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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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Kadam R, Gupta M, Lazarov O, Prabhakar BS. Brain-immune interactions: implication for cognitive impairments in Alzheimer's disease and autoimmune disorders. J Leukoc Biol 2024; 116:1269-1290. [PMID: 38869088 DOI: 10.1093/jleuko/qiae134] [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: 11/13/2023] [Revised: 05/09/2024] [Accepted: 06/11/2024] [Indexed: 06/14/2024] Open
Abstract
Progressive memory loss and cognitive dysfunction, encompassing deficits in learning, memory, problem solving, spatial reasoning, and verbal expression, are characteristics of Alzheimer's disease and related dementia. A wealth of studies has described multiple roles of the immune system in the development or exacerbation of dementia. Individuals with autoimmune disorders can also develop cognitive dysfunction, a phenomenon termed "autoimmune dementia." Together, these findings underscore the pivotal role of the neuroimmune axis in both Alzheimer's disease and related dementia and autoimmune dementia. The dynamic interplay between adaptive and innate immunity, both in and outside the brain, significantly affects the etiology and progression of these conditions. Multidisciplinary research shows that cognitive dysfunction arises from a bidirectional relationship between the nervous and immune systems, though the specific mechanisms that drive cognitive impairments are not fully understood. Intriguingly, this reciprocal regulation occurs at multiple levels, where neuronal signals can modulate immune responses, and immune system-related processes can influence neuronal viability and function. In this review, we consider the implications of autoimmune responses in various autoimmune disorders and Alzheimer's disease and explore their effects on brain function. We also discuss the diverse cellular and molecular crosstalk between the brain and the immune system, as they may shed light on potential triggers of peripheral inflammation, their effect on the integrity of the blood-brain barrier, and brain function. Additionally, we assess challenges and possibilities associated with developing immune-based therapies for the treatment of cognitive decline.
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Affiliation(s)
- Rashmi Kadam
- Department of Microbiology and Immunology, University of Illinois College of Medicine, 835 S Wolcott street, MC 790, Chicago, Chicago, IL 60612, United States
| | - Muskan Gupta
- Department of Anatomy and Cell Biology, University of Illinois College of Medicine, 808 S Wood street, MC 512, Chicago, Chicago, IL 60612, United States
| | - Orly Lazarov
- Department of Anatomy and Cell Biology, University of Illinois College of Medicine, 808 S Wood street, MC 512, Chicago, Chicago, IL 60612, United States
| | - Bellur S Prabhakar
- Department of Microbiology and Immunology, University of Illinois College of Medicine, 835 S Wolcott street, MC 790, Chicago, Chicago, IL 60612, United States
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3
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Lorenzini T, Faigle W, Ruder J, Docampo MJ, Opitz L, Martin R. Alterations of Thymus-Derived Tregs in Multiple Sclerosis. NEUROLOGY(R) NEUROIMMUNOLOGY & NEUROINFLAMMATION 2024; 11:e200251. [PMID: 38838284 PMCID: PMC11160584 DOI: 10.1212/nxi.0000000000200251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 03/12/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND AND OBJECTIVES Multiple sclerosis (MS) is considered a prototypic autoimmune disease of the CNS. It is the leading cause of chronic neurologic disability in young adults. Proinflammatory B cells and autoreactive T cells both play important roles in its pathogenesis. We aimed to study alterations of regulatory T cells (Tregs), which likely also contribute to the disease, but their involvement is less clear. METHODS By combining multiple experimental approaches, we examined the Treg compartments in 41 patients with relapsing-remitting MS and 17 healthy donors. RESULTS Patients with MS showed a reduced frequency of CD4+ T cells and Foxp3+ Tregs and age-dependent alterations of Treg subsets. Treg suppressive function was compromised in patients, who were treated with natalizumab, while it was unaffected in untreated and anti-CD20-treated patients. The changes in natalizumab-treated patients included increased proinflammatory cytokines and an altered transcriptome in thymus-derived (t)-Tregs, but not in peripheral (p)-Tregs. DISCUSSION Treg dysfunction in patients with MS might be related to an altered transcriptome of t-Tregs and a proinflammatory environment. Our findings contribute to a better understanding of Tregs and their subtypes in MS.
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Affiliation(s)
- Tiziana Lorenzini
- From the Neuroimmunology and MS Research (T.L., W.F., J.R., M.J.D., R.M.), Neurology Clinic, University Hospital Zurich; Division of Immunology (T.L.), University Children's Hospital Zurich, University of Zurich; Cellerys AG (W.F., R.M.), Schlieren, Switzerland; Immunity and Cancer (U932) (W.F.), Immune Response to Cancer Laboratory, Institut Curie, 26 rue d'Ulm, CEDEX 05, Paris, France; Functional Genomics Center Zurich (L.O.), Swiss Federal Institute of Technology and University of Zurich; Institute of Experimental Immunology (R.M.), University of Zurich, Switzerland; and Therapeutic Design Unit (R.M.), Center for Molecular Medicine, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
| | - Wolfgang Faigle
- From the Neuroimmunology and MS Research (T.L., W.F., J.R., M.J.D., R.M.), Neurology Clinic, University Hospital Zurich; Division of Immunology (T.L.), University Children's Hospital Zurich, University of Zurich; Cellerys AG (W.F., R.M.), Schlieren, Switzerland; Immunity and Cancer (U932) (W.F.), Immune Response to Cancer Laboratory, Institut Curie, 26 rue d'Ulm, CEDEX 05, Paris, France; Functional Genomics Center Zurich (L.O.), Swiss Federal Institute of Technology and University of Zurich; Institute of Experimental Immunology (R.M.), University of Zurich, Switzerland; and Therapeutic Design Unit (R.M.), Center for Molecular Medicine, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
| | - Josefine Ruder
- From the Neuroimmunology and MS Research (T.L., W.F., J.R., M.J.D., R.M.), Neurology Clinic, University Hospital Zurich; Division of Immunology (T.L.), University Children's Hospital Zurich, University of Zurich; Cellerys AG (W.F., R.M.), Schlieren, Switzerland; Immunity and Cancer (U932) (W.F.), Immune Response to Cancer Laboratory, Institut Curie, 26 rue d'Ulm, CEDEX 05, Paris, France; Functional Genomics Center Zurich (L.O.), Swiss Federal Institute of Technology and University of Zurich; Institute of Experimental Immunology (R.M.), University of Zurich, Switzerland; and Therapeutic Design Unit (R.M.), Center for Molecular Medicine, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
| | - María José Docampo
- From the Neuroimmunology and MS Research (T.L., W.F., J.R., M.J.D., R.M.), Neurology Clinic, University Hospital Zurich; Division of Immunology (T.L.), University Children's Hospital Zurich, University of Zurich; Cellerys AG (W.F., R.M.), Schlieren, Switzerland; Immunity and Cancer (U932) (W.F.), Immune Response to Cancer Laboratory, Institut Curie, 26 rue d'Ulm, CEDEX 05, Paris, France; Functional Genomics Center Zurich (L.O.), Swiss Federal Institute of Technology and University of Zurich; Institute of Experimental Immunology (R.M.), University of Zurich, Switzerland; and Therapeutic Design Unit (R.M.), Center for Molecular Medicine, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
| | - Lennart Opitz
- From the Neuroimmunology and MS Research (T.L., W.F., J.R., M.J.D., R.M.), Neurology Clinic, University Hospital Zurich; Division of Immunology (T.L.), University Children's Hospital Zurich, University of Zurich; Cellerys AG (W.F., R.M.), Schlieren, Switzerland; Immunity and Cancer (U932) (W.F.), Immune Response to Cancer Laboratory, Institut Curie, 26 rue d'Ulm, CEDEX 05, Paris, France; Functional Genomics Center Zurich (L.O.), Swiss Federal Institute of Technology and University of Zurich; Institute of Experimental Immunology (R.M.), University of Zurich, Switzerland; and Therapeutic Design Unit (R.M.), Center for Molecular Medicine, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
| | - Roland Martin
- From the Neuroimmunology and MS Research (T.L., W.F., J.R., M.J.D., R.M.), Neurology Clinic, University Hospital Zurich; Division of Immunology (T.L.), University Children's Hospital Zurich, University of Zurich; Cellerys AG (W.F., R.M.), Schlieren, Switzerland; Immunity and Cancer (U932) (W.F.), Immune Response to Cancer Laboratory, Institut Curie, 26 rue d'Ulm, CEDEX 05, Paris, France; Functional Genomics Center Zurich (L.O.), Swiss Federal Institute of Technology and University of Zurich; Institute of Experimental Immunology (R.M.), University of Zurich, Switzerland; and Therapeutic Design Unit (R.M.), Center for Molecular Medicine, Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden
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Spiezia AL, Scalia G, Petracca M, Caliendo D, Moccia M, Fiore A, Cerbone V, Lanzillo R, Brescia Morra V, Carotenuto A. Effect of siponimod on lymphocyte subsets in active secondary progressive multiple sclerosis and clinical implications. J Neurol 2024; 271:4281-4291. [PMID: 38632126 PMCID: PMC11233419 DOI: 10.1007/s00415-024-12362-9] [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: 01/04/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/19/2024]
Abstract
BACKGROUND Circulating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes. METHODS We enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs. RESULTS At baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression. CONCLUSIONS Patients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes.
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Affiliation(s)
- Antonio Luca Spiezia
- Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Giulia Scalia
- Clinical and Experimental Cytometry Unit, Centre for Advanced Biotechnology Franco Salvatore, CEINGE, Naples, Italy
| | - Maria Petracca
- Department of Human Neurosciences, Sapienza University, Rome, Italy
| | - Daniele Caliendo
- Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Marcello Moccia
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, Naples, Italy
| | - Antonia Fiore
- Clinical and Experimental Cytometry Unit, Centre for Advanced Biotechnology Franco Salvatore, CEINGE, Naples, Italy
| | - Vincenza Cerbone
- Clinical and Experimental Cytometry Unit, Centre for Advanced Biotechnology Franco Salvatore, CEINGE, Naples, Italy
| | - Roberta Lanzillo
- Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Vincenzo Brescia Morra
- Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Antonio Carotenuto
- Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy.
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5
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Rau CN, Severin ME, Lee PW, Deffenbaugh JL, Liu Y, Murphy SP, Petersen-Cherubini CL, Lovett-Racke AE. MicroRNAs targeting TGF-β signaling exacerbate central nervous system autoimmunity by disrupting regulatory T cell development and function. Eur J Immunol 2024; 54:e2350548. [PMID: 38634287 PMCID: PMC11156541 DOI: 10.1002/eji.202350548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 03/04/2024] [Accepted: 03/07/2024] [Indexed: 04/19/2024]
Abstract
Transforming growth factor beta (TGF-β) signaling is essential for a balanced immune response by mediating the development and function of regulatory T cells (Tregs) and suppressing autoreactive T cells. Disruption of this balance can result in autoimmune diseases, including multiple sclerosis (MS). MicroRNAs (miRNAs) targeting TGF-β signaling have been shown to be upregulated in naïve CD4 T cells in MS patients, resulting in a limited in vitro generation of human Tregs. Utilizing the murine model experimental autoimmune encephalomyelitis, we show that perinatal administration of miRNAs, which target the TGF-β signaling pathway, enhanced susceptibility to central nervous system (CNS) autoimmunity. Neonatal mice administered with these miRNAs further exhibited reduced Treg frequencies with a loss in T cell receptor repertoire diversity following the induction of experimental autoimmune encephalomyelitis in adulthood. Exacerbated CNS autoimmunity as a result of miRNA overexpression in CD4 T cells was accompanied by enhanced Th1 and Th17 cell frequencies. These findings demonstrate that increased levels of TGF-β-associated miRNAs impede the development of a diverse Treg population, leading to enhanced effector cell activity, and contributing to an increased susceptibility to CNS autoimmunity. Thus, TGF-β-targeting miRNAs could be a risk factor for MS, and recovering optimal TGF-β signaling may restore immune homeostasis in MS patients.
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Affiliation(s)
- Christina N Rau
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
| | - Mary E Severin
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
- Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio, USA
| | - Priscilla W Lee
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
- Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA
| | - Joshua L Deffenbaugh
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
| | - Yue Liu
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
| | - Shawn P Murphy
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
| | - Cora L Petersen-Cherubini
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
- Neuroscience Graduate Program, The Ohio State University, Columbus, Ohio, USA
| | - Amy E Lovett-Racke
- Department of Microbial Infection and Immunity, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
- Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA
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6
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Arellano G, Acuña E, Loda E, Moore L, Tichauer JE, Castillo C, Vergara F, Burgos PI, Penaloza-MacMaster P, Miller SD, Naves R. Therapeutic role of interferon-γ in experimental autoimmune encephalomyelitis is mediated through a tolerogenic subset of splenic CD11b + myeloid cells. J Neuroinflammation 2024; 21:144. [PMID: 38822334 PMCID: PMC11143617 DOI: 10.1186/s12974-024-03126-3] [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: 03/26/2024] [Accepted: 05/05/2024] [Indexed: 06/02/2024] Open
Abstract
Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-γ are not well understood. In this study, we found that IFN-γ exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models. The frequency of regulatory T (Treg) cells in spinal cords from chronic EAE mice treated with IFN-γ was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-γ, indicating that the therapeutic effect of IFN-γ depends on the presence of Treg cells. However, IFN-γ did not trigger direct in vitro differentiation of Treg cells. In vivo administration of blocking antibodies against either interleukin (IL)-10, transforming growth factor (TGF)-β or program death (PD)-1, revealed that the protective effects of IFN-γ in EAE were also dependent on TGF-β and PD-1, but not on IL-10, suggesting that IFN-γ might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-γ treatment increased the frequency of a subset of splenic CD11b+ myeloid cells expressing TGF-β-Latency Associated Peptide (LAP) and program death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)-1-dependent manner. Furthermore, splenic CD11b+ cells from EAE mice preconditioned in vitro with IFN-γ and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of naïve CD4+ T cells mediated by secretion of TGF-β. Remarkably, adoptive transfer of splenic CD11b+ cells from IFN-γ-treated EAE mice into untreated recipient mice ameliorated clinical symptoms of EAE and limited central nervous system infiltration of mononuclear cells and effector helper T cells. These results reveal a novel cellular and molecular mechanism whereby IFN-γ promotes beneficial effects in EAE by endowing splenic CD11b+ myeloid cells with tolerogenic and therapeutic activities.
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MESH Headings
- Animals
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/drug therapy
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Mice
- Interferon-gamma/metabolism
- Myeloid Cells/drug effects
- Myeloid Cells/immunology
- Myeloid Cells/metabolism
- Spleen/immunology
- Mice, Inbred C57BL
- CD11b Antigen/metabolism
- Female
- Myelin-Oligodendrocyte Glycoprotein/toxicity
- Myelin-Oligodendrocyte Glycoprotein/immunology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/drug effects
- Peptide Fragments/toxicity
- Peptide Fragments/pharmacology
- Transforming Growth Factor beta/metabolism
- Programmed Cell Death 1 Receptor/metabolism
- Programmed Cell Death 1 Receptor/immunology
- Forkhead Transcription Factors/metabolism
- Disease Models, Animal
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Affiliation(s)
- Gabriel Arellano
- Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Eric Acuña
- Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Eileah Loda
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Lindsay Moore
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Juan E Tichauer
- Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Cristian Castillo
- Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Fabian Vergara
- Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Paula I Burgos
- Department of Clinical Immunology and Rheumatology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo Penaloza-MacMaster
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US
| | - Stephen D Miller
- Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US.
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, US.
| | - Rodrigo Naves
- Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
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7
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Soongsathitanon J, Homjan T, Pongcharoen S. Characteristic features of in vitro differentiation of human naïve CD4 + T cells to induced regulatory T cells (iTreg) and T helper (Th) 17 cells: Sharing of lineage-specific markers. Heliyon 2024; 10:e31394. [PMID: 38807879 PMCID: PMC11130651 DOI: 10.1016/j.heliyon.2024.e31394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/30/2024] Open
Abstract
In vitro induced regulatory T cells (iTreg) and IL-17 producing T cells (Th17-like cells) can be generated in culture from native CD4+ T cells in peripheral blood by different sets of cytokines. In the presence of transforming growth factor (TGF)-β plus interleukin (IL)-2, cells differentiate into Treg cells with increased expression of the forkhead box P3 (FOXP3). In the presence of TGF-β, IL-6, IL-1β and IL-23, cells differentiate into Th17 cells that produce IL-17A. However, protocols for the generation of human iTreg and Th17 are still controversial. In this study, we characterized the biological features of iTreg and Th17 cells differentiated from peripheral blood naïve CD4+ T cells in vitro using the established protocols. We showed that cells obtained from Treg or Th17 culture conditions shared some phenotypic markers. Cells under Treg conditions had an up-regulated FOXP3 gene and a down-regulated RAR-related orphan receptor C (RORC) gene. Cells derived from the Th17 condition exhibited a down-regulated FOXP3 gene and had significantly higher RORC gene expression than Treg cells. Both resulting cells showed intracellular production of IL-17A and IL-10. Th17 condition-cultured cells exhibited more glycolytic activity and glucose uptake compared to the Treg cells. The findings suggest that cells obtained from established protocols for the differentiation of iTreg and Th17 cells in vitro are possibly in the intermediate stage of differentiation or may be two different types of cells that share a lineage-specific differentiation program.
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Affiliation(s)
- Jarupa Soongsathitanon
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Ticha Homjan
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Suthatip Pongcharoen
- Division of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok, 65000, Thailand
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8
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Li V, Binder MD, Purcell AW, Kilpatrick TJ. Antigen-specific immunotherapy via delivery of tolerogenic dendritic cells for multiple sclerosis. J Neuroimmunol 2024; 390:578347. [PMID: 38663308 DOI: 10.1016/j.jneuroim.2024.578347] [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: 02/12/2024] [Revised: 03/22/2024] [Accepted: 04/17/2024] [Indexed: 05/13/2024]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system resulting from loss of immune tolerance. Many disease-modifying therapies for MS have broad immunosuppressive effects on peripheral immune cells, but this can increase risks of infection and attenuate vaccine-elicited immunity. A more targeted approach is to re-establish immune tolerance in an autoantigen-specific manner. This review discusses methods to achieve this, focusing on tolerogenic dendritic cells. Clinical trials in other autoimmune diseases also provide learnings with regards to clinical translation of this approach, including identification of autoantigen(s), selection of appropriate patients and administration route and frequency.
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Affiliation(s)
- Vivien Li
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, Australia.
| | - Michele D Binder
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia
| | - Anthony W Purcell
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
| | - Trevor J Kilpatrick
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, Australia
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9
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Park SY, Yang J, Yang H, Cho I, Kim JY, Bae H. Therapeutic Effects of Aβ-Specific Regulatory T Cells in Alzheimer's Disease: A Study in 5xFAD Mice. Int J Mol Sci 2024; 25:783. [PMID: 38255856 PMCID: PMC10815725 DOI: 10.3390/ijms25020783] [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: 12/15/2023] [Revised: 01/05/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The aging global population is placing an increasing burden on healthcare systems, and the social impact of Alzheimer's disease (AD) is on the rise. However, the availability of safe and effective treatments for AD remains limited. Adoptive Treg therapy has been explored for treating neurodegenerative diseases, including AD. To facilitate the clinical application of Treg therapy, we developed a Treg preparation protocol and highlighted the therapeutic effects of Tregs in 5xFAD mice. CD4+CD25+ Tregs, isolated after Aβ stimulation and expanded using a G-rex plate with a gas-permeable membrane, were adoptively transferred into 5xFAD mice. Behavioral analysis was conducted using Y-maze and passive avoidance tests. Additionally, we measured levels of Aβ, phosphorylated tau (pTAU), and nitric oxide synthase 2 (NOS2) in the hippocampus. Real-time RT-PCR was employed to assess the mRNA levels of pro- and anti-inflammatory markers. Our findings indicate that Aβ-specific Tregs not only improved cognitive function but also reduced Aβ and pTAU accumulation in the hippocampus of 5xFAD mice. They also inhibited microglial neuroinflammation. These effects were observed at doses as low as 1.5 × 103 cells/head. Collectively, our results demonstrate that Aβ-specific Tregs can mitigate AD pathology in 5xFAD mice.
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Affiliation(s)
- Seon-Young Park
- Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (S.-Y.P.); (H.Y.)
| | - Juwon Yang
- Department of Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (J.Y.); (I.C.)
| | - Hyejin Yang
- Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (S.-Y.P.); (H.Y.)
| | - Inhee Cho
- Department of Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (J.Y.); (I.C.)
| | - Jae Yoon Kim
- Institute of Life Science & Biotechnology, VT Bio. Co., Ltd., 16 Samseong-ro 76-gil, Gangnam-gu, Seoul 06185, Republic of Korea;
| | - Hyunsu Bae
- Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (S.-Y.P.); (H.Y.)
- Department of Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea; (J.Y.); (I.C.)
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Greilach SA, McIntyre LL, Nguyen QH, Silva J, Kessenbrock K, Lane TE, Walsh CM. Presentation of Human Neural Stem Cell Antigens Drives Regulatory T Cell Induction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1677-1686. [PMID: 37083696 PMCID: PMC10192095 DOI: 10.4049/jimmunol.2200798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 03/30/2023] [Indexed: 04/22/2023]
Abstract
Transplantation of human neural stem cells (hNSCs) is a promising regenerative therapy to promote remyelination in patients with multiple sclerosis (MS). Transplantation of hNSCs has been shown to increase the number of CD4+CD25+Foxp3+ T regulatory cells (Tregs) in the spinal cords of murine models of MS, which is correlated with a strong localized remyelination response. However, the mechanisms by which hNSC transplantation leads to an increase in Tregs in the CNS remains unclear. We report that hNSCs drive the conversion of T conventional (Tconv) cells into Tregs in vitro. Conversion of Tconv cells is Ag driven and fails to occur in the absence of TCR stimulation by cognate antigenic self-peptides. Furthermore, CNS Ags are sufficient to drive this conversion in the absence of hNSCs in vitro and in vivo. Importantly, only Ags presented in the thymus during T cell selection drive this Treg response. In this study, we investigate the mechanisms by which hNSC Ags drive the conversion of Tconv cells into Tregs and may provide key insight needed for the development of MS therapies.
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Affiliation(s)
- Scott A. Greilach
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, 92697
| | - Laura L. McIntyre
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, 92697
| | - Quy H. Nguyen
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697
| | - Jorge Silva
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, 92697
| | - Kai Kessenbrock
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA, 92697
| | - Thomas E. Lane
- Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, 92697
| | - Craig M. Walsh
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, 92697
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Tarighi M, Shahbazi M, Saadat P, Daraei A, Alizadeh Khatir A, Rahimifard K, Mohammadnia-Afrouzi M. Decreased frequency of regulatory T cells and level of helios gene expression in secondary progressive multiple sclerosis patients: Evidence about the development of multiple sclerosis. Int Immunopharmacol 2023; 116:109797. [PMID: 36738680 DOI: 10.1016/j.intimp.2023.109797] [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: 11/12/2022] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Multiple sclerosis (MS) is an aggressive disease characterized by central nervous system (CNS) inflammatory and demyelinating lesions. Tolerance failure is implicated in the development of several autoimmune disorders, including MS. Due to their involvement in maintaining environmental tolerance, regulatory T cells (Tregs) are regarded as efficient immune cells. We examined the frequency of Tregs in this study using CD4/CD25/forkhead box protein P3 (FOXP3)/Helios markers. METHODS Fifty participants, including 25 patients with secondary progressive MS (SPMS) and 25 healthy controls (HCs), were enrolled in this study, and their demographic characteristics were recorded. Peripheral blood samples ranging from 5 to 6 mL were obtained, and the Ficoll technique was used to extract peripheral blood mononuclear cells (PBMCs). Then, the percentage of CD4+CD25+FOXP3+Helios+ regulatory T lymphocytes was examined by flow cytometry in the study groups. Real-time polymerase chain reaction (PCR) was also used to assess the Helios gene expression level. RESULTS This study showed that the percentage of Tregs with CD4 and CD25 markers did not reveal a significant difference compared with HCs despite the decrease in SPMS patients (P = 0.6). However, lymphocytes with CD4/CD25/FOXP3/Helios markers were significantly reduced in the patients (P = 0.01). Additionally, SPMS patients had statistically significantly lower Helios gene expression levels (P = 0.002). CONCLUSION In SPMS patients, a decrease in the frequency of the CD4+CD25+FOXP3+Helios+ Treg population can result in an imbalanced immune system. In other words, one of the immunological mechanisms involved in this disease may be a deficiency in Tregs. Helios gene expression was also decreased in these patients, which may exacerbate functional defects in Tregs.
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Affiliation(s)
- Mona Tarighi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Shahbazi
- Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Payam Saadat
- Mobility Impairment Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Abdolreza Daraei
- Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Medical Genetics, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ali Alizadeh Khatir
- Mobility Impairment Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Kimiya Rahimifard
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mousa Mohammadnia-Afrouzi
- Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran.
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12
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Halder S, Chatterjee S. Bistability regulates TNFR2-mediated survival and death of T-regulatory cells. J Biol Phys 2023; 49:95-119. [PMID: 36780123 PMCID: PMC9958227 DOI: 10.1007/s10867-023-09625-3] [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: 10/15/2022] [Accepted: 01/13/2023] [Indexed: 02/14/2023] Open
Abstract
A subgroup of T cells called T-regulatory cells (Tregs) regulates the body's immune responses to maintain homeostasis and self-tolerance. Tregs are crucial for preventing illnesses like cancer and autoimmunity. However, contrasting patterns of Treg frequency are observed in different autoimmune diseases. The commonality of tumour necrosis factor receptor 2 (TNFR2) defects and decrease in Treg frequency on the onset of autoimmunity demands an in-depth study of the TNFR2 pathway. To unravel this mystery, we need to study the mechanism of cell survival and death in Tregs. Here, we construct an ordinary differential equation (ODE)-based model to capture the mechanism of cell survival and apoptosis in Treg cells via TNFR2 signalling. The sensitivity analysis reveals that the input stimulus, the concentration of tumour necrosis factor (TNF), is the most sensitive parameter for the model system. The model shows that the cell goes into survival or apoptosis via bistable switching. Through hysteretic switching, the system tries to cope with the changing stimuli. In order to understand how stimulus strength and feedback strength influence cell survival and death, we compute bifurcation diagrams and obtain cell fate maps. Our results indicate that the elevated TNF concentration and increased c-Jun N-terminal kinase (JNK) phosphorylation are the major contributors to the death of T-regulatory cells. Biological evidence cements our hypothesis and can be controlled by reducing the TNF concentration. Finally, the system was studied under stochastic perturbation to see the effect of noise on the system's dynamics. We observed that introducing random perturbations disrupts the bistability, reducing the system's bistable region, which can affect the system's normal functioning.
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Affiliation(s)
- Suvankar Halder
- Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001 Haryana India
| | - Samrat Chatterjee
- Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, 121001 Haryana India
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13
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Frequency and function of circulating regulatory T-cells in biliary atresia. Pediatr Surg Int 2022; 39:23. [PMID: 36449184 DOI: 10.1007/s00383-022-05307-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 12/03/2022]
Abstract
PURPOSE Although the impairment of regulatory T-cells (Tregs) has been shown in the liver or portal area of biliary atresia (BA) the frequency and function of circulating Tregs in BA patients is poorly understood. We aimed to investigate the frequency and function of circulating Tregs in BA patients. METHODS Peripheral blood mononuclear cells were collected from 25 BA patients and 24 controls. Treg frequency was measured by flow cytometry; function was determined by T-cell proliferation assay. We also assessed the association between Treg frequency/function and clinical parameters in BA cases. RESULTS There was no significant difference between the two groups in both frequency (BA: 3.4%; control: 3.2%; p = 0.97) and function (BA: 22.0%; control: 7.5%; p = 0.23) of Tregs. We further focused on 13 preoperative BA patients and 14 age-matched controls. Neither Treg frequency nor function were significantly different (frequency: BA: 4.6%; control: 3.4%; p = 0.38, function: BA: 2.7%; control: 7.6%; p = 0.89). There was no association between Treg frequency/function and clinical parameters. CONCLUSION Neither the frequency nor function of circulating Tregs was affected in BA patients, suggesting the negative role of circulating Tregs in the pathogenesis of BA. Further investigation of local Treg profiles is warranted.
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14
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Single-Cell Analysis to Better Understand the Mechanisms Involved in MS. Int J Mol Sci 2022; 23:ijms232012142. [PMID: 36292995 PMCID: PMC9602568 DOI: 10.3390/ijms232012142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/01/2022] [Accepted: 10/03/2022] [Indexed: 11/17/2022] Open
Abstract
Multiple sclerosis is a chronic and inflammatory disease of the central nervous system. Although this disease is widely studied, many of the precise mechanisms involved are still not well known. Numerous studies currently focusing on multiple sclerosis highlight the involvement of many major immune cell subsets, such as CD4+ T cells, CD8+ T cells and more recently B cells. However, our vision of its pathology has remained too broad to allow the proper use of targeted therapeutics. This past decade, new technologies have emerged, enabling deeper research into the different cell subsets at the single-cell level both in the periphery and in the central nervous system. These technologies could allow us to identify new cell populations involved in the disease process and new therapeutic targets. In this review, we briefly introduce the major single-cell technologies currently used in studies before diving into the major findings from the multiple sclerosis research from the past 5 years. We focus on results that were obtained using single-cell technologies to study immune cells and cells from the central nervous system.
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Abstract
Inflammation is a biological process that dynamically alters the surrounding microenvironment, including participating immune cells. As a well-protected organ surrounded by specialized barriers and with immune privilege properties, the central nervous system (CNS) tightly regulates immune responses. Yet in neuroinflammatory conditions, pathogenic immunity can disrupt CNS structure and function. T cells in particular play a key role in promoting and restricting neuroinflammatory responses, while the inflamed CNS microenvironment can influence and reshape T cell function and identity. Still, the contraction of aberrant T cell responses within the CNS is not well understood. Using autoimmunity as a model, here we address the contribution of CD4 T helper (Th) cell subsets in promoting neuropathology and disease. To address the mechanisms antagonizing neuroinflammation, we focus on the control of the immune response by regulatory T cells (Tregs) and describe the counteracting processes that preserve their identity under inflammatory challenges. Finally, given the influence of the local microenvironment on immune regulation, we address how CNS-intrinsic signals reshape T cell function to mitigate abnormal immune T cell responses.
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Affiliation(s)
- Nail Benallegue
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000, Nantes, France
| | - Hania Kebir
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Jorge I. Alvarez
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Ashtari F, Madanian R, Zarkesh SH, Ghalamkari A. Serum levels of interleukin-6 and Vitamin D at the onset of multiple sclerosis and neuromyelitis optica: A pilot study. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2022; 27:67. [PMID: 36353347 PMCID: PMC9639709 DOI: 10.4103/jrms.jrms_796_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 02/07/2022] [Accepted: 05/10/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Interleukin-6 (IL-6) is an important mediator in the acute phase of inflammatory diseases such as neuromyelitis optica (NMO) and multiple sclerosis (MS). The level of IL-6 is higher in cerebrospinal fluid and serum of NMO patients compare to MS. Vitamin D has a regulatory effect on IL-6, so it may have a negative correlation with IL-6 in the acute phase of these diseases. This study was performed to evaluate the serum levels of IL-6 and Vitamin D in NMO and MS patients at the onset of disease to find differences that may help in early diagnosis. MATERIALS AND METHODS This case-control study was done on patients with the first episode of optic neuritis, transverse myelitis, and area postrema syndrome who were referred to Kashani MS Center in Isfahan, Iran, between January 2018 and January 2020. The serum levels of Vitamin D and IL-6 were assessed using enzyme-linked immunosorbent assay in blood sample taken at the time of first presentation in patients who had a definitive diagnosis of NMO and MS during subsequent workup. RESULTS During a 2-year follow-up, definitive diagnosis of NMO was given in 25 cases, and they were compared with 25 cases that were randomly selected from patients with definite MS. Nineteen patients in the NMO group and 21 patients in the MS group were female. The mean age of patients in the NMO and MS groups was 29.64 ± 1.47 and 30.20 ± 1.42, respectively (P = 0.46). The mean of serum level of Vitamin D was 24.88 ± 15.2 in NMO patients and 21.56 ± 18.7 in MS patients without significant difference (P = 0.48). The mean of IL-6 was 30.1 ± 22.62 in the NMO group and 23.35 ± 18.8 in the MS group without significant difference (P = 0.28). The serum levels of Vitamin D were insufficient in both groups. No correlation between Vitamin D and IL-6 levels was found in our study (P > 0.05). CONCLUSION Our results showed that serum IL-6 levels were higher at the onset of NMO disease compared with MS. The serum levels of Vitamin D were low in both groups and there was no association between serum levels of Vitamin D and IL-6 in either group. Future studies with large sample size are needed to confirm these findings.
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Affiliation(s)
- Fereshteh Ashtari
- Isfahan Neuroscience Research Center, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Reyhanehsadat Madanian
- Isfahan Neuroscience Research Center, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Sayyed Hamid Zarkesh
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arshia Ghalamkari
- Isfahan Neuroscience Research Center, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
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Schlöder J, Shahneh F, Schneider FJ, Wieschendorf B. Boosting regulatory T cell function for the treatment of autoimmune diseases – That’s only half the battle! Front Immunol 2022; 13:973813. [PMID: 36032121 PMCID: PMC9400058 DOI: 10.3389/fimmu.2022.973813] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/18/2022] [Indexed: 01/04/2023] Open
Abstract
Regulatory T cells (Treg) represent a subset of specialized T cells that are essential for the regulation of immune responses and maintenance of peripheral tolerance. Once activated, Treg exert powerful immunosuppressive properties, for example by inhibiting T cell-mediated immune responses against self-antigens, thereby protecting our body from autoimmunity. Autoimmune diseases such as multiple sclerosis, rheumatoid arthritis or systemic lupus erythematosus, exhibit an immunological imbalance mainly characterized by a reduced frequency and impaired function of Treg. In addition, there has been increasing evidence that – besides Treg dysfunction – immunoregulatory mechanisms fail to control autoreactive T cells due to a reduced responsiveness of T effector cells (Teff) for the suppressive properties of Treg, a process termed Treg resistance. In order to efficiently treat autoimmune diseases and thus fully induce immunological tolerance, a combined therapy aimed at both enhancing Treg function and restoring Teff responsiveness could most likely be beneficial. This review provides an overview of immunomodulating drugs that are currently used to treat various autoimmune diseases in the clinic and have been shown to increase Treg frequency as well as Teff sensitivity to Treg-mediated suppression. Furthermore, we discuss strategies on how to boost Treg activity and function, and their potential use in the treatment of autoimmunity. Finally, we present a humanized mouse model for the preclinical testing of Treg-activating substances in vivo.
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Affiliation(s)
- Janine Schlöder
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- ActiTrexx GmbH, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- *Correspondence: Janine Schlöder,
| | - Fatemeh Shahneh
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Franz-Joseph Schneider
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- ActiTrexx GmbH, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Björn Wieschendorf
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- ActiTrexx GmbH, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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Golabi M, Fathi F, Samadi M, Hesamian MS, Eskandari N. Identification of Potential Biomarkers in the Peripheral Blood Mononuclear Cells of Relapsing-Remitting Multiple Sclerosis Patients. Inflammation 2022; 45:1815-1828. [PMID: 35347537 DOI: 10.1007/s10753-022-01662-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 02/07/2022] [Accepted: 03/10/2022] [Indexed: 11/26/2022]
Abstract
Multiple sclerosis (MS) is described as an immune disorder with inflammation and neurodegeneration. Relapsing-remitting MS (RRMS) is one of the most common types of MS. The diagnostic manner for this disorder typically includes the usage of magnetic resonance imaging (MRI); however, this is not always a very precise diagnostic method. Identification of molecular biomarkers in RRMS body fluids samples compared to healthy subjects can be useful to indicate the normal and pathogenic biological processes or pharmacological responses to drug interaction. In this regard, this study evaluated different miRNAs in isolated peripheral blood mononuclear cells (PBMCs) of RRMS compared to controls and their correlations with altered T regulatory type 1 (Tr1) cells, osteopontin (OPN), and interleukin 10 (IL-10) levels. The frequency of Tr1 cells was measured using flow cytometry. Also, the expressions of different miRNAs were evaluated via quantitative real-time polymerase chain reaction (RT-qPCR) and plasma levels of IL-10 and OPN were tested by enzyme-linked immunosorbent assay (ELISA). The obtained results showed the Tr1 cells' frequency, Let7c-5p, and miR-299-5p levels decreased in RRMS patients to about 59%, 0.69%, and 20% of HCs, respectively, (P < 0.05). The miR-106a-5p levels increased about 7.5-fold in RRMS patients in comparison to HCs (P < 0.05). Moreover, the results showed that there was an increased negative association between Tr1 frequency and plasma-OPN levels in RRMS patients in comparison to HCs and also, we found a moderate positive correlation between plasma-IL-10 and miR-299-5p expression of RRMS patients. Overall, it may be possible to use these biomarkers to improve the diagnostic process. These biomarkers may also be considered for clinical and therapeutic studies in the future.
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Affiliation(s)
- Marjan Golabi
- Department of Medical Immunology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Farshid Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morteza Samadi
- Recurrent Abortion Research Center, Research and Clinical Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
- Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
- Research Center for Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | - Mohammad Sadegh Hesamian
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Eskandari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Vafaei-Nezhad S, Niknazar S, Payvandi AA, Shirazi Tehrani A, Ahmady Roozbahany N, Ahrabi B, Abbaszadeh HA, Darabi S. Therapeutic Effects of Photobiomodulation Therapy on Multiple Sclerosis by Regulating the Inflammatory Process and Controlling Immune Cell Activity: A Novel Promising Treatment Target. J Lasers Med Sci 2022; 13:e32. [PMID: 36743142 PMCID: PMC9841388 DOI: 10.34172/jlms.2022.32] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/25/2022] [Indexed: 11/22/2022]
Abstract
Introduction: Multiple sclerosis (MS) is one of the autoimmune and chronic diseases of the central nervous system; this disease occurs more frequently in young people and women and leads to neurological symptoms. Oxidative stress, inflammatory processes, and oligodendrocyte dysfunction have a pivotal role in the pathophysiology of this disease. Nowadays it is reported that photobiomodulation (PBM) as a non-invasive treatment has neuroprotective potential, but the exact mechanisms are not understood. Methods: In this study, we reviewed the effects of PBM on MS. In this regard, we used the keywords "Photobiomodulation", "Laser therapy", and "Low-level laser therapy" on MS to find related studies on this subject in PubMed, Google scholar, Elsevier, Medline, and Scopus databases. Results: PBM has positive effects on MS by regulating the inflammatory process, controlling immune cell activity and mitochondrial functions, as well as inhibiting free radicals production which finally leads to a reduction in neurological defects and an improvement in the functional status of patients. Conclusion: Overall, researchers have suggested the use of laser therapy in neurodegenerative diseases due to its numerous therapeutic effects.
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Affiliation(s)
- Saeed Vafaei-Nezhad
- Department of Anatomical Sciences, School of Medicine, Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran,Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Niknazar
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Asghar Payvandi
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefeh Shirazi Tehrani
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Navid Ahmady Roozbahany
- Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behnaz Ahrabi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hojjat Allah Abbaszadeh
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Hearing Disorders Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran,Correspondence to Hojjat Allah Abbaszadeh, Hearing Disorders Research Center, Loghman Hakim Hospital;
; Shahram Darabi, Cellular and Molecular Research Center, Research Institute for NonCommunicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran;
| | - Shahram Darabi
- Cellular and Molecular Research Center, Research Institute for Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran,Correspondence to Hojjat Allah Abbaszadeh, Hearing Disorders Research Center, Loghman Hakim Hospital;
; Shahram Darabi, Cellular and Molecular Research Center, Research Institute for NonCommunicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran;
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Canto-Gomes J, Silva CS, Rb-Silva R, Boleixa D, da Silva AM, Cheynier R, Costa P, González-Suárez I, Correia-Neves M, Cerqueira JJ, Nobrega C. Low Memory T Cells Blood Counts and High Naïve Regulatory T Cells Percentage at Relapsing Remitting Multiple Sclerosis Diagnosis. Front Immunol 2022; 13:901165. [PMID: 35711452 PMCID: PMC9196633 DOI: 10.3389/fimmu.2022.901165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/22/2022] [Indexed: 11/30/2022] Open
Abstract
Objective The aim of this study is to assess the peripheral immune system of newly diagnosed patients with relapsing remitting multiple sclerosis (RRMS) and compare it to healthy controls (HC). Methods This cross-sectional study involves 30 treatment-naïve newly diagnosed patients with RRMS and 33 sex- and age-matched HC. Peripheral blood mononuclear cells were analyzed regarding: i) thymic function surrogates [T cell receptor excision circles (TRECs) and recent thymic emigrants (RTEs)]; ii) naïve and memory CD4+ and CD8+ T cells subsets; iii) T helper (Th) phenotype and chemokine receptors expression on CD8+ T cells subsets; iv) regulatory T cell (Tregs) phenotype; and exclude expression of activating/inhibitory receptors by natural killer (NK) and NKT cells. Analyses were controlled for age, sex, and human cytomegalovirus (HCMV) IgG seroprevalence. Results Newly diagnosed patients with RRMS and HC have equivalent thymic function as determined by similar numbers of RTEs and levels of sjTRECs, DJβTRECs, and sj/DJβTREC ratio. In the CD8+ T cells compartment, patients with RRMS have a higher naive to memory ratio and lower memory cell counts in blood, specifically of effector memory and TemRA CD8+ T cells. Interestingly, higher numbers and percentages of central memory CD8+ T cells are associated with increasing time from the relapse. Among CD4+ T cells, lower blood counts of effector memory cells are found in patients upon controlling for sex, age, and anti-HCMV IgG seroprevalence. Higher numbers of CD4+ T cells (both naïve and memory) and of Th2 cells are associated with increasing time from the relapse; lower numbers of Th17 cells are associated with higher MS severity scores (MSSS). Patients with RRMS have a higher percentage of naïve Tregs compared with HC, and lower percentages of these cells are associated with higher MSSS. Percentages of immature CD56bright NK cells expressing the inhibitory receptor KLRG1 and of mature CD56dimCD57+ NK cells expressing NKp30 are higher in patients. No major alterations are observed on NKT cells. Conclusion Characterization of the peripheral immune system of treatment-naïve newly diagnosed patients with RRMS unveiled immune features present at clinical onset including lower memory T cells blood counts, particularly among CD8+ T cells, higher percentage of naïve Tregs and altered percentages of NK cells subsets expressing inhibitory or activating receptors. These findings might set the basis to better understand disease pathogenesis.
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Affiliation(s)
- João Canto-Gomes
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
| | - Carolina S. Silva
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
- Division of Infectious Diseases and Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Rita Rb-Silva
- Department of Onco-Hematology, Portuguese Institute of Oncology of Porto, Porto, Portugal
- Laboratory of Histology and Embryology, Department of Microscopy, ICBAS, University of Porto, Porto, Portugal
| | | | - Ana Martins da Silva
- Porto University Hospital Center, Porto, Portugal
- Multidisciplinary Unit for Biomedical Research (UMIB) - Instituto de Ciências Biomédicas Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Rémi Cheynier
- Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France
| | - Patrício Costa
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
| | - Inés González-Suárez
- University Hospital Complex of Vigo, Vigo, Spain
- Álvaro Cunqueiro Hospital, Vigo, Spain
| | - Margarida Correia-Neves
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
- Division of Infectious Diseases and Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - João J. Cerqueira
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
- Hospital of Braga, Braga, Portugal
- Clinical Academic Centre, Hospital of Braga, Braga, Portugal
| | - Claudia Nobrega
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s, PT Government Associate Laboratory, Braga, Portugal
- *Correspondence: Claudia Nobrega,
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21
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Guo F, Hancock B, Griffith A, Lin H, Howard K, Keegan J, Zhang F, Chicoine A, Cahill L, Ng J, Lederer J. Distinct Injury Responsive Regulatory T Cells Identified by Multi-Dimensional Phenotyping. Front Immunol 2022; 13:833100. [PMID: 35634302 PMCID: PMC9135044 DOI: 10.3389/fimmu.2022.833100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/11/2022] [Indexed: 01/21/2023] Open
Abstract
CD4+ regulatory T cells (Tregs) activate and expand in response to different types of injuries, suggesting that they play a critical role in controlling the immune response to tissue and cell damage. This project used multi-dimensional profiling techniques to comprehensively characterize injury responsive Tregs in mice. We show that CD44high Tregs expand in response to injury and were highly suppressive when compared to CD44low Tregs. T cell receptor (TCR) repertoire analysis revealed that the CD44high Treg population undergo TCRαβ clonal expansion as well as increased TCR CDR3 diversity. Bulk RNA sequencing and single-cell RNA sequencing with paired TCR clonotype analysis identified unique differences between CD44high and CD44low Tregs and specific upregulation of genes in Tregs with expanded TCR clonotypes. Gene ontology analysis for molecular function of RNA sequencing data identified chemokine receptors and cell division as the most enriched functional terms in CD44high Tregs versus CD44low Tregs. Mass cytometry (CyTOF) analysis of Tregs from injured and uninjured mice verified protein expression of these genes on CD44high Tregs, with injury-induced increases in Helios, Galectin-3 and PYCARD expression. Taken together, these data indicate that injury triggers the expansion of a highly suppressive CD44high Treg population that is transcriptionally and phenotypically distinct from CD44low Tregs suggesting that they actively participate in controlling immune responses to injury and tissue damage.
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Affiliation(s)
- Fei Guo
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, China
| | - Brandon Hancock
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Alec Griffith
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Hui Lin
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
| | - Kaitlyn Howard
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Joshua Keegan
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Fan Zhang
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
- Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Adam Chicoine
- Human Immunology Center, Brigham and Women’s Hospital, Boston, MA, United States
| | - Laura Cahill
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Julie Ng
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, United States
| | - James Lederer
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
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22
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Hossein-khannazer N, Kazem Arki M, Keramatinia A, Rezaei-Tavirani M. The Role of Low-Level Laser Therapy in the Treatment of Multiple Sclerosis: A Review Study. J Lasers Med Sci 2021; 12:e88. [PMID: 35155173 PMCID: PMC8837843 DOI: 10.34172/jlms.2021.88] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/25/2021] [Indexed: 11/12/2023]
Abstract
Introduction: Multiple sclerosis (MS) is an autoimmune disease. Inflammatory cells, cytokines and chemokines play a major role in the pathogenesis of the disease. Low-level laser therapy (LLLT) as a photobiostimulation approach could affect a wide range of cellular responses. LLLT inhibits the inflammatory signaling pathway, improves cell viability, inhibits apoptosis, modulates immune responses and induces the production of growth factors. Methods: In this review, we discuss the effect of LLLT on cellular responses and its application in the treatment of MS. Such keywords as "low-level laser therapy", "photobiomodulation" and "multiple sclerosis" were used to find studies related to laser therapy in MS in Google scholar, PubMed and Medline databases. Results: LLLT reduced the inflammatory immune cells and mediators. It also enhanced the regeneration of neurons. Conclusion: Investigations showed that besides current treatment strategies, LLLT could be a promising therapeutic approach for the treatment of MS.
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Affiliation(s)
- Nikoo Hossein-khannazer
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mandana Kazem Arki
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aliasghar Keramatinia
- Department of Social Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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23
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Modulation of Tregs and iNKT by Fingolimod in Multiple Sclerosis Patients. Cells 2021; 10:cells10123324. [PMID: 34943831 PMCID: PMC8699557 DOI: 10.3390/cells10123324] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 11/17/2022] Open
Abstract
The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127- cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14-CD19- Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4-CD8- double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY.
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24
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Schroeter CB, Huntemann N, Bock S, Nelke C, Kremer D, Pfeffer K, Meuth SG, Ruck T. Crosstalk of Microorganisms and Immune Responses in Autoimmune Neuroinflammation: A Focus on Regulatory T Cells. Front Immunol 2021; 12:747143. [PMID: 34691057 PMCID: PMC8529161 DOI: 10.3389/fimmu.2021.747143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 09/20/2021] [Indexed: 12/22/2022] Open
Abstract
Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.
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Affiliation(s)
- Christina B Schroeter
- Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Niklas Huntemann
- Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Stefanie Bock
- Department of Neurology With Institute of Translational Neurology, University of Münster, Münster, Germany
| | - Christopher Nelke
- Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - David Kremer
- Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Klaus Pfeffer
- Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Sven G Meuth
- Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Tobias Ruck
- Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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25
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Avşar T, Çelikyapi Erdem G, Terzioğlu G, Tahir Turanli E. Investigation of neuro-inflammatory parameters in a cuprizone induced mouse model of multiple sclerosis. Turk J Biol 2021; 45:644-655. [PMID: 34803461 PMCID: PMC8574193 DOI: 10.3906/biy-2104-88] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/27/2021] [Indexed: 01/02/2023] Open
Abstract
Cuprizone, copper chelator, treatment of mouse is a toxic model of multiple sclerosis (MS) in which oligodendrocyte death, demyelination and remyelination can be observed. Understanding T and B cell subset as well as their cytokines involved in MS pathogenesis still requires further scrutiny to better understand immune component of MS. The study presented here, aimed to evaluate relevant cytokines, lymphocytes, and gene expressions profiles during demyelination and remyelination in the cuprizone mouse model of MS. Eighty male C57BL/6J mice fed with 0.2% cuprizone for eight weeks. Cuprizone has been removed from the diet in the following eight weeks. Cuprizone treated and control mice sacrificed biweekly, and corpus callosum of the brain was investigated by staining. Lymphocyte cells of mice analyzed by flow cytometry with CD3e, CD11b, CD19, CD80, CD86, CD4, CD25 and FOXP3 antibodies. IFN-gamma, IL-1alpha, IL-2, IL-5, IL-6, IL-10, IL-17, TNF-alpha cytokines were analyzed in plasma samples. Neuregulin 1 (Nrg1), ciliary neurotrophic factor (Cntf) and C-X-C chemokine receptor type 4 (Cxcr4) gene expressions in corpus callosum sections of the mice brain were quantified. Histochemistry analysis showed that demyelination began at the fourth week of cuprizone administration and total demyelination occurred at the twelfth week in chronic model. Remyelination occurred at the fourth week of following withdrawal of cuprizone from diet. The level of mature and activated T cells, regulatory T cells, T helper cells and mature B cells increased during demyelination and decreased when cuprizone removed from diet. Further, both type 1 and type 2 cytokines together with the proinflammatory cytokines increased. The level of oligodendrocyte maturation and survival genes showed differential gene expression in parallel to that of demyelination and remyelination. In conclusion, for the first-time, involvement of both cellular immune response and antibody response as well as oligodendrocyte maturation and survival factors having role in demyelination and remyelination of cuprizone mouse model of MS have been shown.
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Affiliation(s)
- Timucin Avşar
- Medical Biology Department, School of Medicine, Bahçeşehir University, İstanbul Turkey
| | - Gökçe Çelikyapi Erdem
- Dr. Orhan Ocalgiray Molecular Biology and Genetics Research Center, İstanbul Technical University, İstanbul Turkey
| | - Gökhan Terzioğlu
- Department of Biotechnology, Institute of Science, Yeditepe University, İstanbul Turkey
| | - Eda Tahir Turanli
- Dr. Orhan Ocalgiray Molecular Biology and Genetics Research Center, İstanbul Technical University, İstanbul Turkey
- Molecular Biology and Genetics Department, Acıbadem University, İstanbul Turkey
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26
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Murúa SR, Farez MF, Quintana FJ. The Immune Response in Multiple Sclerosis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:121-139. [PMID: 34606377 DOI: 10.1146/annurev-pathol-052920-040318] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative disease that affects the central nervous system (CNS). MS is characterized by immune dysregulation, which results in the infiltration of the CNS by immune cells, triggering demyelination, axonal damage, and neurodegeneration. Although the exact causes of MS are not fully understood, genetic and environmental factors are thought to control MS onset and progression. In this article, we review the main immunological mechanisms involved in MS pathogenesis. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Sofía Rodríguez Murúa
- Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina;
| | - Mauricio F Farez
- Center for Research on Neuroimmunological Diseases (CIEN), Raúl Carrea Institute for Neurological Research (FLENI), Buenos Aires 1428, Argentina;
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
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27
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Hu W, Wang ZM, Feng Y, Schizas M, Hoyos BE, van der Veeken J, Verter JG, Bou-Puerto R, Rudensky AY. Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity. Nat Immunol 2021; 22:1163-1174. [PMID: 34426690 PMCID: PMC9341271 DOI: 10.1038/s41590-021-01001-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 07/14/2021] [Indexed: 12/22/2022]
Abstract
The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.
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Affiliation(s)
- Wei Hu
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Zhong-Min Wang
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yongqiang Feng
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Michail Schizas
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Beatrice E Hoyos
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joris van der Veeken
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria
| | - Jacob G Verter
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Regina Bou-Puerto
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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28
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Ito K, Ito N, Yadav SK, Suresh S, Lin Y, Dhib-Jalbut S. Effect of switching glatiramer acetate formulation from 20 mg daily to 40 mg three times weekly on immune function in multiple sclerosis. Mult Scler J Exp Transl Clin 2021; 7:20552173211032323. [PMID: 34377526 PMCID: PMC8330487 DOI: 10.1177/20552173211032323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/04/2022] Open
Abstract
Background Many RRMS patients who had been treated for over 20 years with GA 20 mg/ml daily (GA20) switched to 40 mg/ml three times-a-week (GA40) to reduce injection-related adverse events. Although GA40 is as effective as GA20 in reducing annualized relapse rate and MRI activity, it remains unknown how switching to GA40 from GA20 affects the development of pathogenic and regulatory immune cells. Objective To investigate the difference in immunological parameters in response to GA20 and GA40 treatments. Methods We analyzed five pro-inflammatory cytokines (IL-1β, IL-23, IL-12, IL-18, TNF-α), and three anti-inflammatory/regulatory cytokines (IL-10, IL-13, and IL-27) in serum. In addition, we analyzed six cytokines (IFN-γ, IL-17A, GM-CSF, IL-10, IL-6, and IL-27) in cultured PBMC supernatants. The development of Th1, Th17, Foxp3 Tregs, M1-like, and M2-like macrophages were examined by flow cytometry. Samples were analyzed before and 12 months post switching to GA40 or GA20. Results Pro- and anti-inflammatory cytokines were comparable between the GA40 and GA20 groups. Development of Th1, Th17, M1-like macrophages, M2-like macrophages, and Foxp3 Tregs was also comparable between the two groups. Conclusions The immunological parameters measured in RRMS patients treated with GA40 three times weekly are largely comparable to those given daily GA20 treatment.
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Affiliation(s)
- Kouichi Ito
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, USA.,Rutgers-New Jersey Medical School, Newark, NJ, USA.,Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, Piscataway, NJ, USA
| | - Naoko Ito
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, USA.,Rutgers-New Jersey Medical School, Newark, NJ, USA.,Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, Piscataway, NJ, USA
| | - Sudhir K Yadav
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, USA.,Rutgers-New Jersey Medical School, Newark, NJ, USA.,Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, Piscataway, NJ, USA
| | - Shradha Suresh
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, USA
| | - Yong Lin
- Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, Piscataway, NJ, USA
| | - Suhayl Dhib-Jalbut
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, USA.,Rutgers-New Jersey Medical School, Newark, NJ, USA.,Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, Piscataway, NJ, USA
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29
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Lee ES, Sul JH, Shin JM, Shin S, Lee JA, Kim HK, Cho Y, Ko H, Son S, Lee J, Park S, Jo DG, Park JH. Reactive oxygen species-responsive dendritic cell-derived exosomes for rheumatoid arthritis. Acta Biomater 2021; 128:462-473. [PMID: 33878476 DOI: 10.1016/j.actbio.2021.04.026] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 02/08/2023]
Abstract
Although tolerogenic dendritic cell-derived exosomes (TolDex) have emerged as promising therapeutics for rheumatoid arthritis (RA), their clinical applications have been hampered by their poor in vivo disposition after systemic administration. Herein, we report the development of stimuli-responsive TolDex that induces lesion-specific immunoregulation in RA. Responsiveness to reactive oxygen species (ROS), a physiological stimulus in the RA microenvironment, was conferred on TolDex by introducing a thioketal (TK) linker-embedded poly(ethylene glycol) (PEG) on TolDex surface via hydrophobic insertion. The detachment of PEG following overproduction of ROS facilitates the cellular uptake of ROS-responsive TolDex (TKDex) into activated immune cells. Notably, TolDex and TKDex downregulated CD40 in mature dendritic cells (mDCs) and regulated secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) at the cellular level. In the collagen-induced arthritis (CIA) mouse model, PEG prolonged the blood circulation of TKDex following intravenous administration and enhanced their accumulation in the joints. In addition, TKDex decreased IL-6, increased transforming growth factor-β, and induced the CD4+CD25+Foxp3+ regulatory T cells in CIA mice. Overall, ROS-responsive TolDex might have potential as therapeutic agents for RA. STATEMENT OF SIGNIFICANCE: Tolerogenic dendritic cell-derived exosomes (TolDex) are emerging immunoregulators of autoimmune diseases, including rheumatoid arthritis (RA). However, their lack of long-term stability and low targetability are still challenging. To overcome these issues, we developed reactive oxygen species (ROS)-responsive TolDex (TKDex) by incorporating the ROS-sensitive functional group-embedded poly(ethylene glycol) linker into the exosomal membrane of TolDex. Surface-engineered TKDex were internalized in mature DCs because of high ROS-sensitivity and enhanced accumulation in the inflamed joint in vivo. Further, for the first time, we investigated the potential mechanism of action of TolDex relevant to CD40 downregulation and attenuation of tumor necrosis factor (TNF)-α secretion. Our strategy highlighted the promising nanotherapeutic effects of stimuli-sensitive TolDex, which induces immunoregulation.
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Harris KM, Clements MA, Kwilasz AJ, Watkins LR. T cell transgressions: Tales of T cell form and function in diverse disease states. Int Rev Immunol 2021; 41:475-516. [PMID: 34152881 PMCID: PMC8752099 DOI: 10.1080/08830185.2021.1921764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/17/2021] [Accepted: 04/20/2021] [Indexed: 01/03/2023]
Abstract
Insights into T cell form, function, and dysfunction are rapidly evolving. T cells have remarkably varied effector functions including protecting the host from infection, activating cells of the innate immune system, releasing cytokines and chemokines, and heavily contributing to immunological memory. Under healthy conditions, T cells orchestrate a finely tuned attack on invading pathogens while minimizing damage to the host. The dark side of T cells is that they also exhibit autoreactivity and inflict harm to host cells, creating autoimmunity. The mechanisms of T cell autoreactivity are complex and dynamic. Emerging research is elucidating the mechanisms leading T cells to become autoreactive and how such responses cause or contribute to diverse disease states, both peripherally and within the central nervous system. This review provides foundational information on T cell development, differentiation, and functions. Key T cell subtypes, cytokines that create their effector roles, and sex differences are highlighted. Pathological T cell contributions to diverse peripheral and central disease states, arising from errors in reactivity, are highlighted, with a focus on multiple sclerosis, rheumatoid arthritis, osteoarthritis, neuropathic pain, and type 1 diabetes.
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Affiliation(s)
- Kevin M. Harris
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
| | - Madison A. Clements
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
| | - Andrew J. Kwilasz
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
| | - Linda R. Watkins
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
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Devi-Marulkar P, Moraes-Cabe C, Campagne P, Corre B, Meghraoui-Kheddar A, Bondet V, Llibre A, Duffy D, Maillart E, Papeix C, Pellegrini S, Michel F. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment. Front Immunol 2021; 12:628375. [PMID: 34113337 PMCID: PMC8185344 DOI: 10.3389/fimmu.2021.628375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 04/23/2021] [Indexed: 11/25/2022] Open
Abstract
Background Interferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients. Aim To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach. Methods The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors. Results Clinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.
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Affiliation(s)
- Priyanka Devi-Marulkar
- Cytokine Signaling Unit, Department of Immunology, Institut Pasteur, Paris, France.,INSERM U1221, Department of Immunology, Institut Pasteur, Paris, France
| | - Carolina Moraes-Cabe
- Cytokine Signaling Unit, Department of Immunology, Institut Pasteur, Paris, France.,INSERM U1221, Department of Immunology, Institut Pasteur, Paris, France
| | - Pascal Campagne
- Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France
| | - Béatrice Corre
- Cytokine Signaling Unit, Department of Immunology, Institut Pasteur, Paris, France.,INSERM U1221, Department of Immunology, Institut Pasteur, Paris, France
| | - Aida Meghraoui-Kheddar
- Cytokine Signaling Unit, Department of Immunology, Institut Pasteur, Paris, France.,INSERM U1221, Department of Immunology, Institut Pasteur, Paris, France
| | - Vincent Bondet
- Translational Immunology Laboratory, Department of Immunology, Institut Pasteur, Paris, France
| | - Alba Llibre
- Translational Immunology Laboratory, Department of Immunology, Institut Pasteur, Paris, France
| | - Darragh Duffy
- Translational Immunology Laboratory, Department of Immunology, Institut Pasteur, Paris, France
| | | | - Caroline Papeix
- Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France
| | - Sandra Pellegrini
- Cytokine Signaling Unit, Department of Immunology, Institut Pasteur, Paris, France.,INSERM U1221, Department of Immunology, Institut Pasteur, Paris, France
| | - Frédérique Michel
- Cytokine Signaling Unit, Department of Immunology, Institut Pasteur, Paris, France.,INSERM U1221, Department of Immunology, Institut Pasteur, Paris, France
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Multiple sclerosis patients have reduced resting and increased activated CD4 +CD25 +FOXP3 +T regulatory cells. Sci Rep 2021; 11:10476. [PMID: 34006899 PMCID: PMC8131694 DOI: 10.1038/s41598-021-88448-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 04/01/2021] [Indexed: 12/26/2022] Open
Abstract
Resting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.
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Selck C, Dominguez-Villar M. Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation. Front Immunol 2021; 12:661875. [PMID: 34054826 PMCID: PMC8160309 DOI: 10.3389/fimmu.2021.661875] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 04/27/2021] [Indexed: 12/30/2022] Open
Abstract
Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.
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Affiliation(s)
- Claudia Selck
- Faculty of Medicine, Imperial College London, London, United Kingdom
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Regulatory T-cell subset distribution in children with primary hypertension is associated with hypertension severity and hypertensive target organ damage. J Hypertens 2021; 38:692-700. [PMID: 31834124 DOI: 10.1097/hjh.0000000000002328] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The relationship between circulating regulatory T-cell (Tregs) subset distribution and hypertension severity in children with primary hypertension is not known. We aimed to find out if target organ damage (TOD) in children with primary hypertension is related to defects in Tregs distribution reflected by their phenotype characteristics. METHODS The study constituted 33 nontreated hypertensive children and 35 sex-matched and age-matched controls. Using multicolor flow cytometry technique, we assessed a distribution of the total Tregs (CD4CD25CD127) and their subsets (CD45RA-naive Tregs, CD45RA memory/activated Tregs, CD45RACD31 recent thymic emigrants Tregs and mature naive CD45RACD31 Tregs) in the whole blood. RESULTS Hypertensive children showed decreased percentage of the total Tregs, the CD45RA-naive Tregs, the total CD31 Tregs and the recent thymic emigrants Tregs but elevation of the CD45RA memory/activated Treg and mature naive CD45RACD31 Tregs. Decreased frequency of the total Tregs, naive Tregs and CD31-bearing Treg cell subsets (CD31 total Tregs, CD45RACD31 recent thymic emigrants Tregs) negatively correlated to TOD markers, arterial stiffness and blood pressure elevation. In contrast, increased percentage of memory Tregs and CD31 Tregs subsets positively correlated to organ damage markers, arterial stiffness and blood pressure values. These changes were independent of BMI, age, sex and hsCRP. CONCLUSION Both diagnosis of hypertension, TOD and arterial stiffness in hypertensive children were associated with decreased population of total CD4 Tregs, limited output of recent thymic emigrants Tregs, and increased pool of activated/memory Tregs. Hypertension was an independent predictor of the circulating Treg subsets distribution irrespective of hsCRP.
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35
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Vomstein K, Feil K, Strobel L, Aulitzky A, Hofer-Tollinger S, Kuon RJ, Toth B. Immunological Risk Factors in Recurrent Pregnancy Loss: Guidelines Versus Current State of the Art. J Clin Med 2021; 10:869. [PMID: 33672505 PMCID: PMC7923780 DOI: 10.3390/jcm10040869] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 02/06/2023] Open
Abstract
Around 1-5% of all couples experience recurrent pregnancy loss (RPL). Established risk factors include anatomical, genetic, endocrine, and hemostatic alterations. With around 50% of idiopathic cases, immunological risk factors are getting into the scientific focus, however international guidelines hardly take them into account. Within this review, the current state of immunological risk factors in RPL in international guidelines of the European Society of Reproduction and Embryology (ESHRE), American Society of Reproductive Medicine (ASRM), German/Austrian/Swiss Society of Obstetrics and Gynecology (DGGG/OEGGG/SGGG) and the Royal College of Obstetricians and Gynecologists (RCOG) are evaluated. Special attention was drawn to recommendations in the guidelines regarding diagnostic factors such as autoantibodies, natural killer cells, regulatory T cells, dendritic cells, plasma cells, and human leukocyte antigen system (HLA)-sharing as well as treatment options such as corticosteroids, intralipids, intravenous immunoglobulins, aspirin and heparin in RPL. Finally, the current state of the art focusing on both diagnostic and therapeutic options was summarized.
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Affiliation(s)
- Kilian Vomstein
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; (K.F.); (L.S.); (A.A.); (S.H.-T.); (B.T.)
| | - Katharina Feil
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; (K.F.); (L.S.); (A.A.); (S.H.-T.); (B.T.)
| | - Laura Strobel
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; (K.F.); (L.S.); (A.A.); (S.H.-T.); (B.T.)
| | - Anna Aulitzky
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; (K.F.); (L.S.); (A.A.); (S.H.-T.); (B.T.)
| | - Susanne Hofer-Tollinger
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; (K.F.); (L.S.); (A.A.); (S.H.-T.); (B.T.)
| | - Ruben-Jeremias Kuon
- Department of Gynecological Endocrinology and Fertility Disorders, Ruprecht-Karls University Heidelberg, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany;
| | - Bettina Toth
- Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; (K.F.); (L.S.); (A.A.); (S.H.-T.); (B.T.)
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Uchida N, Mori K, Fujita-Nakata M, Nakanishi M, Sanada M, Nagayama S, Sugiyama H, Matsui M. Systemic cellular immunity and neuroinflammation during acute flare-up in multiple sclerosis and neuromyelitis optica spectrum disorder patients. J Neuroimmunol 2021; 353:577500. [PMID: 33592574 DOI: 10.1016/j.jneuroim.2021.577500] [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: 11/26/2020] [Revised: 01/23/2021] [Accepted: 01/24/2021] [Indexed: 11/24/2022]
Abstract
Twenty-seven treatment-naïve patients with relapsing-remitting multiple sclerosis (MS) and 13 with neuromyelitis optica spectrum disorder (NMOSD) were enrolled during a time of acute flare-up. Common cerebrospinal fluid (CSF) features were increased CD29- and/or CD45RO-positive helper T cells capable of propagating inflammation in the central nervous system (CNS). B cell activation in the CSF was unique to MS, while an increase in CD4+CD192 (CCR2)+ cells in blood and breakdown of the blood-brain barrier (BBB) characterized NMOSD. Intravenous corticosteroid therapy suppressed neuroinflammation via modulation of cellular immunity in MS, as opposed to restoration of the BBB in NMOSD.
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Affiliation(s)
- Nobuaki Uchida
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Kentaro Mori
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Michiyo Fujita-Nakata
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Megumi Nakanishi
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Mitsuru Sanada
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Shigemi Nagayama
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan
| | - Hiroshi Sugiyama
- Department of Neurology, National Hospital Organization Utano National Hospital, 8 Narutaki-Ondoyama-cho, Ukyo-ku, Kyoto 616-8255, Japan
| | - Makoto Matsui
- Department of Neurology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
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Saksida T, Jevtić B, Djedović N, Miljković Đ, Stojanović I. Redox Regulation of Tolerogenic Dendritic Cells and Regulatory T Cells in the Pathogenesis and Therapy of Autoimmunity. Antioxid Redox Signal 2021; 34:364-382. [PMID: 32458699 DOI: 10.1089/ars.2019.7999] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Significance: Autoimmune diseases are progressively affecting westernized societies, as the proportion of individuals suffering from autoimmunity is steadily increasing over the past decades. Understanding the role of reactive oxygen species (ROS) in modulation of the immune response in the pathogenesis of autoimmune disorders is of utmost importance. The focus of this review is the regulation of ROS production within tolerogenic dendritic cells (tolDCs) and regulatory T (Treg) cells that have the essential role in the prevention of autoimmune diseases and significant potency in their therapy. Recent Advances: It is now clear that ROS are extremely important for the proper function of both DC and T cells. Antigen processing/presentation and the ability of DC to activate T cells depend upon the ROS availability. Treg differentiation, suppressive function, and stability are profoundly influenced by ROS presence. Critical Issues: Although a plethora of results on the relation between ROS and immune cells exist, it remains unclear whether ROS modulation is a productive way for skewing T cells and DCs toward a tolerogenic phenotype. Also, the possibility of ROS modulation for enhancement of regulatory properties of DC and Treg during their preparation for use in cellular therapy has to be clarified. Future Directions: Studies of DC and T cell redox regulation should allow for the improvement of the therapy of autoimmune diseases. This could be achieved through the direct therapeutic application of ROS modulators in autoimmunity, or indirectly through ROS-dependent enhancement of tolDC and Treg preparation for cell-based immunotherapy. Antioxid. Redox Signal. 34, 364-382.
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Affiliation(s)
- Tamara Saksida
- Department of Immunology, Institute for Biological Research "Siniša Stanković," National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Bojan Jevtić
- Department of Immunology, Institute for Biological Research "Siniša Stanković," National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Neda Djedović
- Department of Immunology, Institute for Biological Research "Siniša Stanković," National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Đorđe Miljković
- Department of Immunology, Institute for Biological Research "Siniša Stanković," National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Ivana Stojanović
- Department of Immunology, Institute for Biological Research "Siniša Stanković," National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
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The contribution of thymic tolerance to central nervous system autoimmunity. Semin Immunopathol 2020; 43:135-157. [PMID: 33108502 PMCID: PMC7925481 DOI: 10.1007/s00281-020-00822-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 10/09/2020] [Indexed: 12/15/2022]
Abstract
Autoimmune diseases of the central nervous system (CNS) are associated with high levels of morbidity and economic cost. Research efforts have previously focused on the contribution of the peripheral adaptive and innate immune systems to CNS autoimmunity. However, a failure of thymic negative selection is a necessary step in CNS-reactive T cells escaping into the periphery. Even with defective thymic or peripheral tolerance, the development of CNS inflammation is rare. The reasons underlying this are currently poorly understood. In this review, we examine evidence implicating thymic selection in the pathogenesis of CNS autoimmunity. Animal models suggest that thymic negative selection is an important factor in determining susceptibility to and severity of CNS inflammation. There are indirect clinical data that suggest thymic function is also important in human CNS autoimmune diseases. Specifically, the association between thymoma and paraneoplastic encephalitis and changes in T cell receptor excision circles in multiple sclerosis implicate thymic tolerance in these diseases. We identify potential associations between CNS autoimmunity susceptibility factors and thymic tolerance. The therapeutic manipulation of thymopoiesis has the potential to open up new treatment modalities, but a better understanding of thymic tolerance in CNS autoimmunity is required before this can be realised.
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Yong KSM, Her Z, Tan SY, Tan WWS, Liu M, Lai F, Heng SM, Fan Y, Chang KTE, Wang CI, Chan JKY, Chen J, Chen Q. Humanized Mouse as a Tool to Predict Immunotoxicity of Human Biologics. Front Immunol 2020; 11:553362. [PMID: 33193321 PMCID: PMC7604536 DOI: 10.3389/fimmu.2020.553362] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 09/28/2020] [Indexed: 11/24/2022] Open
Abstract
Advancements in science enable researchers to constantly innovate and create novel biologics. However, the use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials. In this study, we evaluated and compared the effects of known immunotoxic biologics, Proleukin®/IL-2 and OKT3 in humanized mice (reconstituted with human fetal cells) to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research participants and/or patients at risk.
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Affiliation(s)
- Kylie Su Mei Yong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Zhisheng Her
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Sue Yee Tan
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Wilson Wei Sheng Tan
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Min Liu
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Fritz Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Shi Min Heng
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Yong Fan
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Kenneth Tou En Chang
- Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore.,Department of Pathology, Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Cheng-I Wang
- Singapore Immunology Network, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Jerry Kok Yen Chan
- Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore.,Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jianzhu Chen
- Interdisciplinary Research Group in Infectious Diseases, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology, Singapore, Singapore.,The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, United States
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.,Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Ahmed A, Vyakarnam A. Emerging patterns of regulatory T cell function in tuberculosis. Clin Exp Immunol 2020; 202:273-287. [PMID: 32639588 PMCID: PMC7670141 DOI: 10.1111/cei.13488] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/12/2020] [Accepted: 06/22/2020] [Indexed: 12/22/2022] Open
Abstract
Tuberculosis (TB) is one of the top 10 causes of mortality worldwide from a single infectious agent and has significant implications for global health. A major hurdle in the development of effective TB vaccines and therapies is the absence of defined immune‐correlates of protection. In this context, the role of regulatory T cells (Treg), which are essential for maintaining immune homeostasis, is even less understood. This review aims to address this knowledge gap by providing an overview of the emerging patterns of Treg function in TB. Increasing evidence from studies, both in animal models of infection and TB patients, points to the fact the role of Tregs in TB is dependent on disease stage. While Tregs might expand and delay the appearance of protective responses in the early stages of infection, their role in the chronic phase perhaps is to counter‐regulate excessive inflammation. New data highlight that this important homeostatic role of Tregs in the chronic phase of TB may be compromised by the expansion of activated human leucocyte antigen D‐related (HLA‐DR)+CD4+ suppression‐resistant effector T cells. This review provides a comprehensive and critical analysis of the key features of Treg cells in TB; highlights the importance of a balanced immune response as being important in TB and discusses the importance of probing not just Treg frequency but also qualitative aspects of Treg function as part of a comprehensive search for novel TB treatments.
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Affiliation(s)
- A Ahmed
- Laboratory of Immunology of HIV-TB Co-infection, Center for Infectious Disease Research (CIDR), Indian Institute of Science (IISc), Bangalore, India
| | - A Vyakarnam
- Laboratory of Immunology of HIV-TB Co-infection, Center for Infectious Disease Research (CIDR), Indian Institute of Science (IISc), Bangalore, India.,Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, Guy's Hospital, King's College London (KCL), London, UK
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41
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Bäcker-Koduah P, Infante-Duarte C, Ivaldi F, Uccelli A, Bellmann-Strobl J, Wernecke KD, Sy M, Demetriou M, Dörr J, Paul F, Ulrich Brandt A. Effect of vitamin D supplementation on N-glycan branching and cellular immunophenotypes in MS. Ann Clin Transl Neurol 2020; 7:1628-1641. [PMID: 32830462 PMCID: PMC7480923 DOI: 10.1002/acn3.51148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/17/2020] [Accepted: 07/06/2020] [Indexed: 12/31/2022] Open
Abstract
Objective To investigate the effect of cholecalciferol (vitamin D3) supplementation on peripheral immune cell frequency and N‐glycan branching in patients with relapsing‐remitting multiple sclerosis (RRMS). Methods Exploratory analysis of high‐dose (20 400 IU) and low‐dose (400 IU) vitamin D3 supplementation taken every other day of an 18‐month randomized controlled clinical trial including 38 RRMS patients on stable immunomodulatory therapy (NCT01440062). We investigated cholecalciferol treatment effects on N‐glycan branching using L‐PHA stain (phaseolus vulgaris leukoagglutinin) at 6 months and frequencies of T‐, B‐, and NK‐cell subpopulations at 12 months with flow cytometry. Results High‐dose supplementation did not change CD3+ T cell subsets, CD19+ B cells subsets, and NK cells frequencies, except for CD8+ T regulatory cells, which were reduced in the low‐dose arm compared to the high‐dose arm at 12 months. High‐dose supplementation decreased N‐glycan branching on T and NK cells, measured as L‐PHA mean fluorescence intensity (MFI). A reduction of N‐glycan branching in B cells was not significant. In contrast, low‐dose supplementation did not affect N‐glycan branching. Changes in N‐glycan branching did not correlate with cell frequencies. Interpretation Immunomodulatory effect of vitamin D may involve regulation of N‐glycan branching in vivo. Vitamin D3 supplementation did at large not affect the frequencies of peripheral immune cells.
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Affiliation(s)
- Priscilla Bäcker-Koduah
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Berlin, Germany.,Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Carmen Infante-Duarte
- Charité - Universitätsmedizin Berlin, Institute for Medical Immunology, Berlin, Germany
| | - Federico Ivaldi
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, CEBR University of Genoa, Genoa, Italy
| | - Antonio Uccelli
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, CEBR University of Genoa, Genoa, Italy.,Ospedale Policlinico San Martino-IRCCS, Genoa, Italy
| | - Judith Bellmann-Strobl
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Berlin, Germany.,Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, NeuroCure Cluster of Excellence, Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Klaus-Dieter Wernecke
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Berlin, Germany.,Institute of Biometry and Clinical Epidemiology, Charité -Universitatsmedizin Berlin and CRO SOSTANA GmbH, Berlin, Germany
| | - Michael Sy
- Department of Neurology, University of California, Irvine, CA, USA
| | | | - Jan Dörr
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Berlin, Germany.,Multiple Sclerosis Center Hennigsdorf, Oberhavel Clinics, Berlin, Germany
| | - Friedemann Paul
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Berlin, Germany.,Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany.,Berlin Institute of Health, NeuroCure Cluster of Excellence, Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander Ulrich Brandt
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, NeuroCure Cluster of Excellence, Berlin, Germany.,Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin, Germany.,Department of Neurology, University of California, Irvine, CA, USA
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42
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Targeting Dendritic Cells with Antigen-Delivering Antibodies for Amelioration of Autoimmunity in Animal Models of Multiple Sclerosis and Other Autoimmune Diseases. Antibodies (Basel) 2020; 9:antib9020023. [PMID: 32549343 PMCID: PMC7345927 DOI: 10.3390/antib9020023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/22/2020] [Accepted: 04/30/2020] [Indexed: 02/07/2023] Open
Abstract
The specific targeting of dendritic cells (DCs) using antigen-delivering antibodies has been established to be a highly efficient protocol for the induction of tolerance and protection from autoimmune processes in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), as well as in some other animal disease models. As the specific mechanisms of such induced tolerance are being investigated, the newly gained insights may also possibly help to design effective treatments for patients. Here we review approaches applied for the amelioration of autoimmunity in animal models based on antibody-mediated targeting of self-antigens to DCs. Further, we discuss relevant mechanisms of immunological tolerance that underlie such approaches, and we also offer some future perspectives for the application of similar methods in certain related disease settings such as transplantation.
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43
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van Langelaar J, Rijvers L, Smolders J, van Luijn MM. B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers. Front Immunol 2020; 11:760. [PMID: 32457742 PMCID: PMC7225320 DOI: 10.3389/fimmu.2020.00760] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 04/03/2020] [Indexed: 12/25/2022] Open
Abstract
Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS.
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Affiliation(s)
- Jamie van Langelaar
- Department of Immunology, MS Center ErasMS, Erasmus MC, University Medical Center, Rotterdam, Netherlands
| | - Liza Rijvers
- Department of Immunology, MS Center ErasMS, Erasmus MC, University Medical Center, Rotterdam, Netherlands
| | - Joost Smolders
- Department of Immunology, MS Center ErasMS, Erasmus MC, University Medical Center, Rotterdam, Netherlands
- Department of Neurology, MS Center ErasMS, Erasmus MC, University Medical Center, Rotterdam, Netherlands
- Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, Netherlands
| | - Marvin M. van Luijn
- Department of Immunology, MS Center ErasMS, Erasmus MC, University Medical Center, Rotterdam, Netherlands
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Truffault F, Nazzal D, Verdier J, Gradolatto A, Fadel E, Roussin R, Eymard B, Le Panse R, Berrih-Aknin S. Comparative Analysis of Thymic and Blood Treg in Myasthenia Gravis: Thymic Epithelial Cells Contribute to Thymic Immunoregulatory Defects. Front Immunol 2020; 11:782. [PMID: 32435245 PMCID: PMC7218102 DOI: 10.3389/fimmu.2020.00782] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/06/2020] [Indexed: 11/13/2022] Open
Abstract
The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti-acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently suppressive, and conventional T cells (Tconv) are resistant to suppression. To better understand the specific role of the thymus in MG, we compared the phenotype and function of peripheral and thymic Treg and Tconv from controls and MG patients. Suppression assays with thymic or peripheral CD4 + T cells showed that the functional impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic analysis of Treg showed a significant reduction of resting and effector Treg in the thymus but not in the periphery of MG patients. CD31, a marker lost with excessive immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These results suggest that an altered thymic environment may explain Treg differences between MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG TECs and tested their suppressive function. Co-culture with MG TECs consistently hampers regulatory activity, as compared with control TECs, suggesting that MG TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs restored numbers and function of MG Treg, demonstrating that a favorable environment could correct the immune regulation defects of T cells in MG. Altogether, our data suggest that the severe defect of thymic Treg is at least partially due to MG TECs that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional TECs by healthy TECs. These findings highlight the role of the tissue environment on the immune regulation.
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Affiliation(s)
- Frédérique Truffault
- Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Dani Nazzal
- Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Julien Verdier
- Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Angeline Gradolatto
- Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Elie Fadel
- Marie Lannelongue Hospital, Le Plessis-Robinson, France
| | | | - Bruno Eymard
- AP-HP, Referral Center for Neuromuscular Disorders, Pitié-Salpêtrière Hospital, Institute of Myology, Paris, France
| | - Rozen Le Panse
- Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
| | - Sonia Berrih-Aknin
- Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France
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45
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Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130:2620-2629. [PMID: 32217835 DOI: 10.1172/jci137244] [Citation(s) in RCA: 3395] [Impact Index Per Article: 679.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 03/27/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUNDSince December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODSIn this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTSThe median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSIONThe SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATIONThis is a retrospective observational study without a trial registration number.FUNDINGThis work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).
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Affiliation(s)
- Guang Chen
- Department and Institute of Infectious Disease
| | - Di Wu
- Department and Institute of Infectious Disease
| | - Wei Guo
- Department and Institute of Infectious Disease
| | - Yong Cao
- Department of Respiratory Disease
| | - Da Huang
- Department and Institute of Infectious Disease
| | - Hongwu Wang
- Department and Institute of Infectious Disease
| | - Tao Wang
- Department of Respiratory Disease
| | | | | | - Haijing Yu
- Department and Institute of Infectious Disease
| | | | | | - Shiji Wu
- Department of Laboratory Medicine
| | | | - Tao Chen
- Department and Institute of Infectious Disease
| | - Meifang Han
- Department and Institute of Infectious Disease
| | | | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Qin Ning
- Department and Institute of Infectious Disease
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Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020. [PMID: 32217835 DOI: 10.1101/2020.02.16.20023903] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/15/2023] Open
Abstract
BACKGROUNDSince December 2019, an outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, and is now becoming a global threat. We aimed to delineate and compare the immunological features of severe and moderate COVID-19.METHODSIn this retrospective study, the clinical and immunological characteristics of 21 patients (17 male and 4 female) with COVID-19 were analyzed. These patients were classified as severe (11 cases) and moderate (10 cases) according to the guidelines released by the National Health Commission of China.RESULTSThe median age of severe and moderate cases was 61.0 and 52.0 years, respectively. Common clinical manifestations included fever, cough, and fatigue. Compared with moderate cases, severe cases more frequently had dyspnea, lymphopenia, and hypoalbuminemia, with higher levels of alanine aminotransferase, lactate dehydrogenase, C-reactive protein, ferritin, and D-dimer as well as markedly higher levels of IL-2R, IL-6, IL-10, and TNF-α. Absolute numbers of T lymphocytes, CD4+ T cells, and CD8+ T cells decreased in nearly all the patients, and were markedly lower in severe cases (294.0, 177.5, and 89.0 × 106/L, respectively) than moderate cases (640.5, 381.5, and 254.0 × 106/L, respectively). The expression of IFN-γ by CD4+ T cells tended to be lower in severe cases (14.1%) than in moderate cases (22.8%).CONCLUSIONThe SARS-CoV-2 infection may affect primarily T lymphocytes, particularly CD4+ and CD8+ T cells, resulting in a decrease in numbers as well as IFN-γ production by CD4+ T cells. These potential immunological markers may be of importance because of their correlation with disease severity in COVID-19.TRIAL REGISTRATIONThis is a retrospective observational study without a trial registration number.FUNDINGThis work is funded by grants from Tongji Hospital for the Pilot Scheme Project, and partly supported by the Chinese National Thirteenth Five Years Project in Science and Technology for Infectious Disease (2017ZX10202201).
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Affiliation(s)
- Guang Chen
- Department and Institute of Infectious Disease
| | - Di Wu
- Department and Institute of Infectious Disease
| | - Wei Guo
- Department and Institute of Infectious Disease
| | - Yong Cao
- Department of Respiratory Disease
| | - Da Huang
- Department and Institute of Infectious Disease
| | - Hongwu Wang
- Department and Institute of Infectious Disease
| | - Tao Wang
- Department of Respiratory Disease
| | | | | | - Haijing Yu
- Department and Institute of Infectious Disease
| | | | | | - Shiji Wu
- Department of Laboratory Medicine
| | | | - Tao Chen
- Department and Institute of Infectious Disease
| | - Meifang Han
- Department and Institute of Infectious Disease
| | | | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Qin Ning
- Department and Institute of Infectious Disease
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47
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Modulation of regulatory T cell function and stability by co-inhibitory receptors. Nat Rev Immunol 2020; 20:680-693. [PMID: 32269380 DOI: 10.1038/s41577-020-0296-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2020] [Indexed: 12/12/2022]
Abstract
Regulatory T (Treg) cells constitute a dynamic population that is essential for controlling immune responses in health and disease. Defects in Treg cell function and decreases in Treg cell numbers have been observed in patients with autoimmunity and the opposite effects on Treg cells occur in cancer settings. Current research on new therapies for these diseases is focused on modulating Treg cell function to increase or decrease suppressive activity in autoimmunity and cancer, respectively. In this regard, several co-inhibitory receptors that are preferentially expressed by Treg cells under homeostatic conditions have recently been shown to control Treg cell function and stability in different disease settings. These receptors could be amenable to therapeutic targeting aimed at modulating Treg cell function and plasticity. This Review summarizes recent data regarding the role of co-inhibitory molecules in the control of Treg cell function and stability, with a focus on their roles and potential therapeutic use in autoimmunity and cancer.
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Foley C, Floudas A, Canavan M, Biniecka M, MacDermott EJ, Veale DJ, Mullan RH, Killeen OG, Fearon U. Increased T Cell Plasticity With Dysregulation of Follicular Helper T, Peripheral Helper T, and Treg Cell Responses in Children With Juvenile Idiopathic Arthritis and Down Syndrome–Associated Arthritis. Arthritis Rheumatol 2020; 72:677-686. [DOI: 10.1002/art.41150] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 10/24/2019] [Indexed: 01/25/2023]
Affiliation(s)
- C. Foley
- Our Lady’s Children’s HospitalCrumlin and Trinity College Dublin Dublin Ireland
| | | | | | - M. Biniecka
- Centre for Arthritis and Rheumatic DiseasesEULAR Centre of ExcellenceSt. Vincent’s University Hospital, and University College Dublin Dublin Ireland
| | | | - D. J. Veale
- Centre for Arthritis and Rheumatic DiseasesEULAR Centre of ExcellenceSt. Vincent’s University Hospital, and University College Dublin Dublin Ireland
| | - R. H. Mullan
- Tallaght University Hospital and Trinity College Dublin Dublin Ireland
| | - O. G. Killeen
- Our Lady’s Children’s Hospital Crumlin, Dublin Ireland
| | - U. Fearon
- Trinity College Dublin Dublin Ireland
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Cellerino M, Ivaldi F, Pardini M, Rotta G, Vila G, Bäcker-Koduah P, Berge T, Laroni A, Lapucci C, Novi G, Boffa G, Sbragia E, Palmeri S, Asseyer S, Høgestøl E, Campi C, Piana M, Inglese M, Paul F, Harbo HF, Villoslada P, Kerlero de Rosbo N, Uccelli A. Impact of treatment on cellular immunophenotype in MS: A cross-sectional study. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 7:7/3/e693. [PMID: 32139439 PMCID: PMC7136062 DOI: 10.1212/nxi.0000000000000693] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 01/05/2020] [Indexed: 12/22/2022]
Abstract
Objective To establish cytometry profiles associated with disease stages and immunotherapy in MS. Methods Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. Results In untreated patients with MS, significantly higher frequencies of Th17 cells in the RRMS population compared with HC and lower frequencies of B-memory/B-regulatory cells as well as higher percentages of B-mature cells in patients with PMS compared with HCs emerged. Overall, the greatest deviation in immunophenotype in MS was observed by treatment rather than disease course, with the strongest impact found in fingolimod-treated patients. Fingolimod induced a decrease in total CD4+ T cells and in B-mature and B-memory cells and increases in CD4+ and CD8+ T-regulatory and B-regulatory cells. Conclusions Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.
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Affiliation(s)
- Maria Cellerino
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Federico Ivaldi
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Matteo Pardini
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Gianluca Rotta
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Gemma Vila
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Priscilla Bäcker-Koduah
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Tone Berge
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Alice Laroni
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Caterina Lapucci
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Giovanni Novi
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Giacomo Boffa
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Elvira Sbragia
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Serena Palmeri
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Susanna Asseyer
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Einar Høgestøl
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Cristina Campi
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Michele Piana
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Matilde Inglese
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Friedemann Paul
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Hanne F Harbo
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Pablo Villoslada
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Nicole Kerlero de Rosbo
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy
| | - Antonio Uccelli
- From the Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (M.C., F.I., M.P., A.L., C.L., G.N., G.B., E.S., S.P., M.I., N.K.d.R.) and Center of Excellence for Biomedical Research (A.U.), University of Genoa, Italy; BD Biosciences Italy (G.R.), Milan; Institut d'Investigacions Biomediques August Pi Sunyer (G.V., P.V.), Barcelona, Spain; Charité Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine (P.B.-K., S.A., F.P.), Germany; Department of Research, Innovation and Education (T.B.), Neuroscience Research Unit, Oslo University Hospital; Department of Mechanical Electronics and Chemical Engineering (T.B.), Oslo Metropolitan University, Norway; University of Oslo (E.H., H.F.H.) and Oslo University Hospital (H.F.H.), Norway; Department of Mathematics and Padova Neuroscience Center (C.C.), University of Padua, Italy; Department of Mathematics (M.P.), University of Genoa, Italy; and IRCCS Ospedale Policlinico San Martino (A.L., M.P., M.I., A.U.), Genoa, Italy.
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Chen J, Zhan C, Zhang L, Zhang L, Liu Y, Zhang Y, Du H, Liang C, Chen X. The Hypermethylation of Foxp3 Promoter Impairs the Function of Treg Cells in EAP. Inflammation 2020; 42:1705-1718. [PMID: 31209730 DOI: 10.1007/s10753-019-01030-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Treg cells are crucial for maintaining immune homeostasis in CP/CPPS, but the molecular mechanisms underlying the modulation of the function of Treg in CP/CPPS remain unclear. The main purpose of this study is to investigate the relationship between immunosuppressive function of Treg and the methylation level of Foxp3 promoter in experimental autoimmune prostatitis (EAP) mouse model. EAP model was induced by subcutaneous injecting prostate-steroid-binding protein (PSBP) and complete Freund's adjuvant with NOD mice. Histological analysis revealed that EAP model was successfully induced. The expression of IFN-γ was increased, and TGF-β was decreased in the serum of EAP, respectively. The percentage of Tregs in splenic lymphocyte was increased in EAP. The suppressive ability of Tregs on Teffs was impaired in EAP. The methylation level of Foxp3 promoter was increased, and the expression of Foxp3 was decreased in EAP. By injection AZA which was DNA-methylation inhibitor into EAP mice, prostate inflammation was alleviated, expressions of TGF-β and Foxp3 were increased, and the suppressive function of Tregs was improved in vitro and in vivo. Thus, we concluded that aberrant increased methylation of Foxp3 promoter in Treg cells leads to the impaired suppressive function of Treg cells, exacerbating autoimmune inflammatory injury in EAP.
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Affiliation(s)
- Jing Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Changsheng Zhan
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Li Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Ligang Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Yi Liu
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Yong Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Hexi Du
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.,Institute of Urology, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China
| | - Chaozhao Liang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China. .,Institute of Urology, Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.
| | - Xianguo Chen
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China. .,Institute of Urology, Anhui Medical University, Hefei, China. .,Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, China.
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