George C Tsokos

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

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Publications (506)2446.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Engagement of signaling lymphocytic activation molecule family member 4 (SLAMF4, CD244, 2B4) by its ligand SLAMF2 (CD48) modulates function and expansion of both NK cells and a subset of cytotoxic CD8(+) T cells. As the cytotoxicity of CD8(+) T lymphocytes isolated from systemic lupus erythematosus (SLE) patients is known to be impaired, we assess here whether expression and function of the checkpoint regulator SLAMF4 is altered on SLE CD8(+) T cells. Expression of SLAMF4 by healthy and SLE T cells was determined by Q-PCR and flow cytometry. T cells were activated with anti-CD3 antibody and degranulation activity was monitored by the surface expression of LAMP-1 (CD107a). The SLAMF4(+) and SLAMF4(-) CD8 T cell subpopulations were characterized by LAMP-1, perforin and granzyme B expression and viral peptide-induced proliferation. SLAMF4 gene and surface protein expression is downregulated in CD8(+) T cells from SLE patients as compared to cells obtained from healthy donors. Importantly, SLE patients have significantly fewer SLAMF4(+) CD8(+) T cells compared to healthy subjects. SLAMF4(-) CD8(+) T cells from SLE patients have a decreased cytotoxic capacity and proliferative responses to viral peptides. The loss of memory SLAMF4(+) CD8(+) T cells in SLE patients is linked to the fact that they lose CD8 expression and become double negative T cells. A selective loss of SLAMF4(+) CD8(+) T cells contributes to the compromised ability of SLE T cells to fight against infections. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    Arthritis and Rheumatology 08/2015; DOI:10.1002/art.39410
  • Guo-Min Deng · George C Tsokos
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    ABSTRACT: Skin is the second most common organ (after the kidney) to be affected in patients with systemic lupus erythematosus (SLE), yet the aetiology of skin injury and the mechanisms involved in the development of dermal manifestations of SLE remain unclear. Ultraviolet light (UV), immune cells, cytokines and deposition of immunoglobulins all seem to have a role in the development of skin inflammation and damage in SLE. UV represents the most important environmental factor, and exposure to UV triggers the development of skin lesions in areas where immunoglobulin has been deposited and various other components of the immune system have accumulated. In addition, a number of intracellular kinases and transcription factors have also been demonstrated to be involved in the generation of skin lesions in lupus-prone mice. These molecules can be targeted by small-molecule inhibitors, leading to the prospect that treatments suitable for topical application, and with limited adverse effects, could be developed. Further studies to eliminate the burden of skin inflammation in patients with SLE are clearly required.
    Nature Reviews Rheumatology 08/2015; DOI:10.1038/nrrheum.2015.106 · 10.25 Impact Factor
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    ABSTRACT: The pathogenesis of fibrosis in scleroderma (SSc) is unknown. TGF-β and platelet-derived growth factor are important in the development of fibrosis and tyrosine kinases are involved in these pathways. The possible antifibrotic effects of various kinase inhibitors in SSc have been studied before. Spleen tyro-sine kinase (Syk) is a protein tyrosine kinase which activates intracellular signal transduction pathways; and has been claimed to be involved in the pathogenesis of systemic autoimmune diseases. Inhibition of Syk suppresses IgE- and IgG-associated FcR signal activation in various cell types; and suppresses experimental arthritis and skin and kidney disease in lupus-prone mice. We investigated the ability of a small drug, the Syk inhibitor, fostamatinib, to protect mice from bleomycin-induced SSc. Four study groups of BALB/c mice were included into this study: control, bleomycin (administered subcutaneously to BALB/c mice for 21 days), bleomycin and fostamatinib (mice fed with chow containing a Syk inhibitor for 21 days), and fostamatinib alone groups. Skin and lung tissue specimens were obtained and evaluated histologically. Treatment with fostamatinib significantly reduced skin thickness and fibrosis. Mice treated with fostamatinib also displayed less fibrosis and inflammation in the lung tissue. Following fostamatinib treatment, Syk, phospho-Syk, and TGF-β expression decreased in both skin and lung tissues. The Syk inhibitor fostamatinib prevented bleomycin-induced fibrosis and inflammation in the skin and in the lung. The anti-fibrotic effect of fostamatinib is linked to reduced Syk phosphorylation and TGF-β expression. The Syk pathway appears as a potential molecular target for therapeutic intervention in SSc.
    Clinical and experimental rheumatology 07/2015; · 2.97 Impact Factor
  • PLoS ONE 07/2015; 10(7):e0131073. DOI:10.1371/journal.pone.0131073 · 3.23 Impact Factor
  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):425.1-425. DOI:10.1136/annrheumdis-2015-eular.1415 · 10.38 Impact Factor
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    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
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    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
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    Vaishali R Moulton · George C Tsokos
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    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
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    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
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    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
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    Linda A Lieberman · George C Tsokos
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    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 · 3.23 Impact Factor
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    Journal of Allergy and Clinical Immunology 10/2014; 135(1). DOI:10.1016/j.jaci.2014.07.063 · 11.25 Impact Factor
  • George C Tsokos
    Arthritis Research & Therapy 09/2014; 16(Suppl 1):A30-A30. DOI:10.1186/ar4646 · 3.75 Impact Factor
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    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
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    Dataset: cell report
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    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
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    ABSTRACT: PURPOSE OF REVIEW: To describe our current understanding of the role of T cells in the pathophysiology of systemic lupus erythematosus (SLE). RECENT FINDINGS: Over the last few years, the dominant role of T cells in autoimmunity and SLE was established. Genome-wide-association studies led to the discovery of multiple single-nucleotide polymorphisms associated with SLE. Most of these single-nucleotide polymorphisms fall within the noncoding DNA regions of immune response-related genes and few seem to contribute to the observed abnormal T cell function. The field of epigenetics research developed rapidly and provided us with new insights into the observed generalized hypomethylation in SLE T cells, the abnormal histone modifications and the role of RNA interference. Old observations, such as the decreased interleukin-2 production, are better understood with our evolved knowledge of many signal transduction pathways and the way they converge and regulate the transcription of different genes in T cells. Finally, we are now able to identify subpopulations of T cells, such as Th17 and T regulatory cells, and to define their role in SLE. SUMMARY: T cells are key players in SLE, and over the last few years our understanding of their activation, signal transduction and gene regulation has evolved significantly.
    Current Opinion in Rheumatology 07/2014; 26(5). DOI:10.1097/BOR.0000000000000082 · 5.07 Impact Factor
  • K. Ichinose · T. Ushigusa · T. Koga · G. C. Tsokos · A. Kawakami
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    ABSTRACT: Background Kidney podocytes and their slit diaphragms contribute to prevent urinary protein loss. Previously, we have shown that T cell from patients with systemic lupus erythematosus (SLE) display increased expression of calcium/calmodulin kinase IV (CaMKIV). Pharmacologic inhibition of CaMKIV using spleen cells from lupus prone MRL/lpr mice resulted in decreased expression of CD86. However, the role of CaMKIV in podocytes function in lupus nephritis (LN) remains unknown. Objectives Here we evaluated the expression of CaMKIV in kidney biopsy specimens from patients with LN and the functional roles in a human podocyte cell line (AB8/13) after exposure to purified immunoglobulin G (IgG) from healthy controls and LN patients. Methods We treated kidney podocytes for 24 h with LN or normal IgG and then analyzed the gene expression using a DNA microarray. The localization of IgG in podocytes was analyzed by immunofluorescence staining with or without silencing of FcRn, the receptor of IgG. In addition, we silenced CaMKIV in podocytes and we analyzed selected gene expression by real-time polymerase chain reaction. We also examined the expression of the gene CD86 in kidney podocytes of MRL/lpr, MRL/lpr.camkiv−/− and MRL/MPJ mice by in situ hybridization. Results We found that exposure of podocytes to IgG from LN patients resulted in entry of IgG into the cytoplasm. IgG entered podocytes using the FcRn receptor because when podocytes where treated with FcRn siRNA less IgG was found in the cytoplasm. The DNA microarray studies of podocytes exposed to LN IgG revealed that genes that are related to the activation of immune cells or podocyte damage were upregulated. These genes included CD86, CaMKIV, PTPN22, PDE5A, CD47 and MALT1. Interestingly, CD86 expression decreased after silencing CaMKIV in podocytes. Also, in situ hybridization experiments showed that the expression of CD86 was reduced in podocytes from MRL/lpr.camkiv−/− mice. Conclusions IgG from LN patients may enter podocytes through the FcRn and causes the upregulation of a distinct set of genes which may alter podocyte function. Upregulation of CaMKIV appears to precede that of genes known to be linked to podocyte damage such as CD86. Blocking of FcRN or inhibition of CaMKIV may prove of clinical use in patients with LN References Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1859
    Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):193-193. DOI:10.1136/annrheumdis-2014-eular.1859 · 10.38 Impact Factor

Publication Stats

12k Citations
2,446.69 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
  • 1990–2001
    • University of Maryland, Baltimore
      • • Department of Surgery
      • • Department of Medicine
      • • Division of Rheumatology and Clinical Immunology
      Baltimore, Maryland, United States
  • 1999
    • Henry M Jackson Foundation
      Maryland City, Maryland, United States
  • 1997
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1994–1995
    • Laiko Hospital
      Athínai, Attica, Greece
  • 1991
    • National Eye Institute
      Maryland, United States
  • 1990–1991
    • 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