George C Tsokos

Harvard University, Cambridge, Massachusetts, United States

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Publications (531)2477.85 Total impact

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    ABSTRACT: Objectives The relationship of immune dysregulation and autoantibody production that may contribute to systemic lupus erythematosus (SLE) pathogenesis is unknown. This study evaluates the individual and combined contributions of autoantibodies, type I interferon (IFN-α) activity, and IFN-associated soluble mediators to disease development leading to SLE. Methods Serial serum specimens from 55 individuals collected prior to SLE classification (average timespan=4.3 years) and unaffected healthy controls matched by age (±5 years), gender, race and time of sample procurement were obtained from the Department of Defense Serum Repository. Levels of serum IFN-α activity, IFN-associated mediators and autoantibodies were evaluated and temporal relationships assessed by growth curve modelling, path analysis, analysis of covariance and random forest models. Results In cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p<0.001). Autoantibody positivity coincided with or followed type II IFN dysregulation, preceding IFN-α activity in growth curve models, with elevated IFN-α activity and B-lymphocyte stimulator levels occurring shortly before SLE classification (p≤0.005). Cases were distinguished by multivariate random forest models incorporating IFN-γ, macrophage chemoattractant protein (MCP)-3, anti-chromatin and anti-spliceosome antibodies (accuracy 93% >4 years pre-classification; 97% within 2 years of SLE classification). Conclusions Years before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies and subsequent elevations in IFN-α activity immediately preceding SLE classification. Perturbations in select immunological processes may help identify at-risk individuals for further clinical evaluation or participation in prospective intervention trials.
    No preview · Article · Jan 2016 · Annals of the Rheumatic Diseases
  • Vaishali R. Moulton · Kamalpreet Nagpal · George C. Tsokos
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    ABSTRACT: Autoimmune diseases result from a complex interaction of genetics, environment, and hormones, eventually leading to a break in immune tolerance to “self”-causing pathology and destruction of various tissues. Diseases may be organ specific, affecting mainly the joints (rheumatoid arthritis) or neuronal tissue (multiple sclerosis), or may be systemic, including systemic lupus erythematosus (SLE), Sjögren syndrome and dermatomyositis. SLE is a multi-system autoimmune disease that mainly affects women of child-bearing age with significant morbidity, and it can affect any organ in the body, including the skin, joints, and kidneys.1 T lymphocytes are major effectors of the adaptive immune system and are crucial in host defence against pathogens. Aberrant T cells play a critical role in autoimmune disease, not only by helping B cells to enable autoantibody production but also by infiltrating tissues leading to immunopathology. In this chapter we describe the role and regulation of T cell signalling, activation, gene expression, and cytokines with a focus on T cell defects in SLE, the prototype autoimmune disease.
    No preview · Chapter · Dec 2015
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    ABSTRACT: Treatment of autoimmune diseases is still largely based on the use of systemically acting immunosuppressive drugs, which invariably cause severe side effects. Calcium/calmodulin-dependent protein kinase IV is involved in the suppression of IL-2 and the production of IL-17. Its pharmacologic or genetic inhibition limits autoimmune disease in mice. In this study, we demonstrate that KN93, a small-molecule inhibitor of calcium/calmodulin-dependent protein kinase IV, targeted to CD4(+) T cells via a nanolipogel delivery system, markedly reduced experimental autoimmune encephalomyelitis and was 10-fold more potent than the free systemically delivered drug in the lupus mouse models. The targeted delivery of KN93 did not deplete T cells but effectively blocked Th17 cell differentiation and expansion as measured in the spinal cords and kidneys of mice developing experimental autoimmune encephalomyelitis or lupus, respectively. These results highlight the promise of cell-targeted inhibition of molecules involved in the pathogenesis of autoimmunity as a means of advancing the treatment of autoimmune diseases.
    No preview · Article · Nov 2015 · The Journal of Immunology
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    ABSTRACT: Background: T cells regulate the adaptive immune response and have altered function in autoimmunity. Systemic Lupus Erythematosus (SLE) has great diversity of presentation and treatment response. Peripheral blood component gene expression affords an efficient platform to investigate SLE immune dysfunction and help guide diagnostic biomarker development for patient stratification. Methods: Gene expression in peripheral blood T cell samples for 14 SLE patients and 4 controls was analyzed by high depth sequencing. Unbiased clustering of genes and samples revealed novel patterns related to disease etiology. Functional annotation of these genes highlights pathways and protein domains involved in SLE manifestation. Results: We found transcripts for hundreds of genes consistently altered in SLE T cell samples, for which DAVID analysis highlights induction of pathways related to mitochondria, nucleotide metabolism and DNA replication. Fewer genes had reduced mRNA expression, and these were linked to signaling, splicing and transcriptional activity. Gene signatures associated with the presence of dsDNA antibodies, low complement levels and nephritis were detected. T cell gene expression also indicates the presence of several patient subtypes, such as having only a minimal expression phenotype, male type, or severe with or without induction of genes related to membrane protein production. Conclusions: Unbiased transcriptome analysis of a peripheral blood component provides insight on autoimmune pathophysiology and patient variability. We present an open source workflow and richly annotated dataset to support investigation of T cell biology, develop biomarkers for patient stratification and perhaps help indicate a source of SLE immune dysfunction.
    Preview · Article · Nov 2015 · PLoS ONE
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    ABSTRACT: Objective: Kidney podocytes and their slit diaphragms prevent urinary protein loss. T cells from patients with systemic lupus erythematosus display increased expression of calcium/calmodulin kinase IV (CaMKIV). However, the role of CaMKIV in podocyte function in lupus nephritis (LN) is unknown. Methods: We treated kidney podocytes with IgG from healthy individuals or patients with LN and then analyzed gene expression using a DNA microarray. The localization of IgG in podocytes was analyzed by immunofluorescence staining with or without silencing of neonatal Fc receptor (FcRn). In addition, we silenced CaMK4 in podocytes and we analyzed selected gene expression. We also examined the expression of 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 resulted in entry of IgG into the cytoplasm. IgG entered podocytes using the FcRn receptor because less IgG was found in the cytoplasm of podocytes treated with FcRn siRNA. 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. 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: LN IgG enters podocytes and upregulates CaMKIV followed by increased expression of genes known to be linked to podocyte damage and T cell activation. Targeted inhibition of CaMKIV in podocytes may prove of clinical use in patients with LN. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Arthritis and Rheumatology
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    ABSTRACT: Mutations of the Wiskott-Aldrich syndrome gene (WAS) are responsible for the Wiskott-Aldrich syndrome, a disease characterized by thrombocytopenia, eczema, immunodeficiency and autoimmunity. Mice with conditional deficiency of Was in B lymphocytes (B/WcKO) have revealed a critical role for WAS protein (WASP) expression in B lymphocytes in the maintenance of immune homeostasis. Neural WASP (N-WASP) is a broadly expressed homologue of WASP, and regulates signaling in B cells by modulating B cell receptor (BCR) clustering and internalization. To investigate whether N-WASP expression in B cells plays a role in the development of autoimmunity in WAS, we have generated a double conditional mouse lacking both WASP and N-WASP selectively in B lymphocytes (B/DcKO mouse). As compared to B/WcKO mice, B/DcKO mice showed defective B lymphocyte proliferation in response to simultaneous stimulation via BCR and TLR9, and impaired antibody responses to T cell-dependent antigens. Defective B cell activation in B/DcKO mice was associated with decreased autoantibody production and lack of autoimmune kidney disease, as compared to B/WcKO mice. These results demonstrate that N-WASP expression in B lymphocytes is required for the development of autoimmunity of WAS and may represent a novel therapeutic target in this disease.
    Full-text · Article · Oct 2015 · Blood
  • O N Pamuk · M A Balci · S Donmez · G C Tsokos
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    ABSTRACT: Background: We estimated the prevalence and incidence, clinical features, treatment, and prognosis of systemic lupus erythematosus (SLE) patients in the Thrace region of Turkey. Methods: We retrospectively evaluated 331 patients (307 female, 24 male, mean age 38.5 years) diagnosed with SLE between 2003 and 2014. Clinical features, treatments, and response to various treatment modalities were recorded. Our hospital has been the only tertiary referral center for rheumatological diseases for a mixed rural and urban population of 620,477 people (306,036 females, 314,411 males) for more than 16 years. Results: The mean annual incidence of SLE was 4.44/100,000 (females, 8.4/100,000; males, 0.6/100,000). The overall prevalence of SLE was 51.7/100,000 (females, 97.7/100,000; males, 7/100,000). Major organ involvement was present in the following percentages: neurologic involvement: 20.1%; renal involvement: 28.2%; autoimmune hemolytic anemia: 9.6%; thrombocytopenia: 14.7%. Seventeeen SLE patients (13 females, four males) died at a median follow-up of 48 months. The five-year survival was 94.5%, and the ten-year survival was 89.9%. According to Kaplan-Meier survival analysis, poor prognostic factors were: male gender (p = 0.015); smoking (p = 0.02); pleural involvement (p = 0.011); thrombocytopenia (p = 0.021); myocarditis (p = 0.028); renal involvement (p = 0.037); treatment with cyclophosphamide (p = 0.011); and an initial high SLEDAI score (>4) (p = 0.02). Lymphopenia at the time of diagnosis appeared as a favorable prognostic factor (p = 0.008). Cox regression analysis revealed myocarditis (OR: 20.4, p = 0.018) and age at diagnosis (OR: 1.11, p = 0.035) to be poor, and lymphopenia at the time of diagnosis to be good prognostic factors (OR:0.13, p = 0.031). Conclusions: The annual incidence and prevalence of SLE in the Thrace region of Turkey is lower than those reported in North America, however they are similar to those reported for European countries. Clinical manifestations appear to be milder, whereas survival was similar to those recorded in Western countries.
    No preview · Article · Sep 2015 · Lupus
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    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.
    No preview · Article · Aug 2015 · Arthritis and Rheumatology
  • 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.
    No preview · Article · Aug 2015 · Nature Reviews Rheumatology
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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.
    Full-text · Article · Jul 2015 · Clinical and experimental rheumatology
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    ABSTRACT: T lymphocytes from many patients with systemic lupus erythematosus (SLE) express decreased levels of the T cell receptor (TCR)-associated CD3 zeta (ζ) signaling chain, a feature directly linked to their abnormal phenotype and function. Reduced mRNA expression partly due to defective alternative splicing, contributes to the reduced expression of CD3ζ chain. We previously identified by oligonucleotide pulldown and mass spectrometry approaches, the serine arginine-rich splicing factor 1 (SRSF1) binding to the 3' untranslated region (UTR) of CD3ζ mRNA. We showed that SRSF1 regulates alternative splicing of the 3'UTR of CD3ζ to promote expression of the normal full length 3`UTR over an unstable splice variant in human T cells. In this study we show that SRSF1 regulates transcriptional activation of CD3ζ. Specifically, overexpression and silencing of SRSF1 respectively increases and decreases CD3ζ total mRNA and protein expression in Jurkat and primary T cells. Using promoter-luciferase assays, we show that SRSF1 enhances transcriptional activity of the CD3ζ promoter in a dose dependent manner. Chromatin immunoprecipitation assays show that SRSF1 is recruited to the CD3ζ promoter. These results indicate that SRSF1 contributes to transcriptional activation of CD3ζ. Thus our study identifies a novel mechanism whereby SRSF1 regulates CD3ζ expression in human T cells and may contribute to the T cell defect in SLE.
    Preview · Article · Jul 2015 · PLoS ONE
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    ABSTRACT: Background IL-17 producing T helper (Th17) cells have been closely associated with the development of organ damage in inflammatory and autoimmune diseases. We have previously reported that Calcium/calmodulin-dependent protein kinase IV (CaMK4) plays a crucial role in Th17 cell differentiation invitro and invivo and suggested that CaMK4 inhibition ameliorates clinical and pathological findings in experimental autoimmune encephalomyelitis (EAE) and MRL/lpr mice (1). We have also shown that Il-17 is important in the expression of anti-glomerular basement membrane Ab-induced glomerulonephritis (AIGN) (2). However, the effect of CaMK4 on recruitment of pathogenic T cells to target tissues in inflammatory settings has not been studied. Objectives The aim of this study is to determine the role of CaMK4 in the infiltration of inflammatory cells to target tissues and to explore its mechanism. Methods We induced experimental AIGN in Camk4 sufficient or deficient mice and compared the kidney injury including the number of IL-17 producing cells and the expression of CCR6 and CCL20 in both groups. We also evaluated the effect of KN-93, a compound of CaMK4 antagonist in this AIGN model. Results Camk4 deficient mice displayed less glomerular injury and less proteinuria at day 14 and at day 21 after induction of AIGN. The expression of CCR6 and CCL20 in inflamed kidney is lower in Camk4 deficient mice. Kidney infiltration by Th17 producing CD4+ T cells was decreased significantly in Camk4 deficient mice, suggesting that CaMK4 facilitated AIGN damage by promoting local inflammatory cells accumulation. In line with these observations, KN-93 treatment improved clinical and pathological finings in mice induced AIGN at dose dependent manner. Conclusions Collectively, our results indicate that CaMK4 inhibition might be a novel therapeutic strategy of Th17 cells-mediated inflammatory diseases. References Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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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.
    No preview · Article · May 2015 · Cytokine
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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.
    No preview · Article · May 2015 · Clinical Immunology
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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.
    Full-text · Article · May 2015 · The Journal of clinical investigation
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    ABSTRACT: TCR-αβ+ double-negative (DN; CD4-CD8-) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8+ cells. However, the conditions that govern the loss of CD8 expression after Ag encounter are unknown. In this study, we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate Ags as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate Ag is sensed as self. This process is restricted to tissues where the Ag is present. We also show that DN T cells derived from self-reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated with self-Ag encounter.
    No preview · Article · May 2015 · The Journal of Immunology
  • 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: sagepub.co.uk/journalsPermissions.nav.
    No preview · Article · Apr 2015 · Lupus
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    George C Tsokos

    Preview · Article · Mar 2015 · Circulation
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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.
    No preview · Article · Feb 2015 · Analytical Biochemistry
  • S.A. Apostolidis · J.C. Crispin · G.C. Tsokos
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    ABSTRACT: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology. It affects mostly women in their child-bearing years. In SLE, the immune system attacks multiple organs including the kidneys, joints, skin, and nervous system among others and thus, SLE manifestations correspond to the combination of organs targeted in every patient. Genetic, epigenetic, and environmental factors all contribute to the pathogenesis of SLE and both the innate and adaptive arm of the immune system is involved in the development of this autoimmune disease. With the orchestrated action of T cells, B cells, dendritic cells, monocytes, and neutrophils, immune self-tolerance is lost in patients with SLE and tissue damage and destruction ensues.
    No preview · Article · Dec 2014

Publication Stats

14k Citations
2,477.85 Total Impact Points

Institutions

  • 2008-2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007-2015
    • Beth Israel Deaconess Medical Center
      • • Division of Rheumatology
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2007-2011
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 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
  • 1995-2008
    • 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
    • University of Salzburg
      Salzburg, Salzburg, Austria
  • 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
    • National University of Cordoba, Argentina
      Córdoba, Cordoba, Argentina
    • Wake Forest School of Medicine
      • Department of Internal Medicine
      Winston-Salem, NC, United States
  • 1990-2003
    • University of Maryland, Baltimore
      • • Department of Microbiology and Immunology
      • • Department of Surgery
      • • Division of Rheumatology and Clinical Immunology
      Baltimore, Maryland, United States
    • Children's National Medical Center
      • Division of Rheumatology
      Washington, Washington, D.C., United States
  • 2002
    • Silver Spring Networks
      레드우드시티, California, 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
  • 1991-1995
    • Laiko Hospital
      • First Department of Surgery
      Athínai, Attica, Greece
    • National Eye Institute
      Maryland, 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
  • 1989
    • Kumamoto University
      • Department of Pediatrics
      Kumamoto, Kumamoto, Japan
  • 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