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1
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Carneiro P, Vicente MM, Leite MI, Santos ME, Pinho SS, Fernandes Â. The role of N-glycans in regulatory T cells in autoimmunity. Autoimmun Rev 2025; 24:103791. [PMID: 40043894 DOI: 10.1016/j.autrev.2025.103791] [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: 12/04/2024] [Revised: 02/27/2025] [Accepted: 02/28/2025] [Indexed: 05/17/2025]
Abstract
Regulatory T cells (Tregs) have a key role in the maintenance of immune tolerance and in the prevention of autoimmunity. Recent studies have shown an association between decreased Treg frequency and a deficient suppressive activity with the development of many autoimmune diseases. Although glycosylation, which consists in the addition of glycans to proteins and lipids on the cell surface, is recognized as a critical modification for T cell development and function, the relevance of glycans in Treg biology and activity, as well as their impact in the immunopathogenesis of autoimmune diseases, deserves more attention, as it is far from being fully understood. This review discusses the biological impact of N-glycans in Treg biology, highlighting their potential to uncover novel pathogenic mechanisms in autoimmunity and new targets for promising therapeutic approaches with clinical applications in autoimmune disease patients.
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Affiliation(s)
- Pedro Carneiro
- i3s - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Manuel M Vicente
- i3s - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
| | - Maria Isabel Leite
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Maria Ernestina Santos
- CHUdSA - Centro Hospitalar Universitário de Santo António, Department of Neurology, Porto, Portugal
| | - Salomé S Pinho
- i3s - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal; ICBAS, School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal; Faculty of Medicine, University of Porto, Porto, Portugal.
| | - Ângela Fernandes
- i3s - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.
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2
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Wischnewski S, Rausch HW, Ikenaga C, Leipe J, Lloyd TE, Schirmer L. Emerging mechanisms and therapeutics in inflammatory muscle diseases. Trends Pharmacol Sci 2025; 46:249-263. [PMID: 39939222 DOI: 10.1016/j.tips.2025.01.005] [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: 11/15/2024] [Revised: 01/03/2025] [Accepted: 01/15/2025] [Indexed: 02/14/2025]
Abstract
Idiopathic inflammatory myopathies (IIMs), or myositis, are rare diseases marked by immune-driven muscle damage and complications like skin lesions and interstitial lung disease (ILD). Despite advances, challenges in diagnosis and treatment persist, particularly in inclusion body myositis (IBM), where no effective therapy exists. Recent breakthroughs, including transcriptomics and insights into antibody-mediated immunity and interferon (IFN) signaling, have clarified IIM pathophysiology and spurred the development of new therapies, such as chimeric antigen receptor (CAR) T cells and Janus kinase (JAK) inhibitors. We explore the latest findings on the mechanisms underlying adult-onset IIMs, emphasizing IBM pathobiology and its unique immune and degenerative pathways, such as a selective type 2 myofiber damage and severe cell stress. Finally, we highlight the recent advances in transcriptomics, single-cell analysis, and machine learning in transforming IIM research by improving diagnostic accuracy, uncovering therapeutic targets, and supporting the development of personalized treatment strategies.
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Affiliation(s)
- Sven Wischnewski
- Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Hans-Werner Rausch
- Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chiseko Ikenaga
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Kitasato University Hospital, Tokyo, Japan
| | - Jan Leipe
- Division of Rheumatology, Department of Medicine V, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Division of Rheumatology, Department of Internal Medicine I, University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - Thomas E Lloyd
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
| | - Lucas Schirmer
- Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Center for Translational Neuroscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Mannheim Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany.
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3
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Schnell JT, Briviesca RL, Kim T, Charbonnier LM, Henderson LA, van Wijk F, Nigrovic PA. The 'T reg paradox' in inflammatory arthritis. Nat Rev Rheumatol 2025; 21:9-21. [PMID: 39653758 DOI: 10.1038/s41584-024-01190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 12/12/2024]
Abstract
Classic regulatory T (Treg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Treg cell, exTreg cell (effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.
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Affiliation(s)
- Julia T Schnell
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA
- Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Taehyeung Kim
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA
| | | | | | - Femke van Wijk
- Centre for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Peter A Nigrovic
- Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
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Yoshida H, Magi M, Tamai H, Kikuchi J, Yoshimoto K, Otomo K, Matsumoto Y, Noguchi-Sasaki M, Takeuchi T, Kaneko Y. Effects of interleukin-6 signal inhibition on Treg subpopulations and association of Tregs with clinical outcomes in rheumatoid arthritis. Rheumatology (Oxford) 2024; 63:2515-2524. [PMID: 38530780 PMCID: PMC11371379 DOI: 10.1093/rheumatology/keae196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/15/2024] [Accepted: 03/17/2024] [Indexed: 03/28/2024] Open
Abstract
OBJECTIVES Anti-IL-6 receptor antibodies are clinically efficacious in the management of RA with an associated increase in Tregs; however, the role of functional Treg subsets has yet to be clarified. This study aimed to evaluate how functional Treg subsets are altered by IL-6 receptor blockade and to analyse the relationship between these Treg subsets and the clinical outcome of RA. METHODS We collected frozen peripheral blood mononuclear cells (PBMCs) from 40 patients with RA who started tocilizumab (TCZ) with or without MTX and 11 healthy controls (HCs). We fractionated Tregs with flow cytometry based on markers of phenotype and function and measured the proportions of detailed Treg subsets sequentially from baseline to week 52. RESULTS The proportions of resting Tregs (rTregs) and rTregs+activated Tregs (aTregs) were significantly lower in RA patients at baseline than in HCs. The proportions of all those CD127low Tregs, rTregs, aTregs and rTregs+aTregs were significantly increased with TCZ treatment. In patients treated with TCZ without MTX, rTreg were increased. Patients with an increase in the proportion of rTregs at week 12 had significantly less arthritis flares during the observation period. CONCLUSIONS Blocking the IL-6 receptor with TCZ increased the proportion of rTregs, a functional Treg subpopulation. Patients with an early increase in rTregs showed a favourable treatment course and this increase in rTregs may reflect molecular remission induced by IL-6 signal inhibition.
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Affiliation(s)
- Hiroto Yoshida
- Product Research Department, Chugai Pharmaceutical Co. Ltd, Kanagawa, Japan
| | - Mayu Magi
- Product Research Department, Chugai Pharmaceutical Co. Ltd, Kanagawa, Japan
| | - Hiroya Tamai
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Kikuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Keiko Yoshimoto
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kotaro Otomo
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | | | | | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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5
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Cao S, Budina E, Wang R, Sabados M, Mukherjee A, Solanki A, Nguyen M, Hultgren K, Dhar A, Hubbell JA. Injectable butyrate-prodrug micelles induce long-acting immune modulation and prevent autoimmune arthritis in mice. J Control Release 2024; 372:281-294. [PMID: 38876359 DOI: 10.1016/j.jconrel.2024.06.027] [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: 12/07/2023] [Revised: 05/31/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Short chain fatty acid (SCFAs), such as butyrate, have shown promising therapeutic potential due to their immunomodulatory effects, particularly in maintaining immune homeostasis. However, the clinical application of SCFAs is limited by the need for frequent and high oral dosages. Rheumatoid arthritis (RA) is characterized by aberrant activation of peripheral T cells and myeloid cells. In this study, we aimed to deliver butyrate directly to the lymphatics using a polymeric micelle-based butyrate prodrug to induce long-lasting immunomodulatory effects. Notably, negatively charged micelles (Neg-ButM) demonstrated superior efficacy in targeting the lymphatics following subcutaneous (s.c.) administration and were retained in the draining lymph nodes, spleen, and liver for over one month. In the collagen antibody-induced arthritis (CAIA) mouse model of RA, only two s.c. injections of Neg-ButM successfully prevented disease onset and promoted tolerogenic phenotypes in T cells and myeloid cells, both locally and systemically. These results underscore the potential of this strategy in managing inflammatory autoimmune diseases by directly modulating immune responses via lymphatic delivery.
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Affiliation(s)
- Shijie Cao
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States; Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, United States.
| | - Erica Budina
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States
| | - Ruyi Wang
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States; Department of Chemistry, University of Chicago, Chicago, IL 60637, United States
| | - Matthew Sabados
- Biological Sciences Division, University of Chicago, Chicago, IL 60637, United States
| | - Anish Mukherjee
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States
| | - Ani Solanki
- Animal Resource Center, University of Chicago, Chicago, IL 60637, United States
| | - Mindy Nguyen
- Animal Resource Center, University of Chicago, Chicago, IL 60637, United States
| | - Kevin Hultgren
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States
| | - Arjun Dhar
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States
| | - Jeffrey A Hubbell
- Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States; Committee on Immunology, University of Chicago, Chicago, IL 60637, United States; Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, United States.
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6
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Martin J, Hollowood Z, Chorlton J, Dyer C, Marelli-Berg F. Modulating regulatory T cell migration in the treatment of autoimmunity and autoinflammation. Curr Opin Pharmacol 2024; 77:102466. [PMID: 38906084 DOI: 10.1016/j.coph.2024.102466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/23/2024]
Abstract
Treatment of autoimmunity and autoinflammation with regulatory T cells has received much attention in the last twenty years. Despite the well-documented clinical benefit of Treg therapy, a large-scale application has proven elusive, mainly due to the extensive culture facilities required and associated costs. A possible way to overcome these hurdles in part is to target Treg migration to inflammatory sites using a small molecule. Here we review recent advances in this strategy and introduce the new concept of pharmacologically enhanced delivery of endogenous Tregs to control inflammation, which has been recently validated in humans.
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Affiliation(s)
- John Martin
- Division of Medicine, University College London, London, WC1E 6JF, UK; St George Street Capital, London, EC4R 1BE, UK.
| | | | | | - Carlene Dyer
- William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Federica Marelli-Berg
- William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
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Wang Z, Xu J, Mo L, Zhan R, Zhang J, Liu L, Jiang J, Zhang Y, Bai Y. The Application Potential of the Regulation of Tregs Function by Irisin in the Prevention and Treatment of Immune-Related Diseases. Drug Des Devel Ther 2024; 18:3005-3023. [PMID: 39050796 PMCID: PMC11268596 DOI: 10.2147/dddt.s465713] [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: 04/03/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Irisin is a muscle factor induced by exercise, generated through the proteolytic cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC-5). Numerous studies have shown that irisin plays a significant role in regulating glucose and lipid metabolism, inhibiting oxidative stress, reducing systemic inflammatory responses, and providing neuroprotection. Additionally, irisin can exert immunomodulatory functions by regulating regulatory T cells (Tregs). Tregs are a highly differentiated subset of mature T cells that play a key role in maintaining self-immune homeostasis and are closely related to infections, inflammation, immune-related diseases, and tumors. Irisin exerts persistent positive effects on Treg cell functions through various mechanisms, including regulating Treg cell differentiation and proliferation, improving their function, modulating the balance of immune cells, increasing the production of anti-inflammatory cytokines, and enhancing metabolic functions, thereby helping to maintain immune homeostasis and prevent immune-related diseases. As an important myokine, irisin interacts with receptors on the cell membrane, activating multiple intracellular signaling pathways to regulate cell metabolism, proliferation, and function. Although the specific receptor for irisin has not been fully identified, integrins are considered potential receptors. Irisin activates various signaling pathways, including AMPK, MAPK, and PI3K/Akt, through integrin receptors, thereby exerting multiple biological effects. These research findings provide important clues for understanding the mechanisms of irisin's action and theoretical basis for its potential applications in metabolic diseases and immunomodulation. This article reviews the relationship between irisin and Tregs, as well as the research progress of irisin in immune-related diseases such as multiple sclerosis, myasthenia gravis, acquired immune deficiency syndrome, type 1 diabetes, sepsis, and rheumatoid arthritis. Studies have revealed that irisin plays an important role in immune regulation by improving the function of Tregs, suggesting its potential application value in the treatment of immune-related diseases.
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Affiliation(s)
- Zhengjiang Wang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jiaqi Xu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Liqun Mo
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Renshu Zhan
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Yingying Zhang
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
| | - Yiping Bai
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China
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Mo Q, Bolideei M, Rong SJ, Luo JH, Yang CL, Lu WY, Chen QJ, Zhao JW, Wang FX, Wang T, Li Y, Luo X, Zhang S, Xiong F, Yu QL, Zhang ZY, Liu SW, Sun F, Dong LL, Wang CY. GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis. iScience 2024; 27:109798. [PMID: 38947509 PMCID: PMC11214488 DOI: 10.1016/j.isci.2024.109798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/09/2024] [Accepted: 04/18/2024] [Indexed: 07/02/2024] Open
Abstract
High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.
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Affiliation(s)
- Qian Mo
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
- Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mansoor Bolideei
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Shan-Jie Rong
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Jia-Hui Luo
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Chun-Liang Yang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Wan-Ying Lu
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Qi-Jie Chen
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Jia-Wei Zhao
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Fa-Xi Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Ting Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Yang Li
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Xi Luo
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Shu Zhang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Fei Xiong
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Qi-Lin Yu
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Zi-Yun Zhang
- Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Shi-Wei Liu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China
| | - Fei Sun
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
| | - Ling-Li Dong
- Department of Rheumatology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Cong-Yi Wang
- Department of Respiratory and Critical Care Medicine, the Center for Biomedical Research, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China
- Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, the Key Laboratory of Endocrine and Metabolic Diseases of Shanxi Province, Taiyuan, China
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9
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Su QY, Li HC, Jiang XJ, Jiang ZQ, Zhang Y, Zhang HY, Zhang SX. Exploring the therapeutic potential of regulatory T cell in rheumatoid arthritis: Insights into subsets, markers, and signaling pathways. Biomed Pharmacother 2024; 174:116440. [PMID: 38518605 DOI: 10.1016/j.biopha.2024.116440] [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: 01/21/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 03/24/2024] Open
Abstract
Rheumatoid arthritis (RA) is a complex autoimmune inflammatory rheumatic disease characterized by an imbalance between immunological reactivity and immune tolerance. Regulatory T cells (Tregs), which play a crucial role in controlling ongoing autoimmunity and maintaining peripheral tolerance, have shown great potential for the treatment of autoimmune inflammatory rheumatic diseases such as RA. This review aims to provide an updated summary of the latest insights into Treg-targeting techniques in RA. We focus on current therapeutic strategies for targeting Tregs based on discussing their subsets, surface markers, suppressive function, and signaling pathways in RA.
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Affiliation(s)
- Qin-Yi Su
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Huan-Cheng Li
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Xiao-Jing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Zhong-Qing Jiang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Yan Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - He-Yi Zhang
- Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China
| | - Sheng-Xiao Zhang
- The Second Hospital of Shanxi Medical University, Department of Rheumatology, Taiyuan, China; Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China; Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China.
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10
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Cai N, Gao X, Yang L, Li W, Sun W, Zhang S, Zhao J, Qu J, Zhou Y. Discovery of novel NSAID hybrids as cPLA 2/COX-2 dual inhibitors alleviating rheumatoid arthritis via inhibiting p38 MAPK pathway. Eur J Med Chem 2024; 267:116176. [PMID: 38286094 DOI: 10.1016/j.ejmech.2024.116176] [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: 11/22/2023] [Revised: 01/20/2024] [Accepted: 01/22/2024] [Indexed: 01/31/2024]
Abstract
A series of NSAIDs hybrid molecules were synthesized and characterized, and their ability to inhibit NO release in LPS-induced RAW264.7 macrophages was evaluated. Most of the compounds showed significant anti-inflammatory activity in vitro, of which (2E,6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-2,6,9,12,15-pentaen-2-yl 2-(4-benzoylphenyl) propanoate (VI-60) was the most optimal (IC50 = 3.85 ± 0.25 μΜ) and had no cytotoxicity. In addition, VI-60 notably reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to ketoprofen. Futhur more, VI-60 significantly inhibited the expression of iNOS, cPLA2, and COX-2 and the phosphorylation of p38 MAPK in LPS-stimulated RAW264.7 cells. The binding of VI-60 to cPLA2 and COX-2 was directly verified by the CETSA technique. In vivo studies illustrated that VI-60 exerted an excellent therapeutic effect on adjuvant-induced arthritis in rats by regulating the balance between Th17 and Treg through inhibiting the p38 MAPK/cPLA2/COX-2/PGE2 pathway. Encouragingly, VI-60 showed a lower ulcerative potential in rats at a dose of 50 mg/kg compared to ketoprofen. In conclusion, the hybrid molecules of NSAIDs and trifluoromethyl enols are promising candidates worthy of further investigation for the treatment of inflammation, pain, and other symptoms in which cPLA2 and COX-2 play a role in their etiology.
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Affiliation(s)
- Nan Cai
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Xiang Gao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Li Yang
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Wenjing Li
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Wuding Sun
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Shuaibo Zhang
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Jinfeng Zhao
- Instrumental Analysis Center, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Jingping Qu
- State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
| | - Yuhan Zhou
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China.
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11
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Moghaddam MZ, Mousavi MJ, Ghotloo S. Cell-based therapies for the treatment of rheumatoid arthritis. Immun Inflamm Dis 2023; 11:e1091. [PMID: 38018576 PMCID: PMC10664399 DOI: 10.1002/iid3.1091] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/01/2023] [Accepted: 11/03/2023] [Indexed: 11/30/2023] Open
Abstract
Autoimmune diseases, including rheumatoid arthritis that is the most prevalent rheumatic autoimmune disorder, affect autologous connective tissues caused by the breakdown of the self-tolerance mechanisms of the immune system. During the last two decades, cell-based therapy, including stem cells and none-stem cells has been increasingly considered as a therapeutic option in various diseases. This is partly due to the unique properties of stem cells that divide and differentiate from the specialized cells in the damaged tissue. Moreover, stem cells and none-stem cells, impose immunomodulatory properties affecting the diseases caused by immunological abnormalities such as rheumatic autoimmune disorders. In the present review, the efficacy of cell-based therapy with four main types of stem cells, including mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells, and human amniotic membrane cells, as well as none-stem cells, including regulatory T cells, chimeric antigen receptor T cells, and tolerogenic dendritic cells will be evaluated. Moreover, other related issues, including safety, changes in immunological parameters, suitable choice of stem cell and none-stem cell origin, conditioning regimen, limitations, and complications will be discussed.
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Affiliation(s)
| | - Mohammad Javad Mousavi
- Department of HematologyFaculty of Allied Medicine, Bushehr University of Medical SciencesBushehrIran
| | - Somayeh Ghotloo
- Autoimmune Diseases Research CenterKashan University of Medical SciencesKashanIran
- Department of Clinical Laboratory SciencesKashan University of Medical SciencesKashanIran
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12
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Huang QQ, Hang Y, Doyle R, Mao Q, Fang D, Pope RM. Mechanisms regulating the loss of Tregs in HUPO mice that develop spontaneous inflammatory arthritis. iScience 2023; 26:106734. [PMID: 37216119 PMCID: PMC10193230 DOI: 10.1016/j.isci.2023.106734] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 03/07/2023] [Accepted: 04/20/2023] [Indexed: 05/24/2023] Open
Abstract
T regulatory cells (Tregs) are a potential therapeutic target in many autoimmune diseases including rheumatoid arthritis (RA). The mechanisms responsible for the maintenance of Tregs in chronic inflammatory conditions such as RA are poorly understood. We employed our mouse model of RA in which, the following deletion of Flice-like inhibitory protein in CD11c+ cells, CD11c-FLIP-KO (HUPO) mice develop spontaneous, progressive, erosive arthritis, with reduced Tregs, and the adoptive transfer of Tregs ameliorates the arthritis. HUPO thymic Treg development was normal, but peripheral of Treg Foxp3 was diminished mediated by reduction of dendritic cells and interleukin-2 (IL-2). During chronic inflammatory arthritis Tregs fail to maintain Foxp3, leading to non-apoptotic cell death and conversion to CD4+CD25+Foxp3- cells. Treatment with IL-2 increased Tregs and ameliorated the arthritis. In summary, reduced dendritic cells and IL-2 in the milieu of chronic inflammation, contribute to Treg instability, promoting HUPO arthritis progression, and suggesting a therapeutic approach in RA.
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Affiliation(s)
- Qi-Quan Huang
- Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60091, USA
| | - Yiwei Hang
- Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60091, USA
| | - Renee Doyle
- Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60091, USA
| | - Qinwen Mao
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Deyu Fang
- Departments of Pathology and Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60091, USA
| | - Richard M. Pope
- Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60091, USA
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13
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Fang Y, Zhang Q, Lv C, Guo Y, He Y, Guo P, Wei Z, Xia Y, Dai Y. Mitochondrial fusion induced by transforming growth factor-β1 serves as a switch that governs the metabolic reprogramming during differentiation of regulatory T cells. Redox Biol 2023; 62:102709. [PMID: 37116255 PMCID: PMC10165137 DOI: 10.1016/j.redox.2023.102709] [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: 01/31/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 04/30/2023] Open
Abstract
Although metabolic reprogramming during the differentiation of regulatory T cells (Treg cells) has been extensively studied, the molecular switch to alter energy metabolism remains undefined. The present study explores the critical role of mitochondrial dynamics in the reprogramming and consequent generation of Treg cells. The results showed that during Treg cell differentiation, mitochondrial fusion but not fission led to elevation of oxygen consumption rate values, facilitation of metabolic reprogramming, and increase of number of Treg cells and expression of Foxp3 in vitro and in vivo. Mechanistically, mitochondrial fusion favored fatty acid oxidation but restricted glycolysis in Treg cells through down-regulating the expression of HIF-1α. Transforming growth factor-β1 (TGF-β1) played a crucial role in the induction of mitochondrial fusion, which activated Smad2/3, promoted the expression of PGC-1α and therefore facilitated the expression of mitochondrial fusion proteins. In conclusion, during Treg cell differentiation, TGF-β1 promotes PGC-1α-mediated mitochondrial fusion, which drives metabolic reprogramming from glycolysis to fatty acid oxidation via suppressing HIF-1α expression, and therefore favors the generation of Treg cells. The signals and proteins involved in mitochondrial fusion are potential therapeutic targets for Treg cell-related diseases.
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Affiliation(s)
- Yulai Fang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China; Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Qin Zhang
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Changjun Lv
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Yilei Guo
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Yue He
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Pengxiang Guo
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China
| | - Yufeng Xia
- Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China.
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Long Mian Avenue, Nanjing, 211198, China.
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14
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Brzezicka KA, Paulson JC. Impact of Siglecs on autoimmune diseases. Mol Aspects Med 2023; 90:101140. [PMID: 36055802 PMCID: PMC9905255 DOI: 10.1016/j.mam.2022.101140] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/19/2022] [Accepted: 08/21/2022] [Indexed: 02/08/2023]
Abstract
Autoimmune diseases affect tens of millions of people just in the United States alone. Most of the available treatment options are aimed at reducing symptoms but do not lead to cures. Individuals affected with autoimmune diseases suffer from the imbalance between tolerogenic and immunogenic functions of their immune system. Often pathogenesis is mediated by autoreactive B and T cells that escape central tolerance and react against self-antigens attacking healthy tissues in the body. In recent years Siglecs, sialic-acid-binding immunoglobulin (Ig)-like lectins, have gained attention as immune checkpoints for therapeutic interventions to dampen excessive immune responses and to restore immune tolerance in autoimmune diseases. Many Siglecs function as inhibitory receptors suppressing activation signals in various immune cells through binding to sialic acid ligands as signatures of self. In this review, we highlight potential of Siglecs in suppressing immune responses causing autoimmune diseases. In particular, we cover the roles of CD22 and Siglec-G/Siglec-10 in regulating autoreactive B cell responses. We discuss several functions of Siglec-10 in the immune modulation of other immune cells, and the potential of therapeutic strategies for restoring immune tolerance by targeting Siglecs and expanding regulatory T cells. Finally, we briefly review efforts evaluating Siglec-based biomarkers to monitor autoimmune diseases.
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Affiliation(s)
- Katarzyna Alicja Brzezicka
- Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
| | - James C Paulson
- Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Department of Immunology and Microbiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
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15
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Kotschenreuther K, Yan S, Kofler DM. Migration and homeostasis of regulatory T cells in rheumatoid arthritis. Front Immunol 2022; 13:947636. [PMID: 36016949 PMCID: PMC9398455 DOI: 10.3389/fimmu.2022.947636] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/20/2022] [Indexed: 12/17/2022] Open
Abstract
Regulatory T (Treg) cells are garnering increased attention in research related to autoimmune diseases, including rheumatoid arthritis (RA). They play an essential role in the maintenance of immune homeostasis by restricting effector T cell activity. Reduced functions and frequencies of Treg cells contribute to the pathogenesis of RA, a common autoimmune disease which leads to systemic inflammation and erosive joint destruction. Treg cells from patients with RA are characterized by impaired functions and by an altered phenotype. They show increased plasticity towards Th17 cells and a reduced suppressive capacity. Besides the suppressive function of Treg cells, their effectiveness is determined by their ability to migrate into inflamed tissues. In the past years, new mechanisms involved in Treg cell migration have been identified. One example of such a mechanism is the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Efficient migration of Treg cells requires the presence of VASP. IL-6, a cytokine which is abundantly present in the peripheral blood and in the synovial tissue of RA patients, induces posttranslational modifications of VASP. Recently, it has been shown in mice with collagen-induced arthritis (CIA) that this IL-6 mediated posttranslational modification leads to reduced Treg cell trafficking. Another protein which facilitates Treg cell migration is G-protein-signaling modulator 2 (GPSM2). It modulates G-protein coupled receptor functioning, thereby altering the cellular activity initiated by cell surface receptors in response to extracellular signals. The almost complete lack of GPSM2 in Treg cells from RA patients contributes to their reduced ability to migrate towards inflammatory sites. In this review article, we highlight the newly identified mechanisms of Treg cell migration and review the current knowledge about impaired Treg cell homeostasis in RA.
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Affiliation(s)
- Konstantin Kotschenreuther
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Shuaifeng Yan
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - David M. Kofler
- Laboratory of Molecular Immunology, Division of Rheumatology and Clinical Immunology, Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Cologne, Germany
- *Correspondence: David M. Kofler,
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16
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Sehnert B, Valero-Esquitino V, Schett G, Unger T, Steckelings UM, Voll RE. Angiotensin AT2 Receptor Stimulation Alleviates Collagen-Induced Arthritis by Upregulation of Regulatory T Cell Numbers. Front Immunol 2022; 13:921488. [PMID: 35874732 PMCID: PMC9304956 DOI: 10.3389/fimmu.2022.921488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
The angiotensin AT2 receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT2R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT2R-stimulation with the selective non-peptide AT2R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4+CD25+FoxP3+ regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4+FoxP3+ cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4+IL-17A+ and CD4+IFN-gamma+ T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT2R-stimulation promotes the expansion of CD4+ regulatory T cells and suppresses IL-17A production. Thus, AT2R-stimulation may represent an attractive treatment strategy for arthritis.
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Affiliation(s)
- Bettina Sehnert
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- *Correspondence: Bettina Sehnert, ; Reinhard Edmund Voll,
| | | | - Georg Schett
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Thomas Unger
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Ulrike Muscha Steckelings
- Institute of Molecular Medicine (IMM) – Department of Cardiovascular & Renal Research, University of Southern Denmark, Odense, Denmark
| | - Reinhard Edmund Voll
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency (CCI) Freiburg, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- *Correspondence: Bettina Sehnert, ; Reinhard Edmund Voll,
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17
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Li YJ, Chen Z. Cell-based therapies for rheumatoid arthritis: opportunities and challenges. Ther Adv Musculoskelet Dis 2022; 14:1759720X221100294. [PMID: 35634355 PMCID: PMC9131381 DOI: 10.1177/1759720x221100294] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 04/26/2022] [Indexed: 11/18/2022] Open
Abstract
Rheumatoid arthritis (RA) is the most common immune-mediated inflammatory disease characterized by chronic synovitis that hardly resolves spontaneously. The current treatment of RA consists of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, conventional disease-modifying antirheumatic drugs (cDMARDs), biologic and targeted synthetic DMARDs. Although the treat-to-target strategy has been intensively applied in the past decade, clinical unmet needs still exist since a substantial proportion of patients are refractory or even develop severe adverse effects to current therapies. In recent years, with the deeper understanding of immunopathogenesis of the disease, cell-based therapies have exhibited effective and promising interventions to RA. Several cell-based therapies, such as mesenchymal stem cells (MSC), adoptive transfer of regulatory T cells (Treg), and chimeric antigen receptor (CAR)-T cell therapy as well as their beneficial effects have been documented and verified so far. In this review, we summarize the current evidence and discuss the prospect as well as challenges for these three types of cellular therapies in RA.
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Affiliation(s)
- Yu-Jing Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Second Clinical Medical School, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
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18
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MicroRNA-10b promotes arthritis development by disrupting CD4 + T cell subtypes. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:733-750. [PMID: 35317281 PMCID: PMC8905251 DOI: 10.1016/j.omtn.2021.12.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/15/2021] [Indexed: 12/23/2022]
Abstract
Rheumatoid arthritis (RA) is an inflammation-involved disorder and features the disruption of CD4+ T lymphocytes. Herein, we describe that microRNA-10b-5p (miR-10b) promotes RA progression by disrupting the balance between subsets of CD4+ T cells. MiR-10b-deficient mice protected against collagen antibody-induced arthritis (CAIA) model. RNA sequencing results indicated that disordered genes in miR-10b−/− CAIA model are closely associated with CD4+ T cells differentiation. Moreover, miR-10b mimics promoted Th1/Th17 and suppressed Th2/Treg cells differentiation, whereas miR-10b inhibitor induced contrary effects. In addition, GATA3 and PTEN was confirmed as two targets of miR-10b, and GATA3 siRNA could increase Th1 and reduce Th2 cells meanwhile PTEN siRNA could increase Th17 and decrease Treg cells. Furthermore, miR-10b inhibitor significantly ameliorated collagen-induced arthritis (CIA) development by attenuating the dysfunctional CD4+ T cell subpopulations. The present findings suggest that miR-10b could disrupt the balance of CD4+ T subsets, while suppressed miR-10b could attenuate the severity of experimental arthritis, which provided us a novel mechanistic and therapeutic insight into the RA.
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19
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Furuyama K, Kondo Y, Shimizu M, Yokosawa M, Segawa S, Iizuka A, Tanimura R, Tsuboi H, Matsumoto I, Sumida T. RORγt+Foxp3+ regulatory T cells in the regulation of autoimmune arthritis. Clin Exp Immunol 2021; 207:176-187. [PMID: 35020849 PMCID: PMC8982961 DOI: 10.1093/cei/uxab007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 09/24/2021] [Accepted: 10/19/2021] [Indexed: 02/03/2023] Open
Abstract
RORγt+Foxp3+regulatory T (Treg) cells, known as T regulatory 17 cells (Tr17 cells), are a novel subset of Treg cells, which have the potential to regulate the development of experimental autoimmune encephalomyelitis (EAE) thorough a specific repression of T helper 17 (Th17) cell-mediated inflammation. However, the function of Tr17 cells the development of other autoimmune diseases such as autoimmune arthritis remains unclear. Collagen-induced arthritis (CIA) was found to be prolonged in Foxp3creRORγtfl/fl mice, in which Tr17 cells were deleted, compared with Foxp3wtRORγtfl/fl mice. Tr17 cells were significantly increased in ankle joints (AJ) compared with draining lymph nodes after the onset of arthritis. CC chemokine receptor 6 (CCR6) was up-regulated on Tr17 cells compared to RORγt negative Treg cells. CD25, cytotoxic T-lymphocyte antigen 4 (CTLA-4), glucocorticoid-induced TNF-receptor (GITR), and inducible T-cell co-stimulator (ICOS) expression was also up-regulated on Tr17 cells compared to RORγt negative Treg cells. IL-10-producing cells and Blimp-1+ and T-bet+ cells were increased in Tr17 cells compared to RORγt-negative Treg cells. Tr17-enriched Treg cells significantly suppressed proliferation of conventional T cells through IL-10 compared with CCR6-Treg cells. Tr17 cells increased during the clinical course of CIA and accumulated in inflamed joints. Taken together, it appears that Tr17 cells play a crucial role in the regulation of autoimmune arthritis.
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Affiliation(s)
- Kotona Furuyama
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Yuya Kondo
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Masaru Shimizu
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Masahiro Yokosawa
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Seiji Segawa
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Akira Iizuka
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Reona Tanimura
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Hiroto Tsuboi
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Isao Matsumoto
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
| | - Takayuki Sumida
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan,Correspondence: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City, Ibaraki 305-8575, Japan.
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20
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T-bet represses collagen-induced arthritis by suppressing Th17 lineage commitment through inhibition of RORγt expression and function. Sci Rep 2021; 11:17357. [PMID: 34462459 PMCID: PMC8405656 DOI: 10.1038/s41598-021-96699-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/10/2021] [Indexed: 12/31/2022] Open
Abstract
T-bet is a key transcription factor for the T helper 1 lineage and its expression level is negatively correlated to inflammation in patients with rheumatoid arthritis (RA). Our previous study using T-bet transgenic mice revealed over-expression of T-bet completely suppressed collagen-induced arthritis (CIA), a murine model of RA, indicating a potential suppressive role of T-bet in the pathogenesis of autoimmune arthritis. Here, we show T-bet-deficiency exacerbated CIA. T-bet in CD4 + T cells, but not in CD11c + dendritic cells, was critical for regulating the production of IL-17A, IL-17F, IL-22, and TNFα from CD4 + T cells. T-bet-deficient CD4 + T cells showed higher RORγt expression and increased IL-17A production in RORγt-positive cells after CII immunization. In addition, T-bet-deficient naïve CD4 + T cells showed accelerated Th17 differentiation in vitro. CIA induced in CD4-Cre T-betfl/fl (cKO) mice was more severe and T-bet-deficient CD4 + T cells in the arthritic joints of cKO mice showed higher RORγt expression and increased IL-17A production. Transcriptome analysis of T-bet-deficient CD4 + T cells revealed that expression levels of Th17-related genes were selectively increased. Our results indicate that T-bet in CD4 + T cells repressed RORγt expression and function resulting in suppression of arthritogenic Th17 cells and CIA.
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21
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Mouat IC, Morse ZJ, Shanina I, Brown KL, Horwitz MS. Latent gammaherpesvirus exacerbates arthritis through modification of age-associated B cells. eLife 2021; 10:e67024. [PMID: 34080972 PMCID: PMC8337075 DOI: 10.7554/elife.67024] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/31/2021] [Indexed: 12/16/2022] Open
Abstract
Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we have examined the contribution of viral infection to the severity of arthritis in mice. We have provided the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV's role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (γHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we have provided the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.
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Affiliation(s)
- Isobel C Mouat
- Department of Microbiology and Immunology, The University of British ColumbiaVancouverCanada
| | - Zachary J Morse
- Department of Microbiology and Immunology, The University of British ColumbiaVancouverCanada
| | - Iryna Shanina
- Department of Microbiology and Immunology, The University of British ColumbiaVancouverCanada
| | - Kelly L Brown
- Department of Pediatrics, Division of Rheumatology, and British Columbia Children's Hospital Research Institute, The University of British ColumbiaVancouverCanada
| | - Marc S Horwitz
- Department of Microbiology and Immunology, The University of British ColumbiaVancouverCanada
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22
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Zhang SX, Wang J, Wang CH, Jia RH, Yan M, Hu FY, Liu GY, Liu XY, Luo J, Gao C, Li XF. Low-dose IL-2 therapy limits the reduction in absolute numbers of circulating regulatory T cells in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2021; 13:1759720X211011370. [PMID: 33995604 PMCID: PMC8107675 DOI: 10.1177/1759720x211011370] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/30/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Circulating regulatory T cells (Tregs) are responsible for mediating immune tolerance and maintaining immunological homeostasis. Decreases in Tregs may be involved in the onset of rheumatoid arthritis (RA). Low-dose interleukin-2 (IL-2) has been considered for the treatment of inflammatory diseases mediated by T cells. This study focused on the status of circulating CD4+T subsets and the clinical feasibility of IL-2 therapies in patients with RA. Methods: The subjects included 888 patients with RA and 100 healthy controls (HCs); 233 RA patients received IL-2 treatment with 0.5 million international units (MIU)/day from days 1 through 5. The demographic features, disease activity, and levels of CD4+T cells measured by modified flow cytometry were collected in all RA patients before and after treatment. Results: RA patients had lower absolute Treg counts (but not Th17) compared with HCs, which was associated with disease activity; previously treated RA patients had the fewest circulating Tregs (p < 0.05). Patients treated with low-dose IL-2 had a three-fold increase in absolute anti-inflammatory Treg counts, as well as a two-fold increase in the other CD4+T subsets. Moreover, post-treatment levels of markers of disease activity in RA patients treated with IL-2 were significantly lower than the baseline values (p < 0.001), with no apparent side effects. Conclusion: Decreased absolute counts of circulating CD4+T lymphocyte subsets were observed in patients with RA. Circulating Tregs, which mediate immune tolerance, may be involved in the pathogenesis and progression of RA; however, this was ameliorated by low-dose IL-2, without obvious side effects. Plain language summary Low-dose IL-2 treatment for rheumatoid arthritis • Circulating Tregs may be involved in the pathogenesis and progression of RA. • The absolute count of Tregs was significantly correlated with disease activity measures. • Low-dose IL-2 was able to effectively expade Tregs and help for RA patients’ symptoms remission without evaluated side effects.
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Affiliation(s)
- Sheng-Xiao Zhang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University
| | - Jia Wang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University
| | - Cai-Hong Wang
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Rui-Huan Jia
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ming Yan
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Fang-Yuan Hu
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Guang-Ying Liu
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xue-Yu Liu
- College of Data Science, Taiyuan University of Technology, Taiyuan, Shanxi, China
| | - Jing Luo
- Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chong Gao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xiao-Feng Li
- Department of Rheumatology, the Second Hospital of Shanxi Medical University
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23
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Jiang Q, Yang G, Liu Q, Wang S, Cui D. Function and Role of Regulatory T Cells in Rheumatoid Arthritis. Front Immunol 2021; 12:626193. [PMID: 33868244 PMCID: PMC8047316 DOI: 10.3389/fimmu.2021.626193] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation. The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens. The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases. The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA. Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role. Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury. Treg cells are one of the ideal options. This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.
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Affiliation(s)
- Qi Jiang
- Department of Blood Transfusion, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Guocan Yang
- Department of Blood Transfusion, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Qi Liu
- Department of Blood Transfusion, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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24
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Berberine Delays Onset of Collagen-Induced Arthritis through T Cell Suppression. Int J Mol Sci 2021; 22:ijms22073522. [PMID: 33805383 PMCID: PMC8037694 DOI: 10.3390/ijms22073522] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/17/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023] Open
Abstract
There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund’s adjuvant (day 0) and a booster injection of CII in incomplete Freund’s adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.
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25
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Choi GM, Lee B, Hong R, Park SY, Cho DE, Yeom M, Park HJ, Bae H, Hahm DH. Bee venom phospholipase A2 alleviates collagen-induced polyarthritis by inducing Foxp3 + regulatory T cell polarization in mice. Sci Rep 2021; 11:3511. [PMID: 33568685 PMCID: PMC7876016 DOI: 10.1038/s41598-021-82298-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 01/19/2021] [Indexed: 11/18/2022] Open
Abstract
The mechanism underlying bee venom (BV) therapy is still controversial, with opinions ranging from constituent-based pharmacological action to homeopathic-like activity. The purpose of this study was to examine whether BV phospholipase A2 (bvPLA2), an enzymatic component of BV, is a novel anti-inflammatory and anti-arthritic mediator capable of stimulating CD25+ Foxp3+ regulatory T cell (Treg) polarization in a mouse model of human rheumatoid arthritis (RA). An experimental model of RA was established in male DBA/1 mouse by 2-week-interval injections of 100 μg type II collagen emulsified in complete (first injection) or incomplete Freund's adjuvant (second injection) at the base of the tail. During arthritis development, bvPLA2 (0.1, 0.5, 1.0 mg/kg) and/or Treg inhibitors such as anti-CD25 antibodies and peptide 60 (P60) were injected intraperitoneally for 5 weeks. Arthritic symptoms and the expansion of Tregs were then assessed by behavioral assessments, histological and micro-CT imaging, and flow cytometry. bvPLA2 injections significantly alleviated arthritic behaviors such as squeaking and joint swelling, consistent with changes seen on both histological and micro-CT images. The anti-arthritic effects of bvPLA2 were blocked by intraperitoneal injections of 0.25 mg/kg anti-CD25 antibody and 10 μg/kg P60, as determined by behavioral assessments. Flow cytometric analysis of dendritic cells, B cells, and major T cell subsets from spleens revealed a significant depletion of Tregs following anti-CD25 antibody, but not P60, treatment. bvPLA2 treatment exerted significant anti-inflammatory and anti-arthritic activities in a mouse model of RA via the induction of Tregs.
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Affiliation(s)
- Gwang-Muk Choi
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Bombi Lee
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Riwon Hong
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Seon-Young Park
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Da-Eun Cho
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Mijung Yeom
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Hi-Joon Park
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Hyunsu Bae
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
| | - Dae-Hyun Hahm
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
- BioNanocomposite Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea.
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26
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Mohammadian Haftcheshmeh S, Khosrojerdi A, Aliabadi A, Lotfi S, Mohammadi A, Momtazi-Borojeni AA. Immunomodulatory Effects of Curcumin in Rheumatoid Arthritis: Evidence from Molecular Mechanisms to Clinical Outcomes. Rev Physiol Biochem Pharmacol 2021; 179:1-29. [PMID: 33404796 DOI: 10.1007/112_2020_54] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder characterized by the destruction of the joint and bone resorption. The production of pro-inflammatory cytokines and chemokines, dysregulated functions of three important subtypes of T helper (TH) cells including TH1, TH17, and regulator T (Treg) cells are major causes of the initiation and development of RA. Moreover, B cells as a source of the production of several autoantibodies play key roles in the pathogenesis of RA. The last decades have seen increasingly rapid advances in the field of immunopharmacology using natural origin compounds for the management of various inflammatory diseases. Curcumin, a main active polyphenol compound isolated from turmeric, curcuma longa, possesses a wide range of pharmacologic properties for the treatment of several diseases. This review comprehensively will assess beneficial immunomodulatory effects of curcumin on the production of pro-inflammatory cytokines and also dysregulated functions of immune cells including TH1, TH17, Treg, and B cells in RA. We also seek the clinical efficacy of curcumin for the treatment of RA in several recent clinical trials. In conclusion, curcumin has been found to ameliorate RA complications through modulating inflammatory and autoreactive responses in immune cells and synovial fibroblast cells via inhibiting the expression or function of pro-inflammatory mediators, such as nuclear factor-κB (NF-κB), activated protein-1 (AP-1), and mitogen-activated protein kinases (MAPKs). Of note, curcumin treatment without any adverse effects can attenuate the clinical symptoms of RA patients and, therefore, has therapeutic potential for the treatment of the diseases.
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Affiliation(s)
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ali Aliabadi
- Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shadi Lotfi
- Department of Medical Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Asadollah Mohammadi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.
| | - Amir Abbas Momtazi-Borojeni
- Halal Research center of IRI, FDA, Tehran, Iran.
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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27
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Bassin EJ, Buckley AR, Piganelli JD, Little SR. TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model. PLoS One 2020; 15:e0239396. [PMID: 32966314 PMCID: PMC7510963 DOI: 10.1371/journal.pone.0239396] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 09/06/2020] [Indexed: 12/28/2022] Open
Abstract
Despite recent progress in the treatment of rheumatoid arthritis (RA), many patients still fail to achieve remission or low disease activity. An imbalance between auto-reactive effector T cells (Teff) and regulatory T cells (Treg) may contribute to joint inflammation and damage in RA. Therefore, restoring this balance is a promising approach for the treatment of inflammatory arthritis. Accordingly, our group has previously shown that the combination of TGF-β-releasing microparticles (MP), rapamycin-releasing MP, and IL-2-releasing MP (TRI MP) can effectively increase the ratio of Tregs to Teff in vivo and provide disease protection in several preclinical models. In this study TRI MP was evaluated in the collagen-induced arthritis (CIA) model. Although this formulation has been tested previously in models of destructive inflammation and transplantation, this is the first model of autoimmunity for which this therapy has been applied. In this context, TRI MP effectively reduced arthritis incidence, the severity of arthritis scores, and bone erosion. The proposed mechanism of action includes not only reducing CD4+ T cell proliferation, but also expanding a regulatory population in the periphery soon after TRI MP administration. These changes were reflected in the CD4+ T cell population that infiltrated the paws at the onset of arthritis and were associated with a reduction of immune infiltrate and inflammatory myeloid cells in the paws. TRI MP administration also reduced the titer of collagen antibodies, however the contribution of this reduced titer to disease protection remains uncertain since there was no correlation between collagen antibody titer and arthritis score.
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Affiliation(s)
- Ethan J. Bassin
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Abigail R. Buckley
- Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Jon D. Piganelli
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Steven R. Little
- Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Department of Pharmaceutical Science, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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28
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Zavvar M, Assadiasl S, Zargaran S, Akhtari M, Poopak B, Dinarvand R, Fatahi Y, Tayebi L, Soleimanifar N, Nicknam MH. Adoptive Treg cell-based immunotherapy: Frontier therapeutic aspects in rheumatoid arthritis. Immunotherapy 2020; 12:933-946. [PMID: 32635779 DOI: 10.2217/imt-2020-0071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The major current focus on treating rheumatoid arthritis is to put an end to long-term treatments and instead, specifically block widespread immunosuppression by developing antigen-specific tolerance, while also permitting an intact immune response toward other antigens to occur. There have been promising preclinical findings regarding adoptive Treg cells immunotherapy with a critically responsible function in the prevention of autoimmunity, tissue repair and regeneration, which make them an attractive candidate to develop effective therapeutic approaches to achieve this interesting concept in many human immune-mediated diseases, such as rheumatoid arthritis. Ex vivo or invivo manipulation protocols are not only utilized to correct Treg cells defect, but also to benefit from their specific immunosuppressive properties by identifying specific antigens that are expressed in the inflamedjoint. The methods able to address these deficiencies can be considered as a target for immunity interventions to restore appropriate immune function.
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Affiliation(s)
- Mahdi Zavvar
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Assadiasl
- Molecular Immunology Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Zargaran
- Faculty of Paramedical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Akhtari
- Department of Cell & Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Behzad Poopak
- Department of Hematology, Faculty of Paramedical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Rassoul Dinarvand
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.,Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI 53233, USA
| | - Narjes Soleimanifar
- Molecular Immunology Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Nicknam
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Molecular Immunology Research Centre, Tehran University of Medical Sciences, Tehran, Iran
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29
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Wing JB, Lim EL, Sakaguchi S. Control of foreign Ag-specific Ab responses by Treg and Tfr. Immunol Rev 2020; 296:104-119. [PMID: 32564426 DOI: 10.1111/imr.12888] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/11/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022]
Abstract
Regulatory T cells (Tregs) expressing the transcription factor Foxp3 play a critical role in the control of immune homeostasis including the regulation of humoral immunity. Recently, it has become clear that a specialized subset of Tregs, T-follicular regulatory cells (Tfr), have a particular role in the control of T-follicular helper (Tfh) cell-driven germinal center (GC) responses. Following similar differentiation signals as received by Tfh, Tfr gain expression of characteristic chemokine receptors and transcription factors such as CXCR5 and BCL6 allowing them to travel to the B-cell follicle and deliver in situ suppression. It seems clear that Tfr are critical for the prevention of autoimmune antibody induction. However, their role in the control of foreign antigen-specific antibody responses appears more complex with various reports demonstrating either increased or decreased antigen-specific antibody responses following inhibition of Tfr function. Due to their recent discovery, our understanding of Tfr formation and function still has many gaps. In this review, we discuss our current knowledge of both Tregs and Tfr in the context of humoral immunity and how these cells might be manipulated in order to better control vaccine responses.
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Affiliation(s)
- James B Wing
- Laboritory of Human Immunology (Single Cell Immunology), Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Ee Lyn Lim
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Suita, Japan.,Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
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30
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Inoue M, Tsuji Y, Yoshimine C, Enomoto S, Morita Y, Osaki N, Kunishige M, Miki M, Amano S, Yamashita K, Kamada H, Tsutsumi Y, Tsunoda SI. Structural optimization of a TNFR1-selective antagonistic TNFα mutant to create new-modality TNF-regulating biologics. J Biol Chem 2020; 295:9379-9391. [PMID: 32398258 DOI: 10.1074/jbc.ra120.012723] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 05/08/2020] [Indexed: 02/05/2023] Open
Abstract
Excessive activation of the proinflammatory cytokine tumor necrosis factor-α (TNFα) is a major cause of autoimmune diseases, including rheumatoid arthritis. TNFα induces immune responses via TNF receptor 1 (TNFR1) and TNFR2. Signaling via TNFR1 induces proinflammatory responses, whereas TNFR2 signaling is suggested to suppress the pathophysiology of inflammatory diseases. Therefore, selective inhibition of TNFR1 signaling and preservation of TNFR2 signaling activities may be beneficial for managing autoimmune diseases. To this end, we developed a TNFR1-selective, antagonistic TNFα mutant (R1antTNF). Here, we developed an R1antTNF derivative, scR1antTNF-Fc, which represents a single-chain form of trimeric R1antTNF with a human IgG-Fc domain. scR1antTNF-Fc had properties similar to those of R1antTNF, including TNFR1-selective binding avidity, TNFR1 antagonistic activity, and thermal stability, and had a significantly extended plasma t 1/2 in vivo In a murine rheumatoid arthritis model, scR1antTNF-Fc and 40-kDa PEG-scR1antTNF (a previously reported PEGylated form) delayed the onset of collagen-induced arthritis, suppressed arthritis progression in mice, and required a reduced frequency of administration. Interestingly, with these biologic treatments, we observed an increased ratio of regulatory T cells to conventional T cells in lymph nodes compared with etanercept, a commonly used TNF inhibitor. Therefore, scR1antTNF-Fc and 40-kDa PEG-scR1antTNF indirectly induced immunosuppression. These results suggest that selective TNFR1 inhibition benefits the management of autoimmune diseases and that R1antTNF derivatives hold promise as new-modality TNF-regulating biologics.
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Affiliation(s)
- Masaki Inoue
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan.,Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Yuta Tsuji
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Chinatsu Yoshimine
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Shota Enomoto
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Yuki Morita
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Natsuki Osaki
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Masahiro Kunishige
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Midori Miki
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Shota Amano
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Kanako Yamashita
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan
| | - Haruhiko Kamada
- Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan
| | - Yasuo Tsutsumi
- Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan.,Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Shin-Ichi Tsunoda
- Laboratory of Cellular and Molecular Physiology, The Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan .,Laboratory of Biopharmaceutical Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Suita, Osaka, Japan
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31
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Yoo HJ, Hwang WC, Min DS. Targeting of Phospholipase D1 Ameliorates Collagen-Induced Arthritis via Modulation of Treg and Th17 Cell Imbalance and Suppression of Osteoclastogenesis. Int J Mol Sci 2020; 21:ijms21093230. [PMID: 32370217 PMCID: PMC7247592 DOI: 10.3390/ijms21093230] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 12/20/2022] Open
Abstract
Phospholipase D1 (PLD1) plays a crucial role in various inflammatory and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease. However, the role of PLD1 in the pathogenesis of RA remains unknown. Here, we first investigated the role and effects of PLD1 in collagen-induced arthritis (CIA) and found that genetic and pharmacological inhibition of PLD1 in DBA1/J mice with CIA reduced the incidence of CIA, decreased the clinical score, and abrogated disease symptoms including infiltration of leukocytes, synovial inflammation, bone erosion, and cartilage destruction. Moreover, ablation and inhibition of PLD1 suppressed the production of type II collagen-specific IgG2a autoantibody and proinflammatory cytokines, accompanied by an increase in the regulatory T (Treg) cell population and a decrease in the Th17 cell population in CIA mice. The PLD1 inhibitor also promoted differentiation of Treg cells and suppressed differentiation of Th17 cells in vitro. Furthermore, the PLD1 inhibitor attenuated pathologic bone destruction in CIA mice by suppressing osteoclastogenesis and bone resorption. Thus, our findings indicate that the targeting of PLD1 can ameliorate CIA by modulating the imbalance of Treg and Th17 cells and suppressing osteoclastogenesis, which might be a novel strategy to treat autoimmune diseases, such as RA.
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MESH Headings
- Animals
- Arthritis, Experimental/immunology
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/prevention & control
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/prevention & control
- Benzimidazoles/pharmacology
- Cell Differentiation/drug effects
- Cell Differentiation/immunology
- Cytokines/blood
- Disease Models, Animal
- Knee Joint/drug effects
- Knee Joint/metabolism
- Knee Joint/pathology
- Male
- Mice, Inbred C57BL
- Mice, Inbred DBA
- Mice, Knockout
- Osteogenesis/drug effects
- Osteogenesis/genetics
- Phospholipase D/antagonists & inhibitors
- Phospholipase D/genetics
- Phospholipase D/metabolism
- Piperidines/pharmacology
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/metabolism
- X-Ray Microtomography
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Affiliation(s)
- Hyun Jung Yoo
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea; (H.J.Y.); (W.C.H.)
| | - Won Chan Hwang
- Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Korea; (H.J.Y.); (W.C.H.)
- College of Pharmacy, Yonsei University, Incheon 21983, Korea
| | - Do Sik Min
- College of Pharmacy, Yonsei University, Incheon 21983, Korea
- Correspondence: ; Tel.: +82-32-749-4522
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32
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Hand LE, Gray KJ, Dickson SH, Simpkins DA, Ray DW, Konkel JE, Hepworth MR, Gibbs JE. Regulatory T cells confer a circadian signature on inflammatory arthritis. Nat Commun 2020; 11:1658. [PMID: 32245954 PMCID: PMC7125185 DOI: 10.1038/s41467-020-15525-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 02/26/2020] [Indexed: 12/12/2022] Open
Abstract
The circadian clock is an intrinsic oscillator that imparts 24 h rhythms on immunity. This clock drives rhythmic repression of inflammatory arthritis during the night in mice, but mechanisms underlying this effect are not clear. Here we show that the amplitude of intrinsic oscillators within macrophages and neutrophils is limited by the chronic inflammatory environment, suggesting that rhythms in inflammatory mediators might not be a direct consequence of intrinsic clocks. Anti-inflammatory regulatory T (Treg) cells within the joints show diurnal variation, with numbers peaking during the nadir of inflammation. Furthermore, the anti-inflammatory action of Treg cells on innate immune cells contributes to the night-time repression of inflammation. Treg cells do not seem to have intrinsic circadian oscillators, suggesting that rhythmic function might be a consequence of external signals. These data support a model in which non-rhythmic Treg cells are driven to rhythmic activity by systemic signals to confer a circadian signature to chronic arthritis.
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Affiliation(s)
- L E Hand
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - K J Gray
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - S H Dickson
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - D A Simpkins
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK
| | - D W Ray
- NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK and Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - J E Konkel
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Oxford Road, Manchester, UK
| | - M R Hepworth
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Oxford Road, Manchester, UK
| | - J E Gibbs
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester, UK.
- Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Oxford Road, Manchester, UK.
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Zhang H, Yin L, Lu M, Wang J, Li YT, Gao WL, Yin ZS. Evodiamine attenuates adjuvant-induced arthritis in rats by inhibiting synovial inflammation and restoring the Th17/Treg balance. J Pharm Pharmacol 2020; 72:798-806. [PMID: 32056223 DOI: 10.1111/jphp.13238] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 01/18/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Evodiamine (Evo) possesses strong anti-inflammatory activity. In this study, we determine the antiarthritic effect of Evo. METHODS Evo was administered to rats with adjuvant-induced arthritis (AA). We evaluated arthritis symptoms & histopathological changes and measured inflammatory cell infiltration, pro-inflammatory cytokine production and Th17 & Treg percentages in arthritic rats. KEY FINDINGS Evo significantly improved the clinical signs of AA in rats, including decreases in paw swelling, the polyarthritis index and the number of swollen paw joints. Based on the histopathological analysis, Evo improved synovial inflammation and bone injury by inhibiting inflammatory cell infiltration, synoviocyte proliferation, pannus formation and cartilage erosion. Furthermore, the numbers of synovial CD3+ or CD68+ inflammatory cells were reduced, and the elevated levels of tumour necrosis factor-α, interleukin-1β (IL-1β) and IL-6 were restored to control levels by the Evo treatment. In addition, Evo therapy regulated the abnormal differentiation of Treg and Th17 cells, decreasing IL-17 production and increasing IL-10 levels. Finally, Evo inhibited Stat3 phosphorylation and induced Stat5 phosphorylation in rats with AA. CONCLUSIONS Based on our results, Evo is a promising antiarthritic agent, potentially due to its inhibitory effect on synovial inflammation and regulatory effects on Treg and Th17 differentiation.
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Affiliation(s)
- Hui Zhang
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Yin
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ming Lu
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Wang
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ye-Tian Li
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Lu Gao
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zong-Sheng Yin
- Department of Orthopedics, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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34
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Hosseini A, Gharibi T, Marofi F, Babaloo Z, Baradaran B. CTLA-4: From mechanism to autoimmune therapy. Int Immunopharmacol 2020; 80:106221. [PMID: 32007707 DOI: 10.1016/j.intimp.2020.106221] [Citation(s) in RCA: 170] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/15/2020] [Accepted: 01/15/2020] [Indexed: 12/16/2022]
Abstract
CD28 and CTLA-4 are both important stimulatory receptors for the regulation of T cell activation. Because receptors share common ligands, B7.1 and B7.2, the expression and biological function of CTLA-4 is important for the negative regulation of T cell responses. Therefore, elimination of CTLA-4 can result in the breakdown of immune tolerance and the development of several diseases such as autoimmunity. Inhibitory signals of CTLA-4 suppress T cell responses and protect against autoimmune diseases in many ways. In this review, we summarize the structure, expression and signaling pathway of CTLA-4. We also highlight how CTLA-4 defends against potentially self-reactive T cells. Finally, we discuss how the CTLA-4 regulates a number of autoimmune diseases that indicate manipulation of this inhibitory molecule is a promise as a strategy for the immunotherapy of autoimmune diseases.
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Affiliation(s)
- Arezoo Hosseini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Gharibi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faroogh Marofi
- Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Babaloo
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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35
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Xiao XY, Li YT, Jiang X, Ji X, Lu X, Yang B, Wu LJ, Wang XH, Guo JB, Zhao LD, Fei YY, Yang HX, Zhang W, Zhang FC, Tang FL, Zhang JM, He W, Chen H, Zhang X. EZH2 deficiency attenuates Treg differentiation in rheumatoid arthritis. J Autoimmun 2020; 108:102404. [PMID: 31952907 DOI: 10.1016/j.jaut.2020.102404] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 01/02/2020] [Accepted: 01/05/2020] [Indexed: 01/07/2023]
Abstract
The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+ T cells, CD19+ B cell, and CD14+ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+ T cell differentiation, proliferation and apoptosis. We further examined TGFβ-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4+ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+ T cells. Defective EZH2 in CD4+ T cells might contribute to Treg deficiency in RA.
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Affiliation(s)
- Xin-Yue Xiao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Yue-Ting Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Xu Jiang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Xin Ji
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Xin Lu
- Department of Orthopedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Bo Yang
- Department of Orthopedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Li-Jun Wu
- Department of Rheumatology and Clinical Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumchi, 830001, China
| | - Xiao-Han Wang
- Department of Rheumatology, AnYang District Hospital, AnYang, HeNan Province, 455000, China
| | - Jing-Bo Guo
- Department of Traditional Chinese Medicine, 256th Clinical Department of Bethune International Peace Hospital of PLA, Shijiazhuang, 050800, China
| | - Li-Dan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Yun-Yun Fei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Hua-Xia Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Wen Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Feng-Chun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Fu-Lin Tang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China
| | - Jian-Min Zhang
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China
| | - Wei He
- Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing, 100005, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China.
| | - Xuan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China.
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36
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Immunological adaptations in pregnancy that modulate rheumatoid arthritis disease activity. Nat Rev Rheumatol 2020; 16:113-122. [PMID: 31932747 DOI: 10.1038/s41584-019-0351-2] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2019] [Indexed: 02/08/2023]
Abstract
During pregnancy, the fetus that grows within the maternal uterus is not rejected by the maternal immune system. To enable both tolerance towards the fetus and defence against pathogens, modifications of the maternal immune system occur during gestation. These modifications are able to bring about a natural improvement in disease activity of some autoimmune diseases, such as rheumatoid arthritis (RA). Various mechanisms of the immune system contribute to the phenomenon of pregnancy-related improvement of RA, and the cessation of these immunomodulatory mechanisms after delivery correlates with postpartum disease flare. HLA disparity between mother and fetus, glycosylation of IgG, immunoregulatory pathways, and alterations in innate and adaptive immune cells and their cytokines have important roles in pregnancy and in pregnancy-related amelioration of RA.
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37
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Verma A, Mathur R, Farooque A, Kaul V, Gupta S, Dwarakanath BS. T-Regulatory Cells In Tumor Progression And Therapy. Cancer Manag Res 2019; 11:10731-10747. [PMID: 31920383 PMCID: PMC6935360 DOI: 10.2147/cmar.s228887] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/06/2019] [Indexed: 12/24/2022] Open
Abstract
Regulatory T cells (Tregs) are important members of the immune system regulating the host responses to infection and neoplasms. Tregs prevent autoimmune disorders by protecting the host-cells from an immune response, related to the peripheral tolerance. However, tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response. Thus, Tregs are a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. This has prompted the development of novel adjuvant therapies that obviate their negative effects thereby enhancing the therapeutic efficacy. Our earlier studies have shown the efficacy of the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) by reducing the induced Tregs pool and enhance immune stimulation as well as local tumor control. These findings have suggested its potential for enhancing the efficacy of immunotherapy, besides radiotherapy and chemotherapy. This review provides a brief account of the current status of Tregs as a component of the immune-biology of tumors and various preclinical and clinical strategies pursued to obviate the limitations imposed by them in achieving therapeutic efficacy.
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Affiliation(s)
- Amit Verma
- Armed Forces Radiobiology Research Institute, Uniformed Services University, Bethesda, MD, USA
| | - Rohit Mathur
- Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Vandana Kaul
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Stanford, CA, USA
| | - Seema Gupta
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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38
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Vyas SP, Hansda AK, Goswami R. Rheumatoid arthritis: ‘melting pot’ of T helper subsets. Int Rev Immunol 2019; 38:212-231. [PMID: 31155981 DOI: 10.1080/08830185.2019.1621865] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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39
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Yang M, Liu Y, Mo B, Xue Y, Ye C, Jiang Y, Bi X, Liu M, Wu Y, Wang J, Olsen N, Pan Y, Zheng SG. Helios but not CD226, TIGIT and Foxp3 is a Potential Marker for CD4 + Treg Cells in Patients with Rheumatoid Arthritis. Cell Physiol Biochem 2019; 52:1178-1192. [PMID: 30990587 PMCID: PMC6943339 DOI: 10.33594/000000080] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 01/22/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Rheumatoid arthritis (RA) is a progressive, chronic, even disabling systemic autoimmune disease. Imbalance between pathogenic immune cells and immunosuppressive cells is associated with the pathogenesis and development of RA and other autoimmune diseases. As Foxp3 is also expressed on activated CD4+ cells in the presence of inflammation, the identification of Treg cells in patients with RA remains a challenge. METHODS Comprehensive analyses were carried out by Flow cytometry. Expression of Helios, CD226, T cell immunoreceptor with Ig and ITIM domains clinical samples and healthy controls. RESULTS We have systemically examined three potential markers, Helios, CD226 and TIGIT, that are possibly related to Treg identification, and found that Helios expression on CD4+Foxp3+cells was decreased and negatively correlated with the disease activity of RA patients, while CD226 and TIGIT both showed elevated expression levels in CD4+Foxp3+cells in RA patients and they were not associated with disease activity of RA patients. CONCLUSION Taken together, our findings indicate that CD4+CD25hiCD127low/-Foxp3+Helios+ may represent the real Treg cell population in patients with RA.
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Affiliation(s)
- Mengru Yang
- Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.,Center for Clinical Immunology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yan Liu
- Center for Clinical Immunology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Biyao Mo
- Division of Rheumatology, Department of Internal Medicine, Hainan General Hospital, Haikou, China
| | - Youqiu Xue
- Center for Clinical Immunology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Congxiu Ye
- Center for Clinical Immunology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yutong Jiang
- Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xuan Bi
- Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Meng Liu
- Division of Rheumatology, Department of Internal Medicine, Guangdong Second Provincial Central Hospital, Guangzhou, China
| | - Yunting Wu
- Center for Clinical Immunology, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Julie Wang
- Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA, United States
| | - Nancy Olsen
- Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, Hershey, PA, United States
| | - Yunfeng Pan
- Division of Rheumatology, Department of Internal Medicine, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China,
| | - Song Guo Zheng
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, United States,
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40
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Okeke EB, Uzonna JE. The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells. Front Immunol 2019; 10:680. [PMID: 31024539 PMCID: PMC6465517 DOI: 10.3389/fimmu.2019.00680] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 03/12/2019] [Indexed: 12/11/2022] Open
Abstract
The distinction between innate and adaptive immunity is one of the basic tenets of immunology. The co-operation between these two arms of the immune system is a major determinant of the resistance or susceptibility of the host following pathogen invasion. Hence, this interactive co-operation between cells of the innate and adaptive immunity is of significant interest to immunologists. The sub-population of CD4+ T cells with regulatory phenotype (regulatory T cells; Tregs), which constitute a part of the adaptive immune system, have been widely implicated in the regulation of the immune system and maintenance of immune homeostasis. In the last two decades, there has been an explosion in research describing the role of Tregs and their relevance in several immunopathologies ranging from inflammation to cancer. The majority of these studies focus on the role of Tregs on the cells of the adaptive immune system. Recently, there is significant interest in the role of Tregs on cells of the innate immune system. In this review, we examine the literature on the role of Tregs in immunology. Specifically, we focus on the emerging knowledge of Treg interaction with dendritic cells, macrophages, neutrophils, and γδ T cells. We highlight this interaction as an important link between innate and adaptive immune systems which also indicate the far-reaching role of Tregs in the regulation of immune responses and maintenance of self-tolerance and immune homeostasis.
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Affiliation(s)
- Emeka B Okeke
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, United States
| | - Jude E Uzonna
- Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada
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41
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Dimitrijević M, Arsenović-Ranin N, Kosec D, Bufan B, Nacka-Aleksić M, Pilipović I, Leposavić G. Sexual dimorphism in Th17/Treg axis in lymph nodes draining inflamed joints in rats with collagen-induced arthritis. Brain Behav Immun 2019; 76:198-214. [PMID: 30476564 DOI: 10.1016/j.bbi.2018.11.311] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 10/22/2018] [Accepted: 11/22/2018] [Indexed: 01/11/2023] Open
Abstract
Collagen type II-induced arthritis (CIA) in Dark Agouti rats, a model of rheumatoid arthritis (RA), reproduces sexual dimorphism in the incidence and severity of the human disease. Th17 cells are central in the induction/propagation of autoimmune inflammation in CIA and RA. To assess mechanisms underlying this dimorphism in CIA rats, in lymph nodes draining inflamed joints and adjacent tissues (dLNs) from CIA rats of both sexes Th17/CD25+Foxp3+CD4+ T-regulatory cell (Treg) ratio, Th17 cell redifferentiation in functionally distinct subsets and Treg transdifferentiation into IL-17-producing cells (exTregs) were examined. In female rats (developing more severe CIA than their male counterparts) the higher frequency of all Th17 cells (reflecting partly their greater proliferation), followed by the higher frequency of highly pathogenic IFN-γ/GM-CSF-co-producing cells, but lower frequency of less pathogenic/immunoregulatory IL-10-producing cells among them was found. Additionally, compared with male rats, in female rats the lower frequency of Tregs was observed. Moreover, Tregs from female rats exhibited diminished proliferative and suppressive capacity (judging by PD-1 expression) and enhanced conversion into IL-17-producing cells. Given that TGF-β concentration was comparable in collagen-type II-stimulated dLN cell cultures from female and male rats, the shift in Th17/Treg ratio followed by augmented Th17 cell redifferentiation into IFN-γ/GM-CSF-co-producing cells and Treg transdifferentiation into IL-17-producing cells in female rats was associated with increased concentration of IL-6 in female rat dLN cell cultures, and the higher frequency of IL-1β- and IL-23-producing cells among their dLN cells. The lower frequency of IL-10-producing B cells, presumably B regulatory cells (Bregs) could also contribute to the shift in Th17/Treg ratio in female rat compared with male rat dLNs. Consistently, the lower expression of IL-35 (the cytokine promoting Treg expansion directly and indirectly, by favoring Breg expansion and conversion into IL-10/IL-35-producing cells) in female rat dLN cells was detected. Thus, the study identified putative cellular and molecular substrates of the sexual dimorphism in the immunopathogenesis and clinical outcome of CIA and suggested mechanisms to be targeted in females to improve control of Th17 response, and consequently clinical outcome of CIA, and possibly RA.
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Affiliation(s)
- Mirjana Dimitrijević
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Bulevar despota Stefana 142, Belgrade, Serbia.
| | - Nevena Arsenović-Ranin
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia
| | - Duško Kosec
- Immunology Research Center, Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Vojvode Stepe 458, Belgrade, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia
| | - Mirjana Nacka-Aleksić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia
| | - Ivan Pilipović
- Immunology Research Center, Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Vojvode Stepe 458, Belgrade, Serbia
| | - Gordana Leposavić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia.
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Fischer L, Herkner C, Kitte R, Dohnke S, Riewaldt J, Kretschmer K, Garbe AI. Foxp3 + Regulatory T Cells in Bone and Hematopoietic Homeostasis. Front Endocrinol (Lausanne) 2019; 10:578. [PMID: 31551927 PMCID: PMC6746882 DOI: 10.3389/fendo.2019.00578] [Citation(s) in RCA: 39] [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: 05/17/2019] [Accepted: 08/08/2019] [Indexed: 12/29/2022] Open
Abstract
The bone represents surprisingly dynamic structures that are subject to constant remodeling by the concerted action of bone-forming osteoblasts and bone-resorbing osteoclasts - two cell subsets of distinct developmental origin that are key in maintaining skeletal integrity throughout life. In general, abnormal bone remodeling due to dysregulated bone resorption and formation is an early event in the manifestation of various human bone diseases, such as osteopetrosis/osteoporosis and arthritis. But bone remodeling is also closely interrelated with lympho-hematopoietic homeostasis, as the bone marrow niche is formed by solid and trabecular bone structures that provide a framework for the long-term maintenance and differentiation of HSCs (>blood lineage cells and osteoclasts) and MSCs (>osteoblasts). Numerous studies in mice and humans have implicated innate and adaptive immune cells in the dynamic regulation of bone homeostasis, but despite considerable clinical relevance, the exact mechanisms of such immuno-bone interplay have remained incompletely understood. This holds particularly true for CD4+ regulatory T (Treg) cells expressing the lineage specification factor Foxp3: Foxp3+ Treg cells have been shown to play an indispensable role in maintaining immune homeostasis, but may also exert critical non-immune functions, which includes the control of metabolic and regenerative processes, as well as the differentiation of HSCs and function of osteoclasts. Here, we summarize our current knowledge on the T cell/bone interplay, with a particular emphasis on our own efforts to dissect the role of Foxp3+ Treg cells in bone and hematopoietic homeostasis, employing experimental settings of gain- and loss-of-Treg cell function. These data make a strong case that Foxp3+ Treg cells impinge on lympho-hematopoiesis through indirect mechanisms, i.e., by acting on osteoclast development and function, which translates into changes in niche size. Furthermore, we propose that, besides disorders that involve inflammatory bone loss, the modulation of Foxp3+ Treg cell function in vivo may represent a suitable approach to reinstate bone homeostasis in non-autoimmune settings of aberrant bone remodeling.
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Affiliation(s)
- Luise Fischer
- Osteoimmunology, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
- Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Caroline Herkner
- Osteoimmunology, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Reni Kitte
- Osteoimmunology, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Sebastian Dohnke
- Osteoimmunology, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
- Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Julia Riewaldt
- Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Karsten Kretschmer
- Molecular and Cellular Immunology/Immune Regulation, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
| | - Annette I. Garbe
- Osteoimmunology, DFG-Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany
- *Correspondence: Annette I. Garbe
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Zuo J, Yin Q, Wang L, Zhang W, Fan Y, Zhou YY, Li Y, Wang GD. Mangosteen ethanol extract alleviated the severity of collagen-induced arthritis in rats and produced synergistic effects with methotrexate. PHARMACEUTICAL BIOLOGY 2018; 56:455-464. [PMID: 31070537 PMCID: PMC6282431 DOI: 10.1080/13880209.2018.1506939] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 06/26/2018] [Accepted: 07/26/2018] [Indexed: 06/09/2023]
Abstract
CONTEXT Garcinia mangostana Linn. (Guttiferae) pericarp is used as a traditional medicine in South Asia to treat inflammatory diseases. OBJECTIVE This study investigates therapeutic effects of G. mangostana pericarp ethanol extract (MAN) on collagen-induced arthritis (CIA) and interactions with methotrexate in vivo. MATERIALS AND METHODS Male Sprague-Dawley rats with CIA were treated with MAN (0.5 g/kg/day), methotrexate (0.5 mg/kg, bw) or combination of both for 36 days, respectively (n = 8/group). Another eight healthy and CIA rats served as normal and model control, respectively. Therapeutic effects were evaluated based on paw edema and arthritis score during the experiment and serological markers at the end of the study period. Histological and radiological examinations were used to assess joint destructions. The immune status was investigated by immunohistochemistry and flow cytometry. RESULTS All treatments decreased the arthritis score and paw inflammation in CIA rats. Combination regimen significantly reduced anti-cyclic citrullinated peptide antibody in CIA rats to 85.83% (p < 0.05) and notably alleviated synovial hyperplasia and cartilage degradation in joints. Different from methotrexate, MAN significantly augmented CD25+ cells distribution (from 2.72 to 3.35%) and IL-10 secretion (from 202.4 to 241.2 pg/mL) in CIA rat blood. Meanwhile, MAN induced a greater IL-17 decrease and a FOXP3 increase in immune organs than MTX. Reduced TLR4 and IL-17 expression and elevated FOXP3 expression in joints also occurred under MAN treatment. CONCLUSIONS MAN protected joints from destruction in CIA rats and exerted synergistic effects with methotrexate by improving immune microenvironment. The combination regimen could bring additional benefits to rheumatoid arthritis patients.
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Affiliation(s)
- Jian Zuo
- Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Qin Yin
- The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Lin Wang
- Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Wen Zhang
- Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Yan Fan
- Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Yu-Yan Zhou
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Yan Li
- Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Guo-Dong Wang
- Anhui Provincial Engineering Research Center for Polysaccharide Drugs, School of Pharmacy, Wannan Medical College, Wuhu, China
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Kumar P, Saini S, Khan S, Surendra Lele S, Prabhakar BS. Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells. Cell Immunol 2018; 339:41-49. [PMID: 30482489 DOI: 10.1016/j.cellimm.2018.09.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 09/14/2018] [Accepted: 09/28/2018] [Indexed: 12/16/2022]
Abstract
Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.
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Affiliation(s)
- Prabhakaran Kumar
- Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA
| | - Shikha Saini
- Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA
| | - Saad Khan
- Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA
| | - Swarali Surendra Lele
- Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA.
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Song L, Wang Y, Sui Y, Sun J, Li D, Li G, Liu J, Li T, Shu Q. High Interleukin-37 (IL-37) Expression and Increased Mucin-Domain Containing-3 (TIM-3) on Peripheral T Cells in Patients with Rheumatoid Arthritis. Med Sci Monit 2018; 24:5660-5667. [PMID: 30106887 PMCID: PMC6104553 DOI: 10.12659/msm.909254] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Anti-inflammatory mediators such as mucin-domain containing-3 (TIM-3) and IL-37 play an important role in the regulation of Th1-mediated immunity. This study was designed to investigate the proportions of various T cell subsets and monocytes in the peripheral blood of rheumatoid arthritis (RA) patients, as well as the level of TIM-3 on these cells and serum cytokine levels. Material/Methods We enrolled 59 RA patients and 46 age- and sex-matched healthy controls in this study. The proportion of T cells and TIM-3 expression on these T cells were determined by flow cytometry. Cytokine levels in serum were determined by ELISA. Results Compared with the healthy controls, the proportions of CD3+CD4+ T cells and CD3+CD4+CD25+CD127low T cells in the peripheral blood were significantly higher in RA patients. However, RA patients had significantly lower proportions of CD3+CD8+ T cells and CD3+CD4−CD8− T cells. TIM-3 was highly expressed on CD3+CD4+, CD3+CD8+, CD3+CD4+CD25+CD127low, and CD3+CD4−CD8− T cells, as well as CD14+ monocytes, in RA patients. Nevertheless, no correlation between TIM-3 level and an RA disease activity score of 28 was found. The elevated serum levels of IL-6 and IL-37 were positively correlated with tumor necrosis factor-α (TNF-α). Conclusions Both pro-inflammatory cytokines (TNF-α and IL-6) and anti-inflammatory mediators (TIM-3 and IL-37) simultaneously contribute to the pathogenesis of RA. TIM-3 and IL-37 may be used as potential biomarkers of active RA.
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Affiliation(s)
- Lijun Song
- Shenzhen Research Institute of Shandong University, Shenzhen, Guangdong, China (mainland).,Department of Rheumatology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland)
| | - Yunqing Wang
- Department of Rheumatology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland).,Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China (mainland)
| | - Yameng Sui
- Department of Rheumatology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland).,School of Medicine, Shandong University, Ji'nan, Shandong, China (mainland)
| | - Jiao Sun
- Department of Rheumatology, Qilu Hospital of Shandong University, , China (mainland).,School of Medicine, Shandong University, , China (mainland)
| | - Dong Li
- Shenzhen Research Institute of Shandong University, Shenzhen, Guangdong, China (mainland).,Cryomedicine Laboratory, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland)
| | - Guosheng Li
- Shenzhen Research Institute of Shandong University, Shenzhen, Guangdong, China (mainland).,Department of Hematology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland)
| | - Jianwei Liu
- Department of Rheumatology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland)
| | - Tianwang Li
- Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China (mainland)
| | - Qiang Shu
- Shenzhen Research Institute of Shandong University, Shenzhen, Guangdong, China (mainland).,Department of Rheumatology, Qilu Hospital of Shandong University, Ji'nan, Shandong, China (mainland)
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Fang J, Lin L, Wang Y, Lin D, Liu C, Sunlong Q, Lin X. Regulatory T cells and CD20 + B cells in pediatric very severe aplastic anemia: possible clinical markers for evaluating the therapeutic efficacy and prognosis. ACTA ACUST UNITED AC 2018; 23:823-827. [PMID: 29996743 DOI: 10.1080/10245332.2018.1498566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
OBJECTIVES To investigate the immune status of children with very severe aplastic anemia (VSAA), and evaluate the frequencies of CD20+ B cells and Regulatory T cells (Tregs) as potential markers for evaluating the therapeutic efficacy and prognosis. METHODS We systematically analyzed CD20+ B cells and Tregs using Flow Cytometry in 36 children with VSAA (14 newly diagnosed cases and 22 cases in remission after therapy with HDIVIG + r-ATG + CSA). RESULTS In newly diagnosed VSAA patients, the percentage of CD20+ B cells was higher than that in healthy children (P < .01), whereas the percentage of Tregs was lower than that in healthy children (P < .001). After treatment with HDIVIG + r-ATG + CSA, the percentage of CD20+ B cells in peripheral blood was decreased obviously, and the percentage of Tregs was significantly increased. CONCLUSION There is a moderate negative correlation between the percentage of Tregs and CD20+ B cells in our study. Our results shed light on the roles of Tregs and CD20+ B cells as therapeutic efficacy and prognostic markers of pediatric VSAA. Moreover, the mechanism underlying the decrease of blood Tregs and increase of CD20+ B cells in pediatric VSAA patients have been discussed, indicating that Tregs may suppress B cell responses.
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Affiliation(s)
- Junyue Fang
- a Department of Clinical Laboratory , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
| | - Li Lin
- b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,c Department of Dermatology , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
| | - Ying Wang
- a Department of Clinical Laboratory , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
| | - Dijin Lin
- a Department of Clinical Laboratory , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
| | - Chunyue Liu
- a Department of Clinical Laboratory , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
| | - Qiaozi Sunlong
- a Department of Clinical Laboratory , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
| | - Xianghua Lin
- a Department of Clinical Laboratory , The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China.,b Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation , Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People's Republic of China
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Kojima S, Thukimoto M, Cuttler JM, Inoguchi K, Ootaki T, Shimura N, Koga H, Murata A. Recovery From Rheumatoid Arthritis Following 15 Months of Therapy With Low Doses of Ionizing Radiation: A Case Report. Dose Response 2018; 16:1559325818784719. [PMID: 30013458 PMCID: PMC6043934 DOI: 10.1177/1559325818784719] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 05/27/2018] [Accepted: 05/29/2018] [Indexed: 12/20/2022] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that occurs commonly in old people. Hot spring radon therapy is widely practiced in Central Europe and Japan for relief from the painful symptoms. The usual duration of a spa treatment is a week or two, and the relief is temporary. This article reports on the near-complete recovery of a patient who had been suffering from RA for 10 years. The patient received 15 months of low-dose radon and γ-radiation therapy in a room that reproduced the conditions of a radon spa. The daily 40-minute exposure in the therapy room was supplemented by ten 6-minute radio-nebulizer treatments. The inflammation markers C-reactive protein and matrix metalloproteinase 3 declined strongly to the normal level of 0.07 mg/dL and the near-normal level of 48.9 ng/mL, respectively. After the patient's return to good health, the frequency of the visits was reduced to twice each month. The patient's protection systems appear to have adapted to stimulated conditions, sufficiently to sustain the recovery from RA. Such a long-term course of treatments and follow-up maintenance could be carried out in any hospital that has these low-dose radiation therapy rooms. The therapy could be scheduled to suit patient availability.
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Affiliation(s)
- Shuji Kojima
- Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science (TUS), Noda-shi, Chiba, Japan
| | - Mitsutoshi Thukimoto
- Department of Radiation Biosciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science (TUS), Noda-shi, Chiba, Japan
| | | | | | | | - Noriko Shimura
- Faculty of Pharmaceutical Sciences, Ohu University, Koriyama, Japan
| | - Hironobu Koga
- Lead and Company Co, Ltd, Minami-ku, Yokohama, Japan
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Moschovakis GL, Bubke A, Friedrichsen M, Ristenpart J, Back JW, Falk CS, Kremmer E, Förster R. The chemokine receptor CCR7 is a promising target for rheumatoid arthritis therapy. Cell Mol Immunol 2018; 16:791-799. [PMID: 29973648 DOI: 10.1038/s41423-018-0056-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 05/27/2018] [Indexed: 01/04/2023] Open
Abstract
The chemokine receptor CCR7 and its ligands CCL19 and CCL21 guide the homing and positioning of dendritic and T cells in lymphoid organs, thereby contributing to several aspects of adaptive immunity and immune tolerance. In the present study, we investigated the role of CCR7 in the pathogenesis of collagen-induced arthritis (CIA). By using a novel anti-human CCR7 antibody and humanized CCR7 mice, we evaluated CCR7 as a target in this autoimmune model of rheumatoid arthritis (RA). Ccr7-deficient mice were completely resistant to CIA and presented severely impaired antibody responses to collagen II (CII). Selective CCR7 expression on dendritic cells restored arthritis severity and anti-CII antibody titers. Prophylactic and therapeutic treatment of humanized CCR7 mice with anti-human CCR7 mAb 8H3-16A12 led to complete resistance to CIA and halted CIA progression, respectively. Our data demonstrate that CCR7 signaling is essential for the induction of CIA and identify CCR7 as a potential therapeutic target in RA.
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Affiliation(s)
- Georgios L Moschovakis
- Institute of Immunology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
| | - Anja Bubke
- Institute of Immunology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany
| | - Michaela Friedrichsen
- Institute of Immunology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany
| | - Jasmin Ristenpart
- Institute of Immunology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany
| | | | - Christine S Falk
- Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, IFB.Tx, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany
| | - Elisabeth Kremmer
- Helmholtz-Zentrum München, Institute of Molecular Immunology, D-81377, Munich, Germany.,Biozentrum Martinsried, Dept. Bio II., LMU München, Grosshaderner Str. 2, D-82152, Martinsried, Germany
| | - Reinhold Förster
- Institute of Immunology, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
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Dwarakanath BS, Farooque A, Gupta S. Targeting regulatory T cells for improving cancer therapy: Challenges and prospects. Cancer Rep (Hoboken) 2018; 1:e21105. [PMID: 32729245 DOI: 10.1002/cnr2.1105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/22/2018] [Accepted: 04/07/2018] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Regulatory T cells (Tregs) play a central role in immune responses to infectious agents and tumors. Paradoxically, Tregs protect self-cells from the immune response as a part of peripheral tolerance and prevents autoimmune disorders, whereas during the process of carcinogenesis, they are exploited by tumor cells for protection against antitumor immune responses. Therefore, Tregs are often considered as a major obstacle in anticancer therapy. The objective of this review is to provide a current understanding on Tregs as a potential cellular target for achieving therapeutic gain and discuss various approaches that are implicated at preclinical and clinical scenario. RECENT FINDINGS Several approaches like immunotherapy and adjuvant chemotherapy, which reduce Tregs population, have been found to be useful in improving local tumor control. Our recent observations with the glycolytic inhibitor, 2-deoxy-D-glucose, established as an adjuvant in radiotherapy and chemotherapy of tumors also show that potential of 2-deoxy-D-glucose to improve local tumor control is linked with its ability to reduce the Tregs pool. CONCLUSIONS Several published studies and emerging evidences indicate that suppression of Treg numbers, infiltration into the tumors, and function can improve the cancer therapy by enhancing the antitumor immunity.
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Affiliation(s)
| | | | - Seema Gupta
- Department of Oncology, Georgetown University, Washington, DC, USA
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Kleinman AJ, Sivanandham R, Pandrea I, Chougnet CA, Apetrei C. Regulatory T Cells As Potential Targets for HIV Cure Research. Front Immunol 2018; 9:734. [PMID: 29706961 PMCID: PMC5908895 DOI: 10.3389/fimmu.2018.00734] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/23/2018] [Indexed: 12/19/2022] Open
Abstract
T regulatory cells (Tregs) are a key component of the immune system, which maintain a delicate balance between overactive responses and immunosuppression. As such, Treg deficiencies are linked to autoimmune disorders and alter the immune control of pathogens. In HIV infection, Tregs play major roles, both beneficial and detrimental. They regulate the immune system such that inflammation and spread of virus through activated T cells is suppressed. However, suppression of immune activation also limits viral clearance and promotes reservoir formation. Tregs can be directly targeted by HIV, thereby harboring a fraction of the viral reservoir. The vital role of Tregs in the pathogenesis and control of HIV makes them a subject of interest for manipulation in the search of an HIV cure. Here, we discuss the origin and generation, homeostasis, and functions of Tregs, particularly their roles and effects in HIV infection. We also present various Treg manipulation strategies, including Treg depletion techniques and interventions that alter Treg function, which may be used in different cure strategies, to simultaneously boost HIV-specific immune responses and induce reactivation of the latent virus.
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Affiliation(s)
- Adam J Kleinman
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ranjit Sivanandham
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Ivona Pandrea
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
| | - Claire A Chougnet
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati University, Cincinnati, OH, United States
| | - Cristian Apetrei
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
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