Femke van Wijk

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (79)363.61 Total impact

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    ABSTRACT: For many autoimmune diseases, the underlying mechanism is still unknown. In order to get more insight into the etiology of autoimmune diseases, we recently published a study were we performed epigenetic profiling and RNA sequencing on CD4+CD45RO+ T cells derived from the site of inflammation of Juvenile Idiopathic Arthritis (JIA) patients and compared this with healthy controls [1]. In this “Data in Brief”, we focus on the analysis of our RNA sequencing data reported in this study, of which the raw and processed files can be found in GEO under GSE71595. We provide a detailed description of the downstream analysis, quality controls, and different analysis methods or techniques that validate the results obtained with RNA-sequencing.
    No preview · Article · Nov 2015 · Genomics Data
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    ABSTRACT: Autologous hematopoietic stem cell transplantation (HSCT) is increasingly considered for patients with severe autoimmune diseases whose prognosis is poor with standard treatments. Regulatory T cells (Treg) are thought to be important for disease remission after HSCT. Eliciting the role of donor and host Treg in autologous HSCT is however not possible in humans due to autologous nature of the intervention. Therefore, we investigated their role during immune reconstitution and re-establishment of immune tolerance and their therapeutic potential following congenic bone marrow transplantation (BMT) in a proteoglycan-induced arthritis (PGIA) mouse model. In addition, we determined Treg T cell receptor CDR3 diversity before and after HSCT in patients with juvenile idiopathic arthritis and juvenile dermatomyositis. In the PGIA BMT model, after an initial predominance of host Treg, graft-derived Treg started dominating and displayed a more stable phenotype with better suppressive capacity. Patient samples revealed a striking lack of diversity of the Treg repertoire before HSCT. This ameliorated after HSCT confirming reset of the Treg compartment following HSCT. In the mouse model a therapeutic approach was initiated by infusing extra Foxp3(GFP+)Treg during BMT. Infusion of Foxp3(GFP+)Treg did not elicit additional clinical improvement but conversely delayed reconstitution of the graft-derived T cell compartment. These data indicate that HSCT-mediated amelioration of autoimmune disease involves renewal of the Treg pool. In addition, infusion of extra Treg during BMT results in a delayed reconstitution of T-cell compartments. Treg therapy may therefore hamper development of long-term tolerance and should therefore be approached with caution in the clinical autologous setting.
    No preview · Article · Oct 2015 · Blood
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    ABSTRACT: A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced TH2 effector cytokines in vitro and in vivo and CREM-/- mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the TH2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased TH2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the TH2 response and determines the outcome of allergic asthma.
    Full-text · Article · Oct 2015 · Oncotarget
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    ABSTRACT: The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.
    Full-text · Article · Sep 2015 · Cell Reports
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    ABSTRACT: Objective: Resistance of effector T cells (Teff) to regulatory T cell (Treg)-mediated suppression contributes to the breakdown of peripheral tolerance in the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients. However, an unanswered question is whether this resistant phenotype is self-sustained and whether CD8(+) and CD4(+) Teff share the same mechanism of resistance to suppression. Here, we investigated CD8(+) Teff intrinsic resistance to suppression and how this can be targeted therapeutically. Methods: CD8(+) or CD4(+) Teff were cultured with or without antigen presenting cells (APC) in Treg-dependent and -independent suppression assays. Synovial fluid (SF)-derived Teff were cross-cultured with peripheral blood (PB) Treg from JIA patients or healthy controls. TNF-α or IFN-γ blocking agents were used to restore Teff responsiveness to suppression. Results: Suppression of cell proliferation and cytokine production by CD8(+) Teff from the SF of JIA patients was severely impaired compared to PB of JIA patients, regardless of APC and CD4(+) Teff cell presence. Similarly to CD4(+) Teff, impaired suppression of CD8(+) Teff was shown to be an intrinsic feature of this cell population. Whereas TNF-α blockade rescued both CD8(+) and CD4(+) Teff resistance, autocrine release of IFN-γ selectively sustained CD8(+) Teff resistance, which could be relieved by IFN-γ blockade. Conclusion: Unlike CD4(+) Teff, resistance of CD8(+) Teff to suppression at the site of autoimmune inflammation is maintained by autocrine release of IFN-γ and blockade of IFN-γ restores CD8(+) Teff responsiveness to suppression. These findings indicate a potential therapeutic value of blocking IFN-γ to restore immune regulation in JIA. This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2015 · Arthritis and Rheumatology
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    ABSTRACT: Background Juvenile dermatomyositis (JDM) is a rare, but severe chronic systemic autoimmune disease in children, characterized by muscle weakness and a typical skin rash. Clinical evaluation of disease activity remains challenging. Recently, we identified a protein that highly correlates with disease activity in a Dutch JDM cohort: galectin-9 (gal-9). The immunobiological role of gal-9 in autoimmune diseases is still controversial. On the one hand it is known for its immunosuppressive effects by inducing apoptosis in T-helper (Th) 1 and Th17 cells and activating regulatory T cells, on the other hand it has been implicated in T cell activation and Th1 skewing. Objectives To validate the potential of gal-9 as a biomarker in JDM and investigate its immunobiological effects on T cell skewing and activation. Methods Gal-9 was measured in patient's serum of an independent JDM cohort by multiplex immunoassay. For functional experiments, naive CD4 T cells were isolated and stimulated with different concentrations of gal-9, plus anti-CD3 and antigen presenting cells. To test specificity, a gal-9 blocking agent (TIM-3 fusion protein) as well as a control from the galectin family (galectin-8) were included. Flow cytometric analysis of proliferation and T cell activation markers was performed on day 3 and 5 of culture. Cytokines TNFα, IFNγ, IL-13, IL-17 and IL-10 were measured in the culture supernatants of days 3, 5 and 7 by multiplex immunoassay. Results Measurement of gal-9 in serum confirmed its high discriminative value for active disease versus remission (P=.0001; AUC 0.894; OR 9.17) even under medication, as well as a strong correlation with the clinical disease activity scores CMAS and Physician's Global VAS. On a functional level, the presence of gal-9 induced a slight but significant increase in naive CD4 T cell proliferation after 3 days of culture. The T cell activation markers CD25, CD69 and TIM-3 showed the same pattern. Gal-9 also increased production of IFNγ, TNFα and IL-10, mainly at day 7. These effects were not seen in the control conditions. Conclusions We confirmed the potential use of a very robust biomarker, galectin-9, that highly correlates with disease activity in juvenile dermatomyositis. Introduction of this biomarker into clinical practice will help to personalize treatment. Functionally, we found that gal-9 is a T cell activator, causing increased proliferation, cytokine production and expression of T cell activation markers. The high levels of circulating gal-9 in JDM patients may therefore contribute to the immunopathogenesis of JDM. References Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: The balance between Treg and effector T cells (Teff) is crucial for immune regulation in JIA. How MTX, the cornerstone treatment in JIA, influences this balance in vivo is poorly elucidated. The aim of this study was to investigate quantitative and qualitative effects of MTX on Treg and Teff in JIA patients during MTX treatment. Peripheral blood samples were obtained from JIA patients at the start of MTX and 3 and 6 months thereafter. Treg numbers and phenotypes were determined by flow cytometry and suppressive function in allogeneic suppression assays. Teff proliferation upon stimulation with anti-CD3, activation status and intracellular cytokine production were determined by flow cytometry. Effector cell responsiveness to suppression was investigated in autologous suppression assays. Effector cell cytokines in supernatants of proliferation and suppression assays and in plasma were measured by cytokine multiplex assay. MTX treatment in JIA did not affect Treg phenotype and function. Instead, MTX treatment enhanced, rather than diminished, CD4(+) and CD8(+) T cell proliferation of JIA patients after 6 months of therapy, independent of clinical response. Effector cells during MTX treatment were equally responsive to Treg-mediated suppression. MTX treatment did not attenuate Teff activation status and their capacity to produce IL-13, IL-17, TNF-α and IFN-γ. Similarly to Teff proliferation, plasma IFN-γ concentrations after 6 months were increased. This study provides the novel insight that MTX treatment in JIA does not attenuate Teff function but, conversely, enhances T cell proliferation and IFN-γ plasma concentrations in JIA patients. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Apr 2015 · Rheumatology (Oxford, England)
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    ABSTRACT: CD4+CD25high regulatory T (Treg) cells are key players in the maintenance of peripheral immune tolerance [1]. Stable expression of the FOXP3 transcription factor is essential for Treg cells’ ability to suppress the immune responses of conventional T (Tconv) cells [2]. FOXP3 stability in murine Treg cells has been linked to FOXP3 locus demethylation at the CNS2 [3, 4], also called the Treg-specific demethylated region (TSDR) [5].This article is protected by copyright. All rights reserved
    No preview · Article · Oct 2014 · European Journal of Immunology

  • No preview · Article · Sep 2014 · Annals of the Rheumatic Diseases
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    Full-text · Dataset · Apr 2014
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    ABSTRACT: Background: Juvenile Dermatomyositis (JDM) is a systemic autoimmune disorder of unknown immunopathogenesis in which the immune system targets the microvasculature of skeletal muscles, skin and other organs. The current mainstay of therapy is a steroid regimen in combination with other immunosuppressive treatments. So far there are no validated markers for monitoring disease activity, which hampers a personalized treatment.Objectives: To identify a panel of proteins specifically related to active disease in JDM.Methods: We performed a multiplex immunoassay for plasma levels of 45 proteins related to inflammation in 25 JDM patients in four clinically well-defined groups, as determined by clinical activity and treatment. We compared them with age-matched controls consisting of 14 healthy children and 8 children with non-autoimmune muscle disease.Results: Cluster analysis of circulating proteins showed distinct profiles for JDM patients and controls based on a group of 10 proteins. Next to CXCL10, TNFR2 and galectin-9 were significantly increased in active JDM. The levels of these three proteins were tightly linked to active disease and correlated to clinical scores (CMAS and PhyGloVAS).Conclusion: This study shows that CXCL10, TNFR2 and galectin-9 correspond to the disease status in JDM and thus could be helpful in monitoring disease activity and guiding treatment. Furthermore, they might provide new knowledge about the pathogenesis of this autoimmune disease. © 2014 American College of Rheumatology.
    Full-text · Article · Apr 2014 · Arthritis and Rheumatology
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    Arjan Boltjes · Femke van Wijk
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    ABSTRACT: Dendritic cells (DC) represent a heterogeneous population of antigen-presenting cells that are crucial in initiating and shaping immune responses. Although all DC are capable of antigen-uptake, processing, and presentation to T cells, DC subtypes differ in their origin, location, migration patterns, and specialized immunological roles. While in recent years, there have been rapid advances in understanding DC subset ontogeny, development, and function in mice, relatively little is known about the heterogeneity and functional specialization of human DC subsets, especially in tissues. In steady-state, DC progenitors deriving from the bone marrow give rise to lymphoid organ-resident DC and to migratory tissue DC that act as tissue sentinels. During inflammation additional DC and monocytes are recruited to the tissues where they are further activated and promote T helper cell subset polarization depending on the environment. In the current review, we will give an overview of the latest developments in human DC research both in steady-state and under inflammatory conditions. In this context, we review recent findings on DC subsets, DC-mediated cross-presentation, monocyte-DC relationships, inflammatory DC development, and DC-instructed T-cell polarization. Finally, we discuss the potential role of human DC in chronic inflammatory diseases.
    Full-text · Article · Apr 2014 · Frontiers in Immunology
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    ABSTRACT: Autologous stem cell transplantation (ASCT) induces long-term drug-free disease remission in patients with juvenile idiopathic arthritis. This study was undertaken to further unravel the immunologic mechanisms underlying ASCT by using a mouse model of proteoglycan-induced arthritis (PGIA). For initiation of PGIA, BALB/c mice received 2 intraperitoneal injections of human PG in a synthetic adjuvant on days 0 and 21. Five weeks after the first immunization, the mice were exposed to total body irradiation (7.5 Gy) and received (un)manipulated bone marrow (BM) grafts from mice with PGIA. Clinical scores, T cell reconstitution, (antigen-specific) T cell cytokine production, and intracellular cytokine expression were determined following autologous BM transplantation (ABMT). ABMT resulted in amelioration and stabilization of arthritis scores. BM grafts containing T cells and T cell-depleted grafts provided the same clinical benefit, with similar reductions in PG-induced T cell proliferation and the number of PG-specific autoantibodies. In vivo reexposure to PG did not exacerbate disease. Following ABMT, basal levels of disease-associated proinflammatory cytokines (interferon-γ [IFNγ], interleukin-17 [IL-17], and tumor necrosis factor α [TNFα]) were reduced. In addition, restimulation of T cells with PG induced a strong reduction in disease-associated proinflammatory cytokine production. Finally, although the remaining host T cells displayed a proinflammatory phenotype following ABMT, IFNγ, IL-17, and TNFα production by the newly reconstituted donor-derived T cells was significantly lower. Taken together, our data suggest that ABMT restores immune tolerance by renewal and modulation of the Teff cell compartment, leading to a strong reduction in proinflammatory (self antigen-specific) T cell cytokine production.
    Full-text · Article · Feb 2014 · Arthritis and Rheumatology
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    ABSTRACT: Allergic sensitization is initiated by allergen-specific Th2-cell responses. Data on early allergen-specific T-cell responses in allergic children are scarce. We hypothesized that allergen-specific Th2-cell responses can be detected preceding sensitization. Therefore, peripheral blood mononuclear cells (PBMC) of nonsensitized, 'not-yet' sensitized or sensitized children were cultured with highly purified allergens. Cytokine levels in supernatant were determined using multiplex assay and GATA3 expression by flow cytometry. PBMC of sensitized children aged 3 and 5 years showed higher production of IL4, IL5 and IL13 and higher expression of GATA3 in response to purified allergens compared to nonsensitized children. PBMC of children that were 'not-yet' sensitized already showed higher levels of IL5 and IL13 and higher GATA3 expression at age 3 years. This shows that allergen-specific in vitro Th2 responses precede the detection of allergen-specific IgE, which can provide a window of opportunity for novel therapeutic interventions.
    No preview · Article · Jan 2014 · Allergy
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    ABSTRACT: Objective To determine whether therapeutic strategies that block interleukin-6 (IL-6) or tumor necrosis factor (TNF) can improve the responsiveness of Teff cells to suppression in patients with juvenile idiopathic arthritis (JIA). Methods Synovial fluid mononuclear cells (SFMCs) from the inflamed joints of patients with JIA were cultured in the presence of etanercept or anti-IL-6 in vitro, and protein kinase B (PKB)/c-Akt activation and responsiveness to suppression were measured. In addition, the in vivo effects of TNF blockade were investigated using peripheral blood mononuclear cells obtained from patients before and after the start of etanercept therapy. ResultsIn vitro treatment of SFMCs with anti-IL-6 led to improved Treg cell-mediated suppression of cell proliferation in some but not all patients. Blocking TNF with etanercept, however, clearly enhanced suppression, especially that of CD8+ T cells. In the presence of etanercept, PKB/c-Akt activation of Teff cells was reduced, and cells became more susceptible to transforming growth factor -mediated suppression, indicating that anti-TNF directly targets resistant Teff cells. Conclusion This study is the first to show that anti-TNF targets the resistance of Teff cells to suppression, resulting in improved regulation of inflammatory effector cells.
    No preview · Article · Jan 2014 · Arthritis & Rheumatology
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    ABSTRACT: Self-reactive T cells have shown to have a potential role as regulators of the immune system preventing or even suppressing autoimmunity. One of the most abundant proteins that can be eluted from human HLA molecules is heat shock protein 70 (HSP70). The aims of the current study are to identify HSP70 epitopes based on published HLA elution studies and to investigate whether T cells from healthy individuals may respond to such self-epitopes. A literature search and subsequent in silico binding prediction based on theoretical MHC binding motifs resulted in the identification of seven HSP70 epitopes. PBMCs of healthy controls proliferated after incubation with two of the seven peptides (H167 and H290). Furthermore H161, H290, and H443 induced CD69 expression or production of cytokines IFNγ or TNFα in healthy controls. The identification of these naturally presented epitopes and the response they elicit in the normal immune system make them potential candidates to study during inflammatory conditions as well as in autoimmune diseases.
    Full-text · Article · Jan 2014 · Cell Stress and Chaperones
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    ABSTRACT: To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA). MSC were administered ip or ia after establishment of arthritis. We used serial bioluminescence imaging (BLI) to trace luciferase-transfected MSC. Mice were sacrificed at different time points to examine immunomodulatory changes in blood and secondary lymphoid organs. Both ip and local ia MSC injection resulted in a beneficial clinical and histological effect on established PGIA. BLI showed that MSC ip and ia in arthritic mice are largely retained for several weeks in the peritoneal cavity or injected joint respectively, without signs of migration. Following MSC treatment pathogenic PG-specific IgG2a antibodies in serum decreased. The Th2 cytokine IL-4 was only upregulated in PG-stimulated lymphocytes from spleens in ip treated mice and in lymphocytes from draining lymph nodes in ia treated mice. An increase in production of IL-10 was seen with equal distribution. Although IFN-γ was also elevated, the IFN-γ/IL-4 ratio in MSC treated mice was opposite to the ratio in (untreated) active PGIA. MSC treatment, both ip and ia, suppresses PGIA, a non-collagen induced arthritis model. MSC are largely retained for weeks in the injection region. MSC treatment induced at the region of injection a deviation of PG-specific immune responses, suggesting a more regulatory phenotype with production of IL-4 and IL-10, but also of IFN-γ, and a systemic decrease of pathogenic PG-specific IgG2a antibodies. These findings underpin the potential of MSC treatment in resistant arthritis.
    No preview · Article · Jan 2014 · Annals of the rheumatic diseases
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    Full-text · Article · Dec 2013 · Pediatric Rheumatology
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    G Mijnheer · B Prakken · FV Wijk

    Preview · Article · Dec 2013 · Pediatric Rheumatology
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    Full-text · Article · Dec 2013 · Pediatric Rheumatology

Publication Stats

779 Citations
363.61 Total Impact Points

Institutions

  • 2007-2015
    • University Medical Center Utrecht
      • • Department of Immunology
      • • Division of Pediatrics
      Utrecht, Utrecht, Netherlands
  • 2009-2011
    • La Jolla Institute for Allergy & Immunology
      • Division of Developmental Immunology
      لا هویا, California, United States
  • 2007-2011
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 2004-2010
    • Utrecht University
      • Institute for Risk Assessment Sciences (IRAS)
      Utrecht, Utrecht, Netherlands
    • Netherlands Institute for Space Research, Utrecht
      Utrecht, Utrecht, Netherlands
  • 2008
    • University of California, San Diego
      San Diego, California, United States