George C Tsokos

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

Are you George C Tsokos?

Claim your profile

Publications (500)2418.05 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin 17 is a proinflammatory cytokine produced by CD4+ T cells when in the presence of a distinct set of cytokines and other cells. Preclinical and clinical studies have assigned a role to IL-17 in tissue inflammation and damage in patients with rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis and systemic lupus erythematosus. Antibodies blocking the action of IL-17 have already been approved to treat patients with psoriasis and it is expected that they may also benefit patients with other rheumatic diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine 05/2015; DOI:10.1016/j.cyto.2015.01.003 · 2.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Complement activation takes place in autoimmune diseases and accounts for tissue inflammation. Previously, complement inhibition has been has been considered for the treatment of SLE. Complement receptor of the immunoglobulin superfamily (CRIg) is a selective inhibitor of the alternative pathway of complement and a soluble form reverses established inflammation and bone destruction in experimental autoimmune arthritis. We asked whether specific inhibition of the alternative pathway could inhibit autoimmunity and/or organ damage in lupus-prone mice. Accordingly, we treated lupus-prone MRL/lpr mice with a soluble form of CRIg (CRIg-Fc) and we found that it significantly diminished skin lesions, proteinuria and pyuria, and kidney pathology. Interestingly, serum levels of anti-DNA antibodies were not affected despite the fact that serum complement 3 (C3) levels increased significantly. Immunofluorescent staining of kidney tissues revealed a reduction in staining intensity for C3, IgG, and the macrophage marker Mac-2. Thus our data show that inhibition of the alternative pathway of complement controls skin and kidney inflammation even in the absence of an effect on the production of autoantibodies. We propose that CRIg should be considered for clinical trials in patients with systemic lupus erythematosus. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 05/2015; DOI:10.1016/j.clim.2015.05.006 · 3.99 Impact Factor
  • Vaishali R Moulton, George C Tsokos
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is a prototype systemic autoimmune disease that results from a break in immune tolerance to self-antigens, leading to multi-organ destruction. Autoantibody deposition and inflammatory cell infiltration in target organs such as kidneys and brain lead to complications of this disease. Dysregulation of cellular and humoral immune response elements, along with organ-defined molecular aberrations, form the basis of SLE pathogenesis. Aberrant T lymphocyte activation due to signaling abnormalities, linked to defective gene transcription and altered cytokine production, are important contributors to SLE pathophysiology. A better understanding of signaling and gene regulation defects in SLE T cells will lead to the identification of specific novel molecular targets and predictive biomarkers for therapy.
    The Journal of clinical investigation 05/2015; 125(6):1-8. DOI:10.1172/JCI78087 · 13.77 Impact Factor
  • D Comte, M P Karampetsou, G C Tsokos
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by a loss of tolerance to multiple endogenous antigens. SLE etiology remains largely unknown, despite recent insight into the immunopathogenesis of the disease. T cells are important in the development of the disease by amplifying the immune response and contributing to organ damage. Aberrant signaling, cytokine secretion, and tissue homing displayed by SLE T cells have been extensively studied and the underlying pathogenic molecular mechanisms are starting to be elucidated. T-cell-targeted treatments are being explored in SLE patients. This review is an update on the T-cell abnormalities and related therapeutic options in SLE. © The Author(s) 2015 Reprints and permissions:
    Lupus 04/2015; 24(4-5):351-63. DOI:10.1177/0961203314556139 · 2.48 Impact Factor
  • George C Tsokos
    Circulation 03/2015; 131(13). DOI:10.1161/CIRCULATIONAHA.115.015613 · 14.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Complement is a major effector arm of the innate immune system that responds rapidly to pathogens or altered self. The central protein of the system, C3, participates in an amplification loop that can lead to rapid complement deposition on a target and, if excessive, can result in host tissue damage. Currently, complement activation is routinely monitored by assessing total C3 levels, which is an indirect and relatively insensitive method. An alternative approach would be to measure downstream C3 activation products such as C3a or iC3b. However, in vitro activation can produce falsely elevated levels of these biomarkers. To circumvent this issue, a lateral flow immunoassay system was developed that measures iC3b in whole blood, plasma and serum and avoids in vitro activation by minimizing sample handling. This assay system returns results in 15 minutes and specifically measures iC3b while having minimal cross-reactivity to other C3 split products. While evaluating the potential of this assay, it was observed that circulating iC3b levels can distinguish healthy individuals from those with complement activation-associated diseases. This tool is engineered to provide an improved method to assess complement activation at point-of-care and could facilitate studies to monitor disease progression in a variety of inflammatory conditions. Copyright © 2015. Published by Elsevier Inc.
    Analytical Biochemistry 02/2015; 477. DOI:10.1016/j.ab.2015.01.024 · 2.22 Impact Factor
  • Mindy S Lo, George C Tsokos
    12/2014; 9(6):543-546. DOI:10.2217/ijr.14.50
  • Source
    Linda A Lieberman, George C Tsokos
    [Show abstract] [Hide abstract]
    ABSTRACT: Systemic lupus erythematosus (SLE) is characterized by multiple cellular abnormalities culminating in the production of autoantibodies and immune complexes, resulting in tissue inflammation and organ damage. Besides active disease, the main cause of morbidity and mortality in SLE patients is infections, including those from opportunistic pathogens. To understand the failure of the immune system to fend off infections in systemic autoimmunity, we infected the lupus-prone murine strains B6.lpr and BXSB with the intracellular parasite Toxoplasma gondii and survival was monitored. Furthermore, mice were sacrificed days post infection and parasite burden and cellular immune responses such as cytokine production and cell activation were assessed. Mice from both strains succumbed to infection acutely and we observed greater susceptibility to infection in older mice. Increased parasite burden and a defective antigen-specific IFN-gamma response were observed in the lupus-prone mice. Furthermore, T cell:dendritic cell co-cultures established the presence of an intrinsic T cell defect responsible for the decreased antigen-specific response. An antigen-specific defect in IFN- gamma production prevents lupus-prone mice from clearing infection effectively. This study reveals the first cellular insight into the origin of increased susceptibility to infections in SLE disease and may guide therapeutic approaches.
    PLoS ONE 10/2014; 9(10):e111382. DOI:10.1371/journal.pone.0111382 · 3.53 Impact Factor
  • Source
    Journal of Allergy and Clinical Immunology 10/2014; 135(1). DOI:10.1016/j.jaci.2014.07.063 · 11.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.
    Proceedings of the National Academy of Sciences 09/2014; 111(37). DOI:10.1073/pnas.1408023111 · 9.81 Impact Factor
  • Source
    Dataset: cell report
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IL-2, a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remain unclear. Using an inducible recombinant adeno-associated virus vector, we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Fas(lpr/lpr) (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-recombinant adeno-associated virus resulted in reduced mononuclear cell infiltration and pathology of various tissues, including skin, lungs, and kidneys. In parallel, we noted a significant decrease of IL-17-producing CD3(+)CD4(-)CD8(-) double-negative T cells and an increase in CD4(+)CD25(+)Foxp3(+) immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive double-negative (DN) T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122(+) cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy, whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17-producing DN T cells and expanding Treg.
    The Journal of Immunology 07/2014; 193(5). DOI:10.4049/jimmunol.1400977 · 5.36 Impact Factor
  • Christine Konya, Ziv Paz, George C Tsokos
    [Show abstract] [Hide abstract]
    ABSTRACT: To describe our current understanding of the role of T cells in the pathophysiology of systemic lupus erythematosus (SLE).
    Current Opinion in Rheumatology 07/2014; DOI:10.1097/BOR.0000000000000082 · 5.07 Impact Factor
  • Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):193-193. DOI:10.1136/annrheumdis-2014-eular.1859 · 10.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Objective: Foxp3(+) regulatory T cells (Treg) are pivotal for the maintenance of peripheral tolerance and prevent development of autoimmune diseases. We have reported that calcium/calmodulin-dependent protein kinase IV (CaMK4) deficient MRL/lpr mice display less disease activity by promoting IL-2 production and increasing the activity of Treg cells. To further define the mechanism of CaMK4 on Treg cells in systemic lupus erythematosus (SLE), we used the Foxp3-GFP reporter mice and treated them with KN-93, an inhibitor of CaMK4. Methods: We generated MRL/lpr Foxp3-GFP mice to record Treg cells; stimulated naïve CD4(+) T cells from MRL/lpr Foxp3-GFP mice under Treg polarizing conditions in the absence or presence of KN-93; evaluated the number of GFP positive cells in lymphoid organs and examined skin and kidney pathology at 16 weeks of age. We also examined the infiltration of cells and recruitment of Treg cells in the kidney. Results: We show that culture of MRL/lpr Foxp3-GFP T cells in the presence of KN-93 promotes Treg differentiation in a dose-dependent manner. Treatment of MRL/lpr Foxp3-GFP mice with KN-93 results in a significant induction of Treg cells in the spleen, peripheral lymph nodes and peripheral blood and this is accompanied by decreased skin and kidney damage. Notably, KN-93 clearly diminishes the accumulation of inflammatory cells along with reciprocally increased Treg cells in target organ. Conclusion: Our results indicate that KN-93 treatment enhances the generation of Treg cells in vitro and in vivo highlighting its potential therapeutic use for the treatment of human autoimmune diseases.
    Autoimmunity 05/2014; 47(7):1-6. DOI:10.3109/08916934.2014.915954 · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Epigenetic events play a central role in the priming, differentiation and subset determination of T lymphocytes. Through their influence on chromatin conformation and DNA-accessibility to transcription factors and RNA polymerases, epigenetic marks allow or prevent gene expression and control cellular functions including cytokine expression. CpG-DNA methylation and post-translational modifications to histone tails are the two most well accepted epigenetic mechanisms. The involvement of epigenetic mechanisms in the pathogenesis of systemic lupus erythematosus (SLE) has been suggested by the development of lupus-like symptoms by individuals who received procainamide or hydralazine treatment resulting in a reduction of CpG-DNA methylation. To date, a growing body of literature indicates that the deregulation of cytokine expression through epigenetic disturbances can result in altered immune responses and autoimmune reactions. Over the past decade, various global and regional epigenetic alterations have been reported in immune cells from patients with SLE and other autoimmune disorders. More recently, the molecular mechanisms that result in epigenetic disturbances have been addressed, and deregulated transcription factor networks have been demonstrated to mediate epigenetic alterations in B and T lymphocytes from SLE patients. A better understanding of the molecular events that contribute to epigenetic alterations and subsequent immune imbalance is essential for the establishment of disease biomarkers and identification of potential therapeutic targets.
    Autoimmunity 04/2014; 47(4). DOI:10.3109/08916934.2013.801462 · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein phosphatase 2A (PP2A) is a highly conserved and ubiquitous serine/threonine phosphatase. We have previously shown that PP2A expression is increased in T cells of SLE patients and this increased expression and activity of PP2A plays a central role in the molecular pathogenesis of SLE. Although the control of PP2A expression has been the focus of many studies, many aspects of its regulation still remain poorly understood. In this study, we describe a novel mechanism of PP2A regulation. We propose that the transcription factor Ikaros binds to a variant site in the first intron of PP2A and modulates its expression. Exogenous expression of Ikaros leads to reduced levels of PP2Ac message as well as protein. Conversely, siRNA enabled silencing of Ikaros enhances the expression of PP2A, suggesting that Ikaros acts as a suppressor of PP2A expression. ChIP analysis further proved that Ikaros is recruited to this site in T cells. We also attempt to delineate the mechanism of Ikaros mediated PP2Ac gene suppression. We show that Ikaros mediated suppression of PP2A expression is at least partially dependent on the recruitment of the histone deacetylase HDAC1 to this intronic site. We conclude that the transcription factor Ikaros can regulate the expression of PP2A by binding to a site in the first intron and modulating chromatin modifications at this site via recruitment of HDAC1.
    Journal of Biological Chemistry 04/2014; 289(20). DOI:10.1074/jbc.M114.558197 · 4.57 Impact Factor
  • Katalin Kis-Toth, George C Tsokos
    [Show abstract] [Hide abstract]
    ABSTRACT: Signaling lymphocyte activation molecule family (SLAMF)2/CD48 is a coactivator and adhesion molecule on cells with hematopoietic origin. It ligates mainly SLAMF4 on effector/memory CD8(+) T cells and NK cells, suggesting a potential role during viral infection, with SLAMF2 acting as a ligand to activate SLAMF4-bearing cells. The ability of SLAMF2 to signal on its own after it is engaged and the functional consequences are largely unknown. We found that cytosolic DNA-activated dendritic cells (DCs) upregulate the expression of SLAMF2 molecules. Using anti-SLAMF2 Ab and SLAMF4 recombinant protein, we found that SLAMF2 engagement activates immature DCs and, more interestingly, prolongs the survival of DNA-activated DCs by inhibiting IFN-β production and IFN-β-induced apoptosis and promotes the production of the granzyme B inhibitor protease inhibitor-9. Thus, SLAMF2 can serve as a survival molecule for DNA-activated DCs during their interaction with SLAMF4-expressing cytotoxic T cells. Based on our results, we propose that SLAMF2 engagement regulates adaptive immune responses by providing longer access of putative APCs to virus-specific effector T cells by prolonging the time frame of effective stimulation.
    The Journal of Immunology 03/2014; 192(9). DOI:10.4049/jimmunol.1302909 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.
    The Journal of clinical investigation 03/2014; 124(5). DOI:10.1172/JCI73411 · 13.77 Impact Factor
  • Trevor E. Davis, Katalin Kis‐Toth, George C. Tsokos
    [Show abstract] [Hide abstract]
    ABSTRACT: Background/Purpose:MicroRNA (miRNA, miR) are short RNA species (20–23 nt) that act post-transcriptionally modulating messenger RNA (mRNA) translation or stability. They control many biological processes including cell differentiation and homeostasis. Abnormal levels of miRNA have been implicated in cancers and autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Steroids are first line anti-inflammatory medications that act through transcriptional or posttranscriptional gene regulation. In multiple instances steroids cause mRNA destabilization indicating a potential role for miRNA.Previously, using high-throughput microarray analysis, we found that methylprednisolone (MP) decreased miR-155 expression in CD4+ T cells in vitro. miR-155 is highly expressed in immune cells and influential in cell differentiation. This influence may in part be mediated through suppression of cytokine signaling 1 (SOCS1), a known target of miR-155. SOCS1 inhibits multiple JAK/STAT pathways, which may inhibit cell proliferation and differentiation. Steroids have also been shown to inhibit proliferation, differentiation and the JAK/STAT pathways. Steroids through blocking the IL-12/STAT4 pathway inhibit Th1 differentiation. This pathway is in part controlled by SOCS1, which should be under the control of miR-155. Following our previous work here we explore the potential mechanism of action of miR-155 during MP treatment of T cells.Methods:Total or naive CD4+ T cells were isolated from peripheral blood of healthy donors and activated by anti-CD3/anti-CD28 antibodies for up to 5 days with or without Th1 polarizing conditions (10 nM IL-12 and 5 mM anti-IL-4 neutralizing antibody) and with or without exposure to 10−6 M of methylprednisolone. Some cells were first transfected with mimic miR-155, control mimic miR, anti-miR-155, or control anti-miR by electroporation. Effects on miR-155, SOCS1, STAT phosphorylation, IFNg production and Th1 differentiation were monitored using flow cytometry, RNA quantification by PCR, and protein quantification by ELISA or western blot analysis.Results:Activated T cells treated with MP decrease miR-155 expression and increase SOCS1 expression. In turn, SOCS1 decreases JAK/STAT signaling and inhibits response to cytokines, notably IL-12, resulting in decreased IFNg production by activated T cells.Conclusion:We found that the anti-inflammatory effects of MP, at least in part, act through decreasing miR-155 in T cells by inhibiting JAK/STAT signaling and cytokine production through modulating SOCS1 expression. Based on our findings we propose that miR-155 inhibition could be utilized to suppress inflammation without the myriad of side effects currently inherent in chronic steroid therapy.
    03/2014; 66(S11). DOI:10.1002/art.38535

Publication Stats

11k Citations
2,418.05 Total Impact Points


  • 2007–2015
    • Beth Israel Deaconess Medical Center
      • • Division of Rheumatology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2007–2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007–2013
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2012
    • U.S. Army Institute of Surgical Research
      Houston, Texas, United States
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 1987–2010
    • Uniformed Services University of the Health Sciences
      • Department of Medicine
      베서스다, Maryland, United States
    • National Institute of Arthritis and Musculoskeletal and Skin Diseases
      베서스다, Maryland, United States
  • 1998–2008
    • Walter Reed Army Institute of Research
      • Center for Military Psychiatry and Neuroscience Research
      Silver Spring, Maryland, United States
  • 2006
    • Yale University
      • School of Medicine
      New Haven, CT, United States
  • 2005
    • National and Kapodistrian University of Athens
      • Division of Propedeutic Medicine I
      Athens, Attiki, Greece
  • 1992–2005
    • Walter Reed National Military Medical Center
      Washington, Washington, D.C., United States
    • State University of New York
      New York, New York, United States
  • 2003
    • Washington Hospital Center
      Washington, Washington, D.C., United States
    • National University of Cordoba, Argentina
      Córdoba, Cordoba, Argentina
  • 2002–2003
    • Wake Forest School of Medicine
      • Department of Internal Medicine
      Winston-Salem, NC, United States
  • 2001
    • University of Maryland, College Park
      • Department of Cell Biology & Molecular Genetics
      Maryland, United States
  • 1999
    • Henry M Jackson Foundation
      Maryland City, Maryland, United States
  • 1997
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1995
    • Laiko Hospital
      Athínai, Attica, Greece
  • 1990–1993
    • University of Maryland, Baltimore
      • • Department of Medicine
      • • Division of Rheumatology and Clinical Immunology
      Baltimore, Maryland, United States
  • 1991
    • National Eye Institute
      Maryland, United States
    • Children's National Medical Center
      • Division of Rheumatology
      Washington, Washington, D.C., United States
  • 1981–1991
    • National Institutes of Health
      • • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      • • Branch of Metabolic Diseases Branch (MDB)
      베서스다, Maryland, United States
  • 1986–1990
    • The National Institute of Diabetes and Digestive and Kidney Diseases
      Maryland, United States
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Parasitic Diseases (LPD)
      Maryland, United States
  • 1988
    • University of Toronto
      • Department of Psychiatry
      Toronto, Ontario, Canada
  • 1982–1988
    • U.S. Food and Drug Administration
      • Laboratory of Cellular Hematology
      Washington, Washington, D.C., United States