07/15/2023] Open
Abstract
Some NK cell subpopulations may be involved in the modulation of fibrogenesis in the liver. The aim of the study was to evaluate the relationship between the number and phenotype of NK cell subsets in peripheral blood (PB) and total NK cell percentage, population density and the degree of liver fibrosis of patients infected with hepatitis C virus (HCV+). The study group consisted of 56 HCV+ patients, divided into two subgroups: patients with mild or moderate fibrosis and patients with advanced liver fibrosis or cirrhosis (F ≥ 3 in METAVIR classification). The preparations were stained with H-E and AZAN staining. NK cells were targeted with anti-CD56 antibody and identified automatically in situ using the DakoVision system. Assessment of different NK cell subsets in PB was performed with the flow cytometry technique. In the PB of HCV+ patients with advanced liver fibrosis, there was a lower proportion of CD62L+; CD62L+/CD94++; CD27+; CD127+/CD27+ and CXCR3+/CD27+ NK subsets, as compared to patients with mild/moderate liver fibrosis. The results also showed no association between total PB NK cell level and total intrahepatic NK cell population density between patients with mild/moderate fibrosis and with advanced liver fibrosis. However, positive correlations between the PB levels of CD94+ and CD62L+ NK cell subsets and the intrahepatic total NK cell percentage and population density in the liver, irrespectively to the extent of fibrosis, were observed. Additionally, positive correlation was found between the PB CXCR3+/CD94+ NK cell percentages and intrahepatic NK cell percentages in patients with advanced hepatic fibrosis. Lower blood availability of specific NK subsets in patients with chronic type C hepatitis might be a cause of progression of liver fibrosis via insufficient control over hepatic stellate cells.
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Affiliation(s)
- Anna Kleczka
- Department of Pathology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, 41-200 Sosnowiec, Poland
| | - Bogdan Mazur
- Department of Microbiology and Immunology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, 40-808 Zabrze, Poland
| | - Krzysztof Tomaszek
- Department of Pathomorphology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, 40-800 Zabrze, Poland
| | - Andrzej Gabriel
- Department of Pathomorphology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, 40-800 Zabrze, Poland
| | - Radosław Dzik
- Faculty of Biomedical Engineering, Department of Biosensors and Processing of Biomedical Signals, Silesian University of Technology, Roosevelta 40, 41-800 Zabrze, Poland
| | - Agata Kabała-Dzik
- Department of Pathology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Ostrogórska 30, 41-200 Sosnowiec, Poland
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15
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Regulatory T cells (Tregs) in liver fibrosis. Cell Death Discov 2023; 9:53. [PMID: 36759593 PMCID: PMC9911787 DOI: 10.1038/s41420-023-01347-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/11/2023] Open
Abstract
The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2-dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease.
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16
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Park SJ, Hahn YS. Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment. Clin Mol Hepatol 2023; 29:65-76. [PMID: 35957546 PMCID: PMC9845665 DOI: 10.3350/cmh.2022.0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/11/2022] [Indexed: 02/02/2023] Open
Abstract
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA,Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA,Corresponding author : Young S. Hahn Department of Microbiology, Immunology and Cancer Biology, University of Virginia, 345 Crispell Dr, Charlottesville, VA 22908, USA Tel: +1-434-924-1275, Fax: +1-434-924-1221, E-mail:
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17
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Weeratunga P, Moller DR, Ho LP. Immune mechanisms in fibrotic pulmonary sarcoidosis. Eur Respir Rev 2022; 31:220178. [PMID: 36543347 PMCID: PMC9879330 DOI: 10.1183/16000617.0178-2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/21/2022] [Indexed: 12/24/2022] Open
Abstract
Sarcoidosis is an immune-mediated disorder. Its immunopathology has been steadily mapped out over the past few decades. Despite this, the underpinning mechanisms for progressive fibrotic sarcoidosis is an almost uncharted area. Consequently, there has been little change in the clinical management of fibrotic sarcoidosis over the decades and an unfocused search for new therapeutics. In this review, we provide a comprehensive examination of the relevant immune findings in fibrotic and/or progressive pulmonary sarcoidosis and propose a unifying mechanism for the pathobiology of fibrosis in sarcoidosis.
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Affiliation(s)
- Praveen Weeratunga
- Oxford Sarcoidosis Clinic, Oxford Interstitial Lung Disease Service, Oxford, UK
- MRC Human Immunology Unit, University of Oxford, Oxford, UK
| | - David R Moller
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Ling-Pei Ho
- Oxford Sarcoidosis Clinic, Oxford Interstitial Lung Disease Service, Oxford, UK
- MRC Human Immunology Unit, University of Oxford, Oxford, UK
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18
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Tai C, Xie Z, Li Y, Feng Y, Xie Y, Yang H, Wang L, Wang B. Human skin dermis-derived fibroblasts are a kind of functional mesenchymal stromal cells: judgements from surface markers, biological characteristics, to therapeutic efficacy. Cell Biosci 2022; 12:105. [PMID: 35831878 PMCID: PMC9277801 DOI: 10.1186/s13578-022-00842-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 07/03/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Human mesenchymal stromal cells (MSCs) have been widely advocated to clinical use. Human skin dermis-derived fibroblasts shared similar cellular morphology and biological characteristics to MSCs, while it still keeps elusive whether fibroblasts are functionally equivalent to MSCs for therapeutic use.
Methods
We isolated various fibroblasts derived from human foreskins (HFFs) and human double-fold eyelids (HDF) and MSCs derived from human umbilical cords (UC-MSCs), and then comprehensively investigated their similarities and differences in morphology, surface markers, immunoregulation, multilineage differentiation, transcriptome sequencing, and metabolomics, and therapeutic efficacies in treating 2,4,6-Trinitrobenzenesulfonic acid (TNBS) induced colitis and carbontetrachloride (CCL4) induced liver fibrosis.
Results
Fibroblasts and UC-MSCs shared similar surface markers, strong multilineage differentiation capacity, ability of inhibiting Th1/Th17 differentiation and promoting Treg differentiation in vitro, great similarities in mRNA expression profile and metabolites, and nearly equivalent therapeutic efficacy on TNBS-induced colitis and CCL4-induced hepatic fibrosis.
Conclusion
Human skin dermis-derived fibroblasts were a kind of functional MSCs with functionally equivalent therapeutic efficacy in treating specific complications, indicating fibroblasts potentially had the same lineage hierarchy of origin as MSCs and had a remarkable potential as an alternative to MSCs in the treatment of a variety of diseases.
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19
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Tafuri WL, Tomokane TY, Silva AMG, Kanashiro‐Galo L, Mosser DM, Quaresma JAS, Pagliari C, Sotto MN. Skin fibrosis associated with keloid, scleroderma and Jorge Lobo's disease (lacaziosis): An immuno-histochemical study. Int J Exp Pathol 2022; 103:234-244. [PMID: 36183172 PMCID: PMC9664412 DOI: 10.1111/iep.12456] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/08/2022] [Accepted: 07/27/2022] [Indexed: 11/30/2022] Open
Abstract
Fibrosis is a common pathophysiological response of many tissues and organs subjected to chronic injury. Despite the diverse aetiology of keloid, lacaziosis and localized scleroderma, the process of fibrosis is present in the pathogenesis of all of these three entities beyond other individual clinical and histological distinct characteristics. Fibrosis was studied in 20 samples each of these three chronic cutaneous inflammatory diseases. An immunohistochemical study was carried out to explore the presence of α-smooth muscle actin (α-SMA) and vimentin cytoskeleton antigens, CD31, CD34, Ki67, p16; CD105, CD163, CD206 and FOXP3 antigens; and the central fibrotic cytokine TGF-β. Higher expression of vimentin in comparison to α-SMA in all three lesion types was found. CD31- and CD34-positive blood vessel endothelial cells were observed throughout the reticular dermis. Ki67 expression was low and almost absent in scleroderma. p16-positive levels were higher than ki67 and observed in reticular dermis of keloidal collagen in keloids, in collagen bundles in scleroderma and in the external layers of the granulomas in lacaziosis. The presence of α-actin positive cells and rarely CD34 positive cells, observed primarily in keloids, may be related to higher p16 antigen expression, a measure of cell senescence. Low FOXP3 expression was observed in all lesion types. CD105-positive cells were mainly found in perivascular tissue in close contact with the adventitia in keloids and scleroderma, while, in lacaziosis, these cells were chiefly observed in conjunction with collagen deposition in the external granuloma layer. We did not find high involvement of CD163 or CD206-positive cells in the fibrotic process. TGF-β was notable only in keloid and lacaziosis lesions. In conclusion, we have suggested vimentin to be the main myofibroblast general marker of the fibrotic process in all three studied diseases, while endothelial-to-mesenchymal transition (EndoMT) and mesenchymal stem cells (MSCs) and M2 macrophages may not play an important role.
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Affiliation(s)
- Wagner Luiz Tafuri
- Departamento de Patologia GeralInstituto de Ciências BiológicasUniversidade Federal de Minas GeraisBelo HorizonteBrazil
- Faculdade de Medicina, Departamento de PatologiaUniversidade de São PauloSao PauloBrazil
| | - Thaise Yumie Tomokane
- Laboratório de Patologia das Moléstias Infecciosas – LIM50, Departamento de PatologiaFaculdade de Medicina da Universidade de São PauloSão PauloBrazil
| | | | - Luciane Kanashiro‐Galo
- Faculdade de Medicina, Departamento de PatologiaUniversidade de São PauloSao PauloBrazil
| | | | | | - Carla Pagliari
- Faculdade de Medicina, Departamento de PatologiaUniversidade de São PauloSao PauloBrazil
- Instituto de Assistência Médica ao Servidor Público Estadual e Programa de pós‐graduação em Ciências da SaúdeSão PauloBrazil
| | - Mirian N. Sotto
- Faculdade de Medicina, Departamento de PatologiaUniversidade de São PauloSao PauloBrazil
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20
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Sun R, Xiang Z, Wu B. T cells and liver fibrosis. PORTAL HYPERTENSION & CIRRHOSIS 2022; 1:125-132. [DOI: 10.1002/poh2.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/07/2022] [Indexed: 01/03/2025]
Abstract
AbstractLiver fibrosis develops from the excessive deposition of extracellular matrix in the liver caused by chronic liver inflammation or various chronic injuries, and it eventually develops into liver cirrhosis. The process of liver fibrosis is closely related to the immune response, and increasing evidence reveals the role of T lymphocytes, including Th1, Th2, Th17, regulatory T cells, and mucosa‐associated invariant T cells, in liver fibrosis. These immune cells play antifibrotic or profibrotic roles during fibrosis, and the reversal of fibrosis by targeting immune cells has attracted widespread attention. Activation of hepatic stellate cells, which form the core of fibrosis, is regulated by various immune mediators, including various immune cells and their associated cytokines. Therefore, the mechanism of action elicited by each cell type must be further elucidated to provide a basis for the design of new therapeutic targets. The purpose of this review is to summarize the roles and mechanisms of T lymphocytes and their subsets in liver fibrosis and highlight the biomarkers and potential therapeutic targets associated with these cells.
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Affiliation(s)
- Ruonan Sun
- Department of Gastroenterology Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou Guangdong China
| | - Zheng Xiang
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine University of Hong Kong Hong Kong China
| | - Bin Wu
- Department of Gastroenterology Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou Guangdong China
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21
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Tarique M, Suhail M, Naz H, Muhammad N, Tabrez S, Zughaibi TA, Abuzenadah AM, Hashem AM, Shankar H, Saini C, Sharma A. Where do T cell subsets stand in SARS-CoV-2 infection: an update. Front Cell Infect Microbiol 2022; 12:964265. [PMID: 36034704 PMCID: PMC9399648 DOI: 10.3389/fcimb.2022.964265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 07/12/2022] [Indexed: 01/08/2023] Open
Abstract
An outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019 and spread so rapidly all around the globe. It's continued and spreading more dangerously in India and Brazil with higher mortality rate. Understanding of the pathophysiology of COVID-19 depends on unraveling of interactional mechanism of SARS-CoV-2 and human immune response. The immune response is a complex process, which can be better understood by understanding the immunological response and pathological mechanisms of COVID-19, which will provide new treatments, increase treatment efficacy, and decrease mortality associated with the disease. In this review we present a amalgamate viewpoint based on the current available knowledge on COVID-19 which includes entry of the virus and multiplication of virus, its pathological effects on the cellular level, immunological reaction, systemic and organ presentation. T cells play a crucial role in controlling and clearing viral infections. Several studies have now shown that the severity of the COVID-19 disease is inversely correlated with the magnitude of the T cell response. Understanding SARS-CoV-2 T cell responses is of high interest because T cells are attractive vaccine targets and could help reduce COVID-19 severity. Even though there is a significant amount of literature regarding SARS-CoV-2, there are still very few studies focused on understanding the T cell response to this novel virus. Nevertheless, a majority of these studies focused on peripheral blood CD4+ and CD8+ T cells that were specific for viruses. The focus of this review is on different subtypes of T cell responses in COVID-19 patients, Th17, follicular helper T (TFH), regulatory T (Treg) cells, and less classical, invariant T cell populations, such as δγ T cells and mucosal-associated invariant T (MAIT) cells etc that could influence disease outcome.
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Affiliation(s)
- Mohammad Tarique
- Department of Child Health, University of Missouri, Columbia, MO, United States
| | - Mohd Suhail
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Huma Naz
- Department of Child Health, University of Missouri, Columbia, MO, United States
| | - Naoshad Muhammad
- Department of Radiation Oncology, School of Medicine, Washington University in Saint Louis, Saint Louis, MO, United States
| | - Shams Tabrez
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Torki A. Zughaibi
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Adel M. Abuzenadah
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Anwar M. Hashem
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Hari Shankar
- India Council of Medical Research, New Delhi, India
| | - Chaman Saini
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Alpana Sharma
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India
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22
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Glaubitz J, Wilden A, Golchert J, Homuth G, Völker U, Bröker BM, Thiele T, Lerch MM, Mayerle J, Aghdassi AA, Weiss FU, Sendler M. In mouse chronic pancreatitis CD25 +FOXP3 + regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response. Nat Commun 2022; 13:4502. [PMID: 35922425 PMCID: PMC9349313 DOI: 10.1038/s41467-022-32195-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/20/2022] [Indexed: 12/19/2022] Open
Abstract
Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3+CD25+ Treg cells suppress the type-2 immune response by a repression of GATA3+ T helper cells (Th2), GATA3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue. The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
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Affiliation(s)
- Juliane Glaubitz
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
| | - Anika Wilden
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
| | - Janine Golchert
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Uwe Völker
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Barbara M Bröker
- Department of Immunology, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
| | - Thomas Thiele
- Department of Transfusion Medicine, Institute of Immunology and Transfusion Medicine, University Medicine, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
| | - Julia Mayerle
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany.,Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Ali A Aghdassi
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
| | - Frank U Weiss
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany.
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23
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Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19. J Immunol Res 2022; 2022:5545319. [PMID: 35497875 PMCID: PMC9042623 DOI: 10.1155/2022/5545319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/13/2022] [Accepted: 03/28/2022] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) has been raised as a pandemic disease since December 2019. Immunosuppressive cells including T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) are key players in immunological tolerance and immunoregulation; however, they contribute to the pathogenesis of different diseases including infections. Tregs have been shown to impair the protective role of CD8+ T lymphocytes against viral infections. In COVID-19 patients, most studies reported reduction, while few other studies found elevation in Treg levels. Moreover, Tregs have a dual role, depending on the different stages of COVID-19 disease. At early stages of COVID-19, Tregs have a critical role in decreasing antiviral immune responses, and consequently reducing the viral clearance. On the other side, during late stages, Tregs reduce inflammation-induced organ damage. Therefore, inhibition of Tregs in early stages and their expansion in late stages have potentials to improve clinical outcomes. In viral infections, MDSC levels are highly increased, and they have the potential to suppress T cell proliferation and reduce viral clearance. Some subsets of MDSCs are expanded in the blood of COVID-19 patients; however, there is a controversy whether this expansion has pathogenic or protective effects in COVID-19 patients. In conclusion, further studies are required to investigate the role and function of immunosuppressive cells and their potentials as prognostic biomarkers and therapeutic targets in COVID-19 patients.
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24
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Moreau JM, Velegraki M, Bolyard C, Rosenblum MD, Li Z. Transforming growth factor-β1 in regulatory T cell biology. Sci Immunol 2022; 7:eabi4613. [PMID: 35302863 PMCID: PMC10552796 DOI: 10.1126/sciimmunol.abi4613] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Transforming growth factor-β1 (TGF-β1) is inextricably linked to regulatory T cell (Treg) biology. However, precisely untangling the role for TGF-β1 in Treg differentiation and function is complicated by the pleiotropic and context-dependent activity of this cytokine and the multifaceted biology of Tregs. Among CD4+ T cells, Tregs are the major producers of latent TGF-β1 and are uniquely able to activate this cytokine via expression of cell surface docking receptor glycoprotein A repetitions predominant (GARP) and αv integrins. Although a preponderance of evidence indicates no essential roles for Treg-derived TGF-β1 in Treg immunosuppression, TGF-β1 signaling is crucial for Treg development in the thymus and periphery. Furthermore, active TGF-β1 instructs the differentiation of other T cell subsets, including TH17 cells. Here, we will review TGF-β1 signaling in Treg development and function and discuss knowledge gaps, future research, and the TGF-β1/Treg axis in the context of cancer immunotherapy and fibrosis.
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Affiliation(s)
- Joshua M. Moreau
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Maria Velegraki
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center—James Cancer Hospital, Columbus, OH, USA
| | - Chelsea Bolyard
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center—James Cancer Hospital, Columbus, OH, USA
| | - Michael D. Rosenblum
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center—James Cancer Hospital, Columbus, OH, USA
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25
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Giadans CG, Ríos DA, Ameigeiras B, Haddad L, De Matteo EN, Valva P, Preciado MV. Intrahepatic immune infiltrate in chronic hepatitis B and chronic hepatitis C: Similar but not the same. J Viral Hepat 2022; 29:124-134. [PMID: 34820942 DOI: 10.1111/jvh.13635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 12/09/2022]
Abstract
In chronic hepatitis B (CHB) and C (CHC) infections, the composition of the immune cell microenvironment at the site of infection is poorly understood. Thus, our aim was to characterize and compare liver infiltrates to identify shared and exclusive hepatic immune components. Immunohistochemistry was performed on 26 CHB and 42 CHC liver biopsies to determine Th (CD4+), Th1 (T-bet+), Th17 (IL-17A+), Treg (Foxp3+) and CTL (CD8+) cells frequency in portal/periportal and intralobular areas and relate them to liver damage. CHB and CHC cases shared a portal/periportal CD4+ lymphocyte predominance and a lobular CD8+ lymphocyte majority. However, CHC exhibited a concomitant lobular T-bet+ cell dominance while in CHB FoxP3+ cells prevail. CHC disclosed higher frequencies of P/P FoxP3+, IL-17A+ and T-bet+ cells and intralobular CD4+, IL-17A+ and T-bet+ lymphocytes. HBeAg+ chronic hepatitis and CHC cell frequencies were similar except for lobular T-bet+ that remained higher among CHC cases. Comparison among cases with less severe liver disease revealed lower lymphocyte frequencies in CHB samples, while no differences were observed between patients with more severe stages. Interestingly, in CHB portal/periportal CD4+ and lobular CD4+, CD8+ and IL-17A+ cells were associated with severe hepatitis. Even when all studied populations were identified in both infections preferential lymphocyte frequencies and prevalence at different areas along with their association with liver damage highlighted that CHB and CHC immune responses are not the same.
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Affiliation(s)
- Cecilia Graciela Giadans
- Pathology Division, Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, CABA, Argentina
| | - Daniela Alejandra Ríos
- Pathology Division, Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, CABA, Argentina
| | | | - Leila Haddad
- Liver Unit, Ramos Mejía Hospital, CABA, Argentina
| | - Elena Noemí De Matteo
- Pathology Division, Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, CABA, Argentina
| | - Pamela Valva
- Pathology Division, Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, CABA, Argentina
| | - María Victoria Preciado
- Pathology Division, Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, CABA, Argentina
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26
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Arjomandnejad M, Kopec AL, Keeler AM. CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications. Biomedicines 2022; 10:287. [PMID: 35203496 PMCID: PMC8869296 DOI: 10.3390/biomedicines10020287] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 01/27/2023] Open
Abstract
Regulatory T cells are critical for maintaining immune tolerance. Recent studies have confirmed their therapeutic suppressive potential to modulate immune responses in organ transplant and autoimmune diseases. However, the unknown and nonspecific antigen recognition of polyclonal Tregs has impaired their therapeutic potency in initial clinical findings. To address this limitation, antigen specificity can be conferred to Tregs by engineering the expression of transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR). In contrast to TCR Tregs, CAR Tregs are major histocompatibility complex (MHC) independent and less dependent on interleukin-2 (IL-2). Furthermore, CAR Tregs maintain Treg phenotype and function, home to the target tissue and show enhanced suppressive efficacy compared to polyclonal Tregs. Additional development of engineered CAR Tregs is needed to increase Tregs' suppressive function and stability, prevent CAR Treg exhaustion, and assess their safety profile. Further understanding of Tregs therapeutic potential will be necessary before moving to broader clinical applications. Here, we summarize recent studies utilizing CAR Tregs in modulating immune responses in autoimmune diseases, transplantation, and gene therapy and future clinical applications.
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Affiliation(s)
- Motahareh Arjomandnejad
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; (M.A.); (A.L.K.)
| | - Acadia L. Kopec
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; (M.A.); (A.L.K.)
| | - Allison M. Keeler
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA; (M.A.); (A.L.K.)
- Department of Pediatrics, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
- NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
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27
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Rios DA, Casciato PC, Caldirola MS, Gaillard MI, Giadans C, Ameigeiras B, De Matteo EN, Preciado MV, Valva P. Chronic Hepatitis C Pathogenesis: Immune Response in the Liver Microenvironment and Peripheral Compartment. Front Cell Infect Microbiol 2021; 11:712105. [PMID: 34414132 PMCID: PMC8369367 DOI: 10.3389/fcimb.2021.712105] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C (CHC) pathogenic mechanisms as well as the participation of the immune response in the generation of liver damage are still a topic of interest. Here, we evaluated immune cell populations and cytokines in the liver and peripheral blood (PB) to elucidate their role in CHC pathogenesis. B, CTL, Th, Treg, Th1, Th17, and NK cell localization and frequency were evaluated on liver biopsies by immunohistochemistry, while frequency, differentiation, and functional status on PB were evaluated by flow cytometry. TNF-α, IL-23, IFN-γ, IL-1β, IL-6, IL-8, IL-17A, IL-21, IL-10, and TGF-β expression levels were quantified in fresh liver biopsy by RT-qPCR and in plasma by CBA/ELISA. Liver CTL and Th1 at the lobular area inversely correlated with viral load (r = −0.469, p =0.003 and r = −0.384, p = 0.040). Treg correlated with CTL and Th1 at the lobular area (r = 0.784, p < 0.0001; r = 0.436, p = 0.013). Th17 correlated with hepatic IL-8 (r = 0.52, p < 0.05), and both were higher in advanced fibrosis cases (Th17 p = 0.0312, IL-8 p = 0.009). Hepatic cytokines were higher in severe hepatitis cases (IL-1β p = 0.026, IL-23 p = 0.031, IL-8 p = 0.002, TGF-β, p= 0.037). Peripheral NK (p = 0.008) and NK dim (p = 0.018) were diminished, while NK bright (p = 0.025) was elevated in patients vs. donors. Naïve Th (p = 0.011) and CTL (p = 0.0007) were decreased, while activated Th (p = 0.0007) and CTL (p = 0.0003) were increased. IFN-γ production and degranulation activity in NK and CTL were normal. Peripheral cytokines showed an altered profile vs. donors, particularly elevated IL-6 (p = 0.008) and TGF-β (p = 0.041). Total hepatic CTLs favored damage. Treg could not prevent fibrogenesis triggered by Th17 and IL-8. Peripheral T-lymphocyte differentiation stage shift, elevated cytokine levels and NK-cell count decrease would contribute to global disease.
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Affiliation(s)
- Daniela Alejandra Rios
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | | | - María Soledad Caldirola
- Immunology Unit, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - María Isabel Gaillard
- Immunology Unit, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - Cecilia Giadans
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | | | - Elena Noemí De Matteo
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - María Victoria Preciado
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
| | - Pamela Valva
- Laboratory of Molecular Biology, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Pathology Division, Ricardo Gutiérrez Children's Hospital, Buenos Aires, Argentina
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28
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Xie Y, Liu S, Wang L, Yang H, Tai C, Ling L, Chen L, Liu S, Wang B. Individual heterogeneity screened umbilical cord-derived mesenchymal stromal cells with high Treg promotion demonstrate improved recovery of mouse liver fibrosis. Stem Cell Res Ther 2021; 12:359. [PMID: 34158112 PMCID: PMC8220795 DOI: 10.1186/s13287-021-02430-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 06/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background To investigate the heterogeneities of human umbilical cord mesenchymal stromal cells (HUCMSCs) derived from different donors and their therapeutic variations when applied to mouse liver fibrosis model. Methods The characteristics of HUCMSCs derived from multiple donors were comprehensively analyzed including expressions of surface markers, viability, growth curve, karyotype analysis, tumorigenicity, differentiation potentials, and immune regulation capability. Then, the HUCMSCs with distinct immunomodulatory effects were applied to treat mouse liver fibrosis and their therapeutic effects were observed. Results The HUCMSCs derived from multiple donors kept a high consistency in surface marker expressions, viability, growth curve, and tumorigenicity in nude mice but had robust heterogeneities in differentiation potentials and immune regulations. In addition, three HUCMSC lines applied to mice liver fibrosis model had different therapeutic outcomes, in line with individual immune regulation capability. Conclusion The HUCMSCs derived from different donors have individual heterogeneity, which potentially lead to distinct therapeutic outcomes in mouse liver fibrosis, indicating we could make use of the donor-variation of MSCs to screen out guaranteed general indicators of MSCs for specific diseases in further stromal cell therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02430-6.
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Affiliation(s)
- Yuanyuan Xie
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Shuo Liu
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Liudi Wang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Hui Yang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Chenxu Tai
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China
| | - Li Ling
- Department of Endocrinology, University Health Science Center, Hua Zhong University of Science and Technology Union Shenzhen Hospital and The 6th Affiliated Hospital of Shenzhen, Shenzhen, 518052, Guangdong, People's Republic of China
| | - Libo Chen
- Department of Endocrinology, University Health Science Center, Hua Zhong University of Science and Technology Union Shenzhen Hospital and The 6th Affiliated Hospital of Shenzhen, Shenzhen, 518052, Guangdong, People's Republic of China
| | - Shanshan Liu
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210000, People's Republic of China.
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29
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Zientarska A, Kaczmarek M, Mozer-Lisewska I, Kowala-Piaskowska A, Witkowska A, Żeromski J. Treg cells in the course of chronic hepatitis C virus infection partially normalize in longitudinal observation after successful DAA treatment regardless of hepatic fibrosis stage. Clin Exp Hepatol 2021; 7:196-204. [PMID: 34295988 PMCID: PMC8284172 DOI: 10.5114/ceh.2021.107122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/03/2021] [Indexed: 11/17/2022] Open
Abstract
AIM OF THE STUDY Elevated circulating CD4+ CD25+ Foxp3+ regulatory T cells in patients with chronic hepatitis C (CHC) play an unspecified role in liver fibrosis development. This study aimed to determine whether Treg cells diminish after successful treatment with directacting antivirals (DAA) in patients at different liver fibrosis stages. MATERIAL AND METHODS We examined 44 patients with CHC (including 29 with liver cirrhosis) seven days before DAA treatment (T0), six months later (T1) and then 22 of them were examined one year (T2) after the first dose. Subsequently, these were compared with 28 volunteers without hepatitis C virus (HCV) (15 with excessive alcohol intake). We assessed the degree of liver fibrosis with FibroScan, aspartate transaminase (AST) to platelet ratio index (APRI), FibroIndex, the Forns index and Fib-4. Circulating Treg cells were measured using flow cytometry. RESULTS All patients achieved a sustained virological response (SVR). After the treatment, all liver fibrosis indicators decreased significantly. The number of circulating Tregs was lower in healthy controls than in patients with CHC (0.0066 × 103 cells/µl and 0.0084 × 103 cells/µl, respectively, p = 0.048). After the treatment we observed an insignificant change to 0.0047 × 103 cells/µl for T1 (p > 0.05) and a significant fall to 0.0041 × 103 cells/µl for T2 (p = 0.03). There was no correlation between the degree of hepatic fibrosis and number of Tregs or post-treatment dynamics. CONCLUSIONS Our study shows that Treg cells normalize gradually over a prolonged period of time after a successful DAA treatment. Their number and dynamics remain independent of liver fibrosis degree. The correlation of this revelation with metabolic disorders, increased susceptibility to infections or persistent risk of HCC remains unclear.
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Affiliation(s)
- Agata Zientarska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Mariusz Kaczmarek
- Chair of Clinical Immunology and Department of Cancer Immunology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland
| | - Iwona Mozer-Lisewska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Arleta Kowala-Piaskowska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Aleksandra Witkowska
- Chair and Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
| | - Jan Żeromski
- Chair of Clinical Immunology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland
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30
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Kaufmann B, Reca A, Kim AD, Feldstein AE. Novel Mechanisms for Resolution of Liver Inflammation: Therapeutic Implications. Semin Liver Dis 2021; 41:150-162. [PMID: 34107544 DOI: 10.1055/s-0041-1723031] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Traditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a highly dynamic and active event that is essential to counteract the dysregulated inflammatory response that drives diverse disease states. Abrogation of the hepatic inflammatory response through the stimulation of proresolving mechanisms represents a new paradigm in the setting of chronic inflammatory-driven liver diseases. Elucidation of the role of different cells of the innate and adaptive immune system has highlighted the interplay between them as an important orchestrator of liver repair. A finely tuned interaction between neutrophils and macrophages has risen as revolutionary mechanism that drives the restoration of hepatic function and architecture. Specialized proresolving mediators have also been shown to act as stop signals of the inflammatory response and promote resolution as well as tissue regeneration. In this review, we discuss the discovery and understanding of the mechanisms by which inflammation is resolved and highlight novel proresolving pathways that represent promising therapeutic strategies.
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Affiliation(s)
- Benedikt Kaufmann
- Department of Pediatrics, University of California, San Diego (UCSD), California and Rady Children's Hospital, San Diego, California.,Department of Surgery, TUM School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Agustina Reca
- Department of Pediatrics, University of California, San Diego (UCSD), California and Rady Children's Hospital, San Diego, California
| | - Andrea D Kim
- Department of Pediatrics, University of California, San Diego (UCSD), California and Rady Children's Hospital, San Diego, California
| | - Ariel E Feldstein
- Department of Pediatrics, University of California, San Diego (UCSD), California and Rady Children's Hospital, San Diego, California
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31
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Rahimzadeh M, Naderi N. Toward an understanding of regulatory T cells in COVID-19: A systematic review. J Med Virol 2021; 93:4167-4181. [PMID: 33605463 DOI: 10.1002/jmv.26891] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
A more detailed understanding of Treg cells in COVID-19 infection will broaden our knowledge of the COVID-19 immunopathology and give us more insight into the curative immune-based strategies. We systematically searched electronic databases (PubMed, Google Scholar, EMBASE) and identified 18 eligible studies. Despite the inconsistencies between the results, we observed a trend toward decreasing Treg levels in severe COVID-19 patients. This finding underlines the hypothesis that Tregs play a role in the pathogenesis of COVID-19. Further studies on Tregs' functional aspects are necessary to illustrate Tregs' potential role in COVID-19 disease.
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Affiliation(s)
- Mahsa Rahimzadeh
- Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nadereh Naderi
- Department of Immunology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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32
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Wan M, Han J, Ding L, Hu F, Gao P. Novel Immune Subsets and Related Cytokines: Emerging Players in the Progression of Liver Fibrosis. Front Med (Lausanne) 2021; 8:604894. [PMID: 33869241 PMCID: PMC8047058 DOI: 10.3389/fmed.2021.604894] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 03/05/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is a pathological process caused by persistent chronic injury of the liver. Kupffer cells, natural killer (NK) cells, NKT cells, and dendritic cells (DCs), which are in close contact with T and B cells, serve to bridge innate and adaptive immunity in the liver. Meanwhile, an imbalanced inflammatory response constitutes a challenge in liver disease. The dichotomous roles of novel immune cells, including T helper 17 (Th17), regulatory T cells (Tregs), mucosa-associated invariant T cells (MAIT), and innate lymphoid cells (ILCs) in liver fibrosis have gradually been revealed. These cells not only induce damage during liver fibrosis but also promote tissue repair. Hence, immune cells have unique, and often opposing, roles during the various stages of fibrosis. Due to this heterogeneity, the treatment, or reversal of fibrosis through the target of immune cells have attracted much attention. Moreover, activation of hepatic stellate cells (HSCs) constitutes the core of fibrosis. This activation is regulated by various immune mediators, including Th17, Th22, and Th9, MAIT, ILCs, and γδ T cells, as well as their related cytokines. Thus, liver fibrosis results from the complex interaction of these immune mediators, thereby complicating the ability to elucidate the mechanisms of action elicited by each cell type. Future developments in biotechnology will certainly aid in this feat to inform the design of novel therapeutic targets. Therefore, the aim of this review was to summarize the role of specific immune cells in liver fibrosis, as well as biomarkers and treatment methods related to these cells.
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Affiliation(s)
- Minjie Wan
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, China.,Central Laboratory, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Jiawen Han
- Central Laboratory, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Lili Ding
- Central Laboratory, The First Hospital of Jilin University, Jilin University, Changchun, China.,Intensive Care Unit, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Feng Hu
- Department of Hepatology and Gastroenterology, The Second Part of First Hospital, Jilin University, Changchun, China
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, Changchun, China
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33
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Liu S, Liu Z, Shan Z, Liu Y, Chen T, Fang L, Quan H. Skewed Th17/Treg balance during progression and malignant transformation of oral submucous fibrosis. Oral Dis 2021; 28:2119-2130. [PMID: 33749974 DOI: 10.1111/odi.13853] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/01/2021] [Accepted: 03/16/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVES The aim of our study was to determine the impact of Th17/Treg imbalance on the progression and malignant transformation of oral submucosal fibrosis (OSF). MATERIALS AND METHODS To assess Th17 and Treg expression, overall 52 peripheral blood samples from OSF, oral squamous cell carcinoma (OSCC) patients, and healthy donors were analyzed by flow cytometry. Thirty normal oral mucosa, 72 OSF, and 90 OSCC samples were analyzed by immunohistochemistry. RESULTS In peripheral blood samples, in OSCC with OSF, Th17 and Treg expression were significantly higher than those in OSF and OSCC without OSF as confirmed by immunohistochemistry. During OSF progression, Th17 and Th17/Treg ratio showed an increasing trend, while Treg expression showed a decreasing trend. Treg expression was significantly higher in OSCC with OSF than in OSF and OSCC without OSF, whereas the Th17/Treg ratio was significantly lower in OSCC with OSF. Treg expression was significantly correlated with smoking and clinical stage. Th17/Treg ratio was significantly associated with tumor size, lymph node metastasis, and clinical stage. A low Th17/Treg ratio was significantly associated with poor prognosis. CONCLUSIONS Th17/Treg ratio is a potential diagnostic indicator for OSF occurrence and malignant transformation and was an independent prognostic factor for OSCC.
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Affiliation(s)
- Sixuan Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Ziyi Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Zhongyan Shan
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Yuxin Liu
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Tianjun Chen
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
| | - Liangjuan Fang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China
| | - Hongzhi Quan
- Hunan Key Laboratory of Oral Health Research & Hunan 3D Printing Engineering Research Center of Oral Care & Hunan Clinical Research Center of Oral Major Diseases and Oral Health Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China.,Department of Oral Maxillofacial Surgery, Xiangya Stomatological Hospital & School of Stomatology, Central South University, Changsha, China
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Sung PS, Shin EC. Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection. J Clin Med 2021; 10:E221. [PMID: 33435135 PMCID: PMC7827927 DOI: 10.3390/jcm10020221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/08/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.
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Affiliation(s)
- Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
- The Catholic Liver Research Center, The Catholic University of Korea, Seoul 06591, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
- The Center for Epidemic Preparedness, KAIST Institute, Daejeon 34141, Korea
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Serum Interleukin-35 Level in Correlation with T Regulatory and T helper-17 Cells Frequency in Chronic Viral Hepatitis C Patients. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2020. [DOI: 10.22207/jpam.14.4.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Interleukin-35 (IL-35), secreted mainly by T-regulatory cells (T-regs), has been considered to have immunosuppressive actions in many auto-immune diseases and tumors. However, information about its role in chronic hepatitis C (CHC) infection is still limited. We aimed to study the role of IL-35 within CHC infection and to assess its correlation with T-regs and T-helper 17 cells (Th-17). Therefore, we measured serum IL-35 concentrations using ELISA assay in 25 normal controls (NCs) and in 30 CHC patients before receiving direct antiviral agents (DAA) treatment and after 3 months of treatment end. T-regs and Th-17 cells frequencies were assessed via flow-cytometry in control group and patients’ group before treatment. The results showed that serum IL-35 levels revealed a highly significant increase in CHC patients compared to NCs (P <0.001). Moreover, IL-35 levels significantly decreased in patients 3 months after treatment end (P =0.02). Both Th-17 and T-regs were significantly increased in patients more than in NCs and a positive correlation was observed between them. However, T-regs/Th-17 ratio did not show significant difference from the ratio in NCs. IL-35 levels were positively correlated with viral load and T-regs frequency, but not with Th-17 frequency. IL-35 levels did not correlate with liver enzymes or functions. These results suggested that IL-35 enhances the immunosuppressive functions of T-regs, protecting the liver from HCV induced damage and contributes to viral persistence. IL-35 may represent a possible immunotherapeutic strategy for chronic persistent infection if given with DAA, especially in relapsing or non-responding cases.
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Gonzalez K, Calzada JE, Tomokane TY, Pacheco CMS, Flores GVA, Castro Gomes CM, Pereira Corbett CE, Saldaña A, Laurenti MD. In situ study of cellular immune response in human cutaneous lesions caused by Leishmania (Viannia) panamensis in Panama. Parasite Immunol 2020; 43:e12801. [PMID: 33068443 DOI: 10.1111/pim.12801] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/11/2020] [Accepted: 10/12/2020] [Indexed: 12/19/2022]
Abstract
AIMS Leishmaniasis is considered a disease with multiple clinical/immunopathological characteristics, depending on the immunity of the host and the species of the parasite. In Panama, the most prevalent species that causes localized cutaneous leishmaniasis (LCL) is Leishmania (Viannia) panamensis, and its immune response is poorly studied. Therefore, we evaluated by immunohistochemistry, the in situ immune response during this infection. METHODS AND RESULTS Biopsies from Panamanian patients with LCL were collected and processed by histological techniques. Infection by L. (V.) panamensis was demonstrated by isolation in culture and molecular characterization by Hsp70-RFLP. The in situ immune response was assessed by immunohistochemistry. The immune response was characterized by predominance of T cells, mainly CD8 cells that showed positive correlation with IFN-γ and Granzyme B. CD4 cells presented positive correlation with both IFN-γ and IL-13, pointed by mixed cellular immune response. Regulatory response was characterized by FoxP3 cells, which showed positive correlation to IL-10 but not with TGF-β. CONCLUSIONS L. (V.) panamensis infection triggers a mixed cellular immune response, characterized by the presence of pro-inflammatory, anti-inflammatory and regulatory elements in the skin lesion of Panamanian patients. These data contribute to a better understanding of the immunopathogenesis of Leishmania Viannia infection in Panama.
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Affiliation(s)
- Kadir Gonzalez
- Departamento de Parasitología Molecular, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panama, Panamá.,Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - José Eduardo Calzada
- Departamento de Parasitología Molecular, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panama, Panamá.,Facultad de Medicina Veterinaria, Universidad de Panamá, Panamá, Panamá
| | - Thaise Yumie Tomokane
- Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Carmen Maria Sandoval Pacheco
- Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Gabriela Venicia Araujo Flores
- Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Cláudia Maria Castro Gomes
- Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Carlos Eduardo Pereira Corbett
- Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
| | - Azael Saldaña
- Departamento de Parasitología Molecular, Instituto Conmemorativo Gorgas de Estudios de la Salud, Panama, Panamá.,Centro de Investigación y Diagnóstico de Enfermedades Parasitarias, Facultad de Medicina, Universidad de Panamá, Panamá, Panamá
| | - Marcia Dalastra Laurenti
- Departamento de Patologia, Laboratório de Patologia de Moléstias Infecciosas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil
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Ikeno Y, Ohara D, Takeuchi Y, Watanabe H, Kondoh G, Taura K, Uemoto S, Hirota K. Foxp3+ Regulatory T Cells Inhibit CCl 4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity. Front Immunol 2020; 11:584048. [PMID: 33178216 PMCID: PMC7593684 DOI: 10.3389/fimmu.2020.584048] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Foxp3+ regulatory T (Treg) cells are pivotal in maintaining immunological self-tolerance and tissue homeostasis; however, it remains unclear how tissue Treg cells respond to liver injury and regulate chronic inflammation, which can cause liver fibrosis. We report here that hepatic Treg cells play a critical role in preventing liver pathology by suppressing inflammatory cellular immunity that can promote liver damage and fibrosis. Chronic liver inflammation induced by injections of carbon tetrachloride (CCl4) led to preferential expansion of hepatic Treg cells that prevented liver fibrosis. In contrast, depletion of Treg cells in the CCl4-induced liver fibrosis model exacerbated the severity of liver pathology. Treg depletion unleashed tissue cellular immunity and drove the activation and expansion of the pro-fibrotic IL-4-producing T helper 2 cells, as well as CCR2high Ly-6Chigh inflammatory monocytes/macrophages in the inflamed liver. Although Treg expression of amphiregulin plays a key role in tissue remodeling and repair in various inflammation models, amphiregulin from hepatic Treg cells, the largest producer among liver immune cells, was dispensable for maintaining liver homeostasis and preventing liver fibrosis during CCl4-induced chronic inflammation. Our results indicate that Treg cells control chronic liver inflammation and fibrosis by regulating the aberrant activation and functions of immune effector cells. Harnessing Treg functions, which effectively regulate tissue cellular immunity, may be a therapeutic strategy for preventing and treating liver fibrosis.
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Affiliation(s)
- Yoshinobu Ikeno
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Daiya Ohara
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hitomi Watanabe
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Gen Kondoh
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Kojiro Taura
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Department of Hepatobiliary, Pancreas and Transplant Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Lymphocyte Landscape after Chronic Hepatitis C Virus (HCV) Cure: The New Normal. Int J Mol Sci 2020; 21:ijms21207473. [PMID: 33050486 PMCID: PMC7589490 DOI: 10.3390/ijms21207473] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 12/17/2022] Open
Abstract
Chronic HCV (CHC) infection is the only chronic viral infection for which curative treatments have been discovered. These direct acting antiviral (DAA) agents target specific steps in the viral replication cycle with remarkable efficacy and result in sustained virologic response (SVR) or cure in high (>95%) proportions of patients. These treatments became available 6–7 years ago and it is estimated that their real impact on HCV related morbidity, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC), will not be known for the next decade or so. The immune system of a chronically infected patient is severely dysregulated and questions remain regarding the immune system’s capacity in limiting liver pathology in a cured individual. Another important consequence of impaired immunity in patients cleared of HCV with DAA will be the inability to generate protective immunity against possible re-infection, necessitating retreatments or developing a prophylactic vaccine. Thus, the impact of viral clearance on restoring immune homeostasis is being investigated by many groups. Among the important questions that need to be answered are how much the immune system normalizes with cure, how long after viral clearance this recalibration occurs, what are the consequences of persisting immune defects for protection from re-infection in vulnerable populations, and does viral clearance reduce liver pathology and the risk of developing hepatocellular carcinoma in individuals cured with these agents. Here, we review the recent literature that describes the defects present in various lymphocyte populations in a CHC patient and their status after viral clearance using DAA treatments.
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Tseng CW, Wu SF, Chen CY, Ho YC, He YT, Tseng KC. Characteristics of regulatory T-cell function in patients with chronic hepatitis B and C coinfection. J Viral Hepat 2020; 27:800-809. [PMID: 32243022 DOI: 10.1111/jvh.13298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 03/16/2020] [Indexed: 12/11/2022]
Abstract
Regulatory T cells (Tregs) affect the pathogenesis and disease progression of chronic viral hepatitis. This study evaluated the frequency and function of Tregs in patients with chronic HBV/HCV coinfection. Seventy-four untreated HBV/HCV co-infected patients were enrolled in this study. These subjects were divided into four subgroups: HBV-active/HCV-active (BACA), HBV-inactive/HCV-active (BICA), HBV-active/HCV-inactive (BACI) and HBV-inactive/HCV-inactive (BICI). Treg frequency was calculated as the fraction of CD4+ Foxp3+ T cells among CD4+ T cells. Treg-mediated inhibition was measured as percent of inhibition of T-cell proliferation. The expression of interferon (IFN)-γ, tumour necrosis factor (TNF)-α and interleukin (IL)-10 with/without Treg inhibition was also studied. Among the patients, there were 8 cases of BACA (10.8%), 38 of BICA (51.4%), 14 of BACI (18.9%) and 14 of BICI (18.9%). The frequency of CD4+ Foxp3+ T cells was comparable between the four groups. The inhibitory function of Tregs among the patients in the BACA and BICA was higher than that in the BICI (BACA vs BICI, P = .0210; BICA vs BICI, P = .0301). Patients in the BACA and BICA had higher fibrosis-4 (FIB-4) scores and serum ALT levels and lower serum albumin levels than those of the other groups. ALT abnormality was significantly and independently associated with a higher Treg immunosuppressive ability. The IFN-γ expression of the effector T cells in the BACA was higher than that of the other groups. In conclusion, the inhibitory function of Tregs is higher among the HBV/HCV co-infected patients with active HCV infection. ALT abnormality plays a dominant role in Treg function.
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Affiliation(s)
- Chih-Wei Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.,School of Medicine, Tzuchi University, Hualien, Taiwan
| | - Shu-Fen Wu
- Department of Biomedical Sciences and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan
| | - Chi-Yi Chen
- Department of Internal Medicine, Ditmanson Medical FoundationChia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Yun-Che Ho
- Department of Biomedical Sciences and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan
| | - Yi-Ting He
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan
| | - Kuo-Chih Tseng
- Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan.,School of Medicine, Tzuchi University, Hualien, Taiwan
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40
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de Castro GLC, Bichara CDA, Santiago AM, de Brito WB, Pereira LMS, Moura TCF, da Silva Graça Amoras E, de Araújo MSM, da Silva Conde SRS, Queiroz MAF, Ishak R, Vallinoto ACR. Polymorphisms in the TGFB1 and FOXP3 genes are associated with the presence of antinuclear antibodies in chronic hepatitis C. Heliyon 2020; 6:e04524. [PMID: 32743104 PMCID: PMC7387822 DOI: 10.1016/j.heliyon.2020.e04524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/11/2020] [Accepted: 07/17/2020] [Indexed: 11/18/2022] Open
Abstract
Chronic infection with Hepacivirus C (HCV) can lead to the occurrence of antinuclear antibodies (ANAs) and changes in cytokine profiles that can be similar to autoimmune diseases. The aim of the study was to identify polymorphisms in important mediators of the immune response in association with ANAs, which could contribute to the development of autoimmunity in hepatitis C. The study included 87 patients with chronic hepatitis C who were evaluated for the presence of ANA (indirect immunofluorescence) and for polymorphisms in the FOXP3, IFNG, IL6, IL8, IL10, MBL2, CRP, TGFΒ1 and TNFA genes (real-time PCR). Of the patients evaluated, 17 (19.54%) had ANA reactivity. The G allele of the FOXP3 rs2232365 polymorphism was more frequent in ANA-positive women (p = 0.0231; OR = 3,285). The C allele of the TGFΒ1 rs1800469 polymorphism was associated with ANA production (p = 0.0169; OR = 2.88). The results suggest that polymorphisms in genes related to immunological regulation may be associated with mechanisms that lead to the emergence of autoantibodies in the context of chronic Hepacivirus C infection.
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Affiliation(s)
| | - Carlos David A. Bichara
- Laboratório de Virologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Angélica Menezes Santiago
- Laboratório de Virologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - William Botelho de Brito
- Laboratório de Virologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | | | | | | | - Mauro Sérgio Moura de Araújo
- Laboratório de Virologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém, PA, Brazil
| | | | | | - Ricardo Ishak
- Laboratório de Virologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
| | - Antonio Carlos Rosário Vallinoto
- Laboratório de Virologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
- Corresponding author.
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Zhang M, Zhang S. T Cells in Fibrosis and Fibrotic Diseases. Front Immunol 2020; 11:1142. [PMID: 32676074 PMCID: PMC7333347 DOI: 10.3389/fimmu.2020.01142] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/11/2020] [Indexed: 01/08/2023] Open
Abstract
Fibrosis is the extensive deposition of fibrous connective tissue, and it is characterized by the accumulation of collagen and other extracellular matrix (ECM) components. Fibrosis is essential for wound healing and tissue repair in response to a variety of triggers, which include infection, inflammation, autoimmune disorder, degenerative disease, tumor, and injury. Fibrotic remodeling in various diseases, such as liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD), can impair organ function, causing high morbidity and mortality. Both innate and adaptive immunity are involved in fibrogenesis. Although the roles of macrophages in fibrogenesis have been studied for many years, the underlying mechanisms concerning the manner in which T cells regulate fibrosis are not completely understood. The T cell receptor (TCR) engages the antigen and shapes the repertoire of antigen-specific T cells. Based on the divergent expression of surface molecules and cell functions, T cells are subdivided into natural killer T (NKT) cells, γδ T cells, CD8+ cytotoxic T lymphocytes (CTL), regulatory T (Treg) cells, T follicular regulatory (Tfr) cells, and T helper cells, including Th1, Th2, Th9, Th17, Th22, and T follicular helper (Tfh) cells. In this review, we summarize the pro-fibrotic or anti-fibrotic roles and distinct mechanisms of different T cell subsets. On reviewing the literature, we conclude that the T cell regulations are commonly disease-specific and tissue-specific. Finally, we provide perspectives on microbiota, viral infection, and metabolism, and discuss the current advancements of technologies for identifying novel targets and developing immunotherapies for intervention in fibrosis and fibrotic diseases.
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Affiliation(s)
- Mengjuan Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Song Zhang
- College of Life Sciences, Nankai University, Tianjin, China
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42
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Chen Y, Chang G, Chen X, Li Y, Li H, Cheng D, Tang Y, Sang H. IL-6-miR-210 Suppresses Regulatory T Cell Function and Promotes Atrial Fibrosis by Targeting Foxp3. Mol Cells 2020; 43:438-447. [PMID: 32345003 PMCID: PMC7264473 DOI: 10.14348/molcells.2019.2275] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/07/2018] [Accepted: 10/01/2018] [Indexed: 02/08/2023] Open
Abstract
The aim of this study was to explore the role of IL-6-miR-210 in the regulation of Tregs function and atrial fibrosis in atrial fibrillation (AF). The levels of interleukin (IL)-6 and IL-10 in AF patients were detected by using ELISA. Proportions of Treg cells were detected by fluorescence activated cell sorting analysis in AF patients. The expression of Foxp3, α-SMA, collagen I and collagen III were determined by western blot. The atrial mechanocytes were authenticated by vimentin immunostaining. The expression of miR-210 was performed by quantitative real-time polymerase chain reaction (qRT-PCR). TargetScan was used to predict potential targets of miR-210. The cardiomyocyte transverse sections in AF model group were observed by H&E staining. The myocardial filaments were observed by masson staining. The level of IL-6 was highly increased while the level of IL-10 (Tregs) was significantly decreased in AF patients as compared to normal control subjects, and IL-6 suppressed Tregs function and promoted the expression of α-SMA, collagen I and collagen III. Furthermore, miR-210 regulated Tregs function by targeting Foxp3, and IL-6 promoted expression of miR-210 via regulating hypoxia inducible factor-1α (HIF-1α). IL-6-miR-210 suppresses regulatory T cell function and promotes atrial fibrosis by targeting Foxp3.
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Affiliation(s)
- YingWei Chen
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - GuoDong Chang
- Department of Cardiology, The First People’s Hospital of Shangqiu, Shangqiu 476100, China
| | - XiaoJie Chen
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - YunPeng Li
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - HaiYu Li
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - Dong Cheng
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - Yi Tang
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - HaiQiang Sang
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
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43
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Wan Z, Zhou Z, Liu Y, Lai Y, Luo Y, Peng X, Zou W. Regulatory T cells and T helper 17 cells in viral infection. Scand J Immunol 2020; 91:e12873. [PMID: 32090360 DOI: 10.1111/sji.12873] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 02/10/2020] [Accepted: 02/20/2020] [Indexed: 12/16/2022]
Abstract
CD4+ T cells are the central element of the adaptive immune responses and protect the body from a variety of pathogens. Starting from naive cells, CD4+ T cells can differentiate into various effector cell subsets with specialized functions including T helper (Th) 1, Th2, Th17, regulatory T (Treg) and T follicular helper (Tfh) cells. Among them, Tregs and Th17 cells show a strong plasticity allowing the functional adaptation to various physiological and pathological environments during immune responses. Although they are derived from the same precursor cells and their differentiation pathways are interrelated, the terminally differentiated cells have totally opposite functions. Studies have shown that Tregs and Th17 cells have rather complex interplays in viral infection: Th17 cells may contribute to immune activation and disease progression while Tregs may inhibit this process and play a key role in the maintenance of immune homoeostasis, possibly at the cost of compromised viral control. In this review, we take respiratory syncytial virus (RSV), hepatitis B virus (HBV)/hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections as examples to discuss these interplays and their impacts on disease progression in viral infection.
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Affiliation(s)
- Zhikai Wan
- Medical College of Nanchang University, Nanchang, China
| | - Zhifeng Zhou
- Medical College of Nanchang University, Nanchang, China
| | - Yao Liu
- Medical College of Nanchang University, Nanchang, China
| | - Yuhan Lai
- Medical College of Nanchang University, Nanchang, China
| | - Yuan Luo
- Medical College of Nanchang University, Nanchang, China
| | - Xiaoping Peng
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wei Zou
- Department of Infectious Diseases, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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Lan YT, Wang ZL, Tian P, Gong XN, Fan YC, Wang K. Treg/Th17 imbalance and its clinical significance in patients with hepatitis B-associated liver cirrhosis. Diagn Pathol 2019; 14:114. [PMID: 31639000 PMCID: PMC6805395 DOI: 10.1186/s13000-019-0891-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 09/12/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Recent studies have shown that T cell-mediated cellular immune mechanisms play important roles in the progression of hepatitis B to liver cirrhosis, but the underlying mechanisms remain unclear. This present study was aimed to determine the relationship between Treg/Th17 and hepatitis B-associated liver cirrhosis. METHODS The Treg and Th17 cell frequencies in the peripheral blood of all participants, including 93 patients with hepatitis B-associated liver cirrhosis and 40 healthy subjects, were measured by flow cytometer. Cox regression model and receiver operating characteristic(ROC) curves were applied to investigate the prognostic significance of Treg/Th17 ratio in decompensated liver cirrhosis. RESULTS We observed the Treg/Th17 imbalance was present in patients with hepatitis B-associated liver cirrhosis, with reduced Treg cells in their peripheral blood, increased Th17 cells and decreased Treg/Th17 ratio. Treg and Th17 cells were negatively correlated. Treg/Th17 imbalance was closely related to the clinical stage of hepatitis B-associated liver cirrhosis. The Virus load, Treg frequencies and the Treg/Th17 ratio were independent factors predicting decompensated liver cirrhosis from a Cox regression model. The ROC analysis showed that the Treg/Th17 ratio was the best marker for predicting decompensated liver cirrhosis. CONCLUSIONS Treg/Th17 imbalance is involved in the pathogenesis of hepatitis B-associated liver cirrhosis and the Treg/Th17 ratio can be used as a potential marker for predicting decompensated liver cirrhosis.
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Affiliation(s)
- Yong-Ting Lan
- Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, People's Republic of China
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong, People's Republic of China
| | - Zhen-Li Wang
- Department of Hepatology, Qing Dao No. 6 People's Hospital, Qingdao, Shandong, People's Republic of China
| | - Peng Tian
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong, People's Republic of China
| | - Xiao-Na Gong
- Department of Gastroenterology, Zibo Central Hospital, Zibo, Shandong, People's Republic of China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, People's Republic of China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, People's Republic of China.
- Institute of Hepatology, Shandong University, Jinan, Shandong, People's Republic of China.
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Tang X, Shu Z, Zhang W, Cheng L, Yu J, Zhang M, Zheng S. Clinical significance of the immune cell landscape in hepatocellular carcinoma patients with different degrees of fibrosis. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:528. [PMID: 31807510 DOI: 10.21037/atm.2019.09.122] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background The major causes of morbidity and mortality of patients with chronic liver disease are liver fibrosis and cirrhosis. Previous studies have been concerned with immune dysfunction in the pathogenesis of cirrhosis progress. However, the potential molecular mechanism of how the liver's fibrotic state favors tumor progression is still unclear. We attempted to reveal deviations of the immune cell landscape between various liver tissues and identify key biomarkers associated with patients' outcomes. Method CIBERSORT was used for estimating the proportions of immune cells in various liver tissues. Comparative studies were carried out by Kruskal-Wallis test and Wilcoxon test. For survival analyses, the Cox proportional hazard regression model, Kaplan-Meier estimates, and log-rank test were used. Results Significantly different adaptive and innate immune cell types were selected, including T cells, plasma cells, and resting mast cells. Meanwhile, the immune cell landscapes in The Cancer Genome Atlas' (TCGA) hepatocellular carcinoma (HCC) patients with different degrees of fibrosis were also calculated. Comparative studies and survival analysis were carried out. Resting mast cell and activated NK cells in HCC patients with fibrosis was significantly lower than that in other HCC patients without fibrosis. Then, the potential genes involved in immune cells and significantly associated with patients' outcome were identified. These genes may be potential novel checkpoints for immunotherapy, including PVRIG related to NK resting/activated cells and T cell CD8+ infiltration which was recently targeted in breast cancer. Furthermore, Pearson correlation coefficient analysis suggested that PVRIG is significantly positively related to other checkpoint molecules and Teff gene signatures. Conclusions Alternative treatments, including immunotherapies, are necessary and urgent for HCC. Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. Our studies may find possible ways to select novel targets and improve immunotherapy efficacy by disrupting their function and promoting immune infiltration in advanced HCC patients with higher fibrosis and even cirrhosis.
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Affiliation(s)
- Xiaofeng Tang
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Zheyue Shu
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Weichen Zhang
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Longyu Cheng
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Jun Yu
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Min Zhang
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary & Pancreatic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
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Zanoni M, Cortesi M, Zamagni A, Tesei A. The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis. Int J Mol Sci 2019; 20:E3876. [PMID: 31398940 PMCID: PMC6719901 DOI: 10.3390/ijms20163876] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 08/05/2019] [Indexed: 02/06/2023] Open
Abstract
Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field.
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Affiliation(s)
- Michele Zanoni
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Michela Cortesi
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
| | - Alice Zamagni
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
| | - Anna Tesei
- Bioscience Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
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Stevenson TJ, Barbour Y, McMahon BJ, Townshend-Bulson L, Hewitt AM, Espera HGF, Homan C, Holck P, Luna SV, Knall C, Simons BC. Observed Changes in Natural Killer and T cell Phenotypes with Evaluation of Immune Outcome in a Longitudinal Cohort Following Sofosbuvir-Based Therapy for Chronic Hepatitis C Infection. Open Forum Infect Dis 2019; 6:ofz223. [PMID: 31249845 PMCID: PMC6589029 DOI: 10.1093/ofid/ofz223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022] Open
Abstract
Background Chronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown. Methods We examined natural killer (NK) cell, CD4+, and CD8+ T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes. Results We show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8+ T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4+ regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors. Conclusion Our study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.
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Affiliation(s)
- Timothy J Stevenson
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Youssef Barbour
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Lisa Townshend-Bulson
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Annette M Hewitt
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Hannah G F Espera
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Chriss Homan
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Peter Holck
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Sarah V Luna
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Cindy Knall
- WWAMI (Washington, Wyoming, Alaska, Montana, and Idaho) School of Medical Education, University of Alaska, Anchorage
| | - Brenna C Simons
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage.,WWAMI (Washington, Wyoming, Alaska, Montana, and Idaho) School of Medical Education, University of Alaska, Anchorage
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de Camargo AR, Tenório JR, Martins F, Grando LJ, Corrêa EBD, Trierveiler M, Ortega KL. Subset of CD8+ and FOXP3 + T cells in lichen planus associated with chronic hepatitis C infection. Oral Dis 2019; 25:1100-1106. [PMID: 30801844 DOI: 10.1111/odi.13069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/05/2019] [Accepted: 02/19/2019] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To verify whether there are differences between populations of CD8 + and FoxP3 + T cells in lesions of oral lichen planus associated with hepatitis C virus chronic infection (OLP-HCV) and lesions of idiopathic oral lichen planus (OLP-I). MATERIALS AND METHODS A case-control study was performed using a convenience sample of 11 paraffin-embedded tissue blocks of OLP-HCV and 19 of OLP-I. Histological sections stained with haematoxylin and eosin were used to classify the intensity of inflammatory infiltrate. Immunohistochemistry was used to identify CD8 + and FoxP3 + T cells. The count of positive cells was compared between the two groups and correlated to clinical and demographic data (p < 0.05). RESULTS There were no statistically significant differences in the distribution of CD8 + and FoxP3 + T cells regarding the inflammatory infiltrate in lesions of OLP-HCV and OLP-I. Atrophic/erosive lesions showed a higher relationship between counts of CD8/FoxP3 T cells per mm2 (p = 0.018) and counts of CD8 + T cells per mm2 (p = 0.034) in OLP-HCV group compared to OLP-I group. CONCLUSION Overall, no difference was found between cell populations in the lesions of OLP-HCV and OLP-I. However, atrophic/erosive lesions of OLP-HCV had a higher amount of CD8 + T cells and lower FoxP3 expression.
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Affiliation(s)
| | - Jefferson Rocha Tenório
- Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Fabiana Martins
- School of Dentistry, University of Santo Amaro, São Paulo, Brazil
| | - Liliane Janete Grando
- Department of Oral Pathology, Health Sciences Centre, Federal University of Santa Catarina, Florianopolis, Brazil
| | - Esther Buzaglo Dantas Corrêa
- Department of Medical Clinics, Health Sciences Centre, Federal University of Santa Catarina, Florianopolis, Brazil
| | - Marília Trierveiler
- Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil
| | - Karem L Ortega
- Oral and Maxillofacial Pathology, School of Dentistry, University of São Paulo, São Paulo, Brazil
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Zhang H, Jiang Z, Zhang L. Dual effect of T helper cell 17 (Th17) and regulatory T cell (Treg) in liver pathological process: From occurrence to end stage of disease. Int Immunopharmacol 2019; 69:50-59. [PMID: 30669025 DOI: 10.1016/j.intimp.2019.01.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 02/06/2023]
Abstract
Liver disease is a complicated pathological status with acute or chronic progressions, causing a series of damages to liver and massive burden to public health and society. Th17 and Treg, two subsets of CD4+ T helper cells, seem to keep a subtle balance in the maintenance of organic immune homeostasis including liver. The dysfunction of Th17/Treg balance in liver has been proved associated with hepatic injury and disease. Herein, we summarized the research advance of Th17 and Treg cells in different phenotypes of liver diseases in the past decade. It is known to all that hepatic diseases start from stimulations or infections like virus, autoimmune, alcohol and so on in the early stage, which would cause inflammation. With the disease consistently existed, severe outcomes like cirrhosis and hepatocellular carcinoma appear finally. In conclusion, it is found that Th17 and Treg cells serve as an important role in the immune response imbalance of liver diseases from the beginning to the end stage. However, the effect of these two subsets of CD4+ T helper cells is not a stereotype. Pathological role which exacerbates the disease and protective character which inhibits damage to liver are co-existed in the effect of Th17 and Treg cells. Still, more studies should be carried out to enrich the understandings of liver disease and Th17/Treg immune balance in the future.
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Affiliation(s)
- Haoran Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Zhenzhou Jiang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China.
| | - Luyong Zhang
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Luxenburger H, Neumann-Haefelin C, Thimme R, Boettler T. HCV-Specific T Cell Responses During and After Chronic HCV Infection. Viruses 2018; 10:v10110645. [PMID: 30453612 PMCID: PMC6265781 DOI: 10.3390/v10110645] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/14/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV)-specific T cell responses are closely linked to the clinical course of infection. While T cell responses in self-limiting infection are typically broad and multi-specific, they display several distinct features of functional impairment in the chronic phase. Moreover, HCV readily adapts to immune pressure by developing escape mutations within epitopes targeted by T cells. Much of our current knowledge on HCV-specific T cell responses has been gathered under the assumption that this might eventually pave the way for a therapeutic vaccine. However, with the development of highly efficient direct acting antivirals (DAAs), there is less interest in the development of a therapeutic vaccine for HCV and the scope of T cell research has shifted. Indeed, the possibility to rapidly eradicate an antigen that has persisted over years or decades, and has led to T cell exhaustion and dysfunction, provides the unique opportunity to study potential T cell recovery after antigen cessation in a human in vivo setting. Findings from such studies not only improve our basic understanding of T cell immunity but may also advance immunotherapeutic approaches in cancer or chronic hepatitis B and D infection. Moreover, in order to edge closer to the WHO goal of HCV elimination by 2030, a prophylactic vaccine is clearly required. Thus, in this review, we will summarize our current knowledge on HCV-specific T cell responses and also provide an outlook on the open questions that require answers in this field.
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Affiliation(s)
- Hendrik Luxenburger
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Christoph Neumann-Haefelin
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Robert Thimme
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
| | - Tobias Boettler
- Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
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