Femke van Wijk

University Medical Center Utrecht, Utrecht, Utrecht, Netherlands

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Publications (60)249.71 Total impact

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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
    European Journal of Immunology 07/2014; · 4.97 Impact Factor
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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.
    Arthritis & Rheumatology. 04/2014;
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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.
    Arthritis & rheumatology (Hoboken, N.J.). 02/2014; 66(2):350-6.
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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.
    Allergy 01/2014; · 5.88 Impact Factor
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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.
    Cell Stress and Chaperones 01/2014; · 2.48 Impact Factor
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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.
    Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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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.
    Frontiers in Immunology 01/2014; 5:131.
  • The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 10/2013; 188(8):1039-1040. · 11.04 Impact Factor
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    ABSTRACT: Objective. Resistance of effector T cells (Teff) to suppression contributes to disturbed immune regulation in autoimmune disease. Targeting this unresponsiveness to suppression might therefore have beneficial effects in autoimmune inflammation. In juvenile idiopathic arthritis (JIA) we have recently shown that Teff from inflamed joints are refractory to suppression, which was associated with enhanced PKB/c-akt activation in these cells. Here we investigated whether therapeutic strategies that block IL-6 or TNFα can improve responsiveness of Teff to suppression in patients with JIA. Methods. Mononuclear cells from inflamed joints of JIA patients (SFMCs) were cultured in the presence of etanercept or anti-IL-6 in vitro and PKB/c-akt activation and responsiveness to suppression was measured. In addition, in vivo effects of TNFα blockade were investigated using PBMCs of patient before and after start of etanercept therapy. Results. In vitro treatment of SFMCs with anti-IL-6 led to improved Treg mediated suppression of cell proliferation in some, but not all patients. Blocking TNFα with etanercept however clearly enhanced suppression, especially for CD8(+) T cells. In the presence of etanercept PKB/c-akt activation of Teff was reduced and cells became more susceptible to TGFβ mediated suppression, indicating that anti-TNFα directly targets resistant Teff. Conclusion. This study is the first to show that anti-TNFα targets resistance of Teff to suppression, resulting in improved regulation of inflammatory effector cells © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 08/2013; · 7.48 Impact Factor
  • The Journal of allergy and clinical immunology 07/2013; · 12.05 Impact Factor
  • Berent Prakken, Ellen Wehrens, Femke van Wijk
    Arthritis & Rheumatology 03/2013; 65(3). · 7.48 Impact Factor
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    ABSTRACT: TCRαβ thymocytes differentiate into either CD8αβ(+) cytotoxic T lymphocytes or CD4(+) helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II-restricted CD4(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4(+) T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4(+) T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II-restricted CD4(+) cytotoxic T lymphocytes.
    Nature Immunology 01/2013; · 26.20 Impact Factor
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    ABSTRACT: Prophylactic vaccinations are generally performed to protect naïve individuals with or without suppressed immune responsiveness. In a mouse model for Influenza vaccinations the specific alterations of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) in the immune modulation induced by orally supplied oligosaccharides containing scGOS/lcFOS/pAOS was assessed. This dietary intervention increased vaccine specific DTH responses. In addition, a significant increased percentage of T-bet(+) (Th1) activated CD69(+)CD4(+) T cells (p<0.001) and reduced percentage of Gata-3(+) (Th2) activated CD69(+)CD4(+)T cells (p<0.001) was detected in the mesenteric lymph nodes (MLN) of mice receiving scGOS/lcFOS/pAOS compared to control mice. Although no difference in the number or percentage of Tregs (CD4(+)Foxp3(+)) could be determined after scGOS/lcFOS/pAOS intervention, the percentage of CXCR3 (+) /T-bet(+) (Th1-Tregs) was significantly reduced (p<0.05) in mice receiving scGOS/lcFOS/pAOS as compared to mice receiving placebo diets. Moreover, although no absolute difference in suppressive capacity could be detected, an alteration in cytokine profile suggests a regulatory T cell shift towards a reducing Th1 suppression profile, supporting an improved vaccination response. These data are indicative for improved vaccine responsiveness due to reduced Th1 suppressive capacity in the Treg population of mice fed the oligosaccharide specific diet, showing compartmentalization within the Treg population. The modulation of Tregs to control immune responses provides an additional arm of intervention using alternative strategies possibly leading to the development of improved vaccines.
    PLoS ONE 01/2013; 8(9):e75148. · 3.53 Impact Factor
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    ABSTRACT: Mucosal administration of an antigen eliciting bystander suppression at the site of inflammation results in effective antigen-specific immunotherapy for autoimmune diseases. Heat shock proteins are bystander antigens that are effective in peptide-specific immunotherapy in both experimental and human autoimmune disease. The efficacy of preventive peptide immunotherapy is increased by enhancing peptide-specific immune responses with proinflammatory agents. Combining peptide-specific immunotherapy with general suppression of inflammation may improve its therapeutic effect.
    Clinical & Experimental Immunology 01/2013; 171(1):20-9. · 3.41 Impact Factor
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    ABSTRACT: Since the discovery of FOXP3+ regulatory T (T(REG)) cells over 15 years ago, intensive research has focused on their presence, phenotype and function in autoimmune disease. Whether deficiencies in T(REG) cells underlie autoimmune pathology and whether, or how, therapeutic approaches based on these cells might be successful is still the subject of debate. The potential role of T(REG)-cell extrinsic factors, such as proinflammatory cytokines and resistance of effector T cells to suppression, as the cause of regulatory defects in chronic autoimmune inflammation is an intensive area of research. It is now clear that, at the site of inflammation, antigen presenting cells (APCs) and proinflammatory cytokines drive effector T cell skewing and plasticity, and that these T cells can become unresponsive to regulation. In addition, expansion and function of T(REG) cells is affected by the inflammatory environment; indeed, new data suggest that, in certain conditions, T(REG) cells promote inflammation. This Review summarizes the latest findings on changes in effector T cell homeostasis in autoimmune disease and focuses on how mechanisms that normally regulate these cells are affected in the inflamed joints of patients with arthritis. These findings have important clinical implications and will affect the development of new therapeutic strategies for autoimmune arthritis.
    Nature Reviews Rheumatology 01/2013; 9(1):34-42. · 9.75 Impact Factor
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    ABSTRACT: PURPOSE OF REVIEW: Since their discovery over 15 years ago, intensive research has focused on the presence, phenotype and function of FOXP3 regulatory T cells (Treg) in autoimmune diseases such as rheumatoid arthritis (RA). The questions of whether Treg deficiencies underlie autoimmune pathology and whether or how Treg-related therapeutic approaches might be successful are still a subject of a vivid debate. In this review we give an overview of how current therapies influence Treg numbers and function in RA and juvenile idiopathic arthritis (JIA) and discuss these findings in the light of new Treg-based intervention strategies for autoimmune arthritis. RECENT FINDINGS: The attempt to relate rheumatic diseases like rheumatoid arthritis and juvenile idiopathic arthritis to Treg has led to somewhat heterogeneous observations. So far, no clear defects in Treg numbers or function have been identified in autoimmune arthritis. The current standard therapies, that is methotrexate and biologicals, are generally effective, but the exact mechanism of action and their effect on Treg is not fully known. Nevertheless, the majority of in-vitro and ex-vivo data point towards a positive influence of these treatments on Treg number and function. These observations are not all consistent, however, and it is not known whether the observed effects on Treg are primary or secondary effects. To safely conduct targeted regulatory T-cell therapy in rheumatic diseases more knowledge about regulatory T-cell function in an inflammatory environment is needed that coincides with the initiative to elucidate the exact mechanism of current therapies.
    Current opinion in rheumatology 12/2012; · 4.60 Impact Factor
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    Journal of Translational Medicine 11/2012; 10(3). · 3.46 Impact Factor
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    ABSTRACT: Peptide-based immune tolerance induction is considered an attractive treatment option for autoimmune diseases. The authors have developed a novel method that can enhance the induction of protective peptide-specific T-cell responses, using a rat arthritis model. The authors focused on the Toll-like receptor 9 ligand CpG, which was shown to stimulate regulatory T-cell proliferation when added to plasmacytoid dendritic cells (pDC) using in-vitro cultures. The peptide used is a heat shock protein 60 epitope (p1) that elicits tolerogenic peptide-specific immune responses in human arthritis patients and was recently shown to have protective capacity as a bystander antigen in the rat adjuvant arthritis model. Rats were treated with three nasal doses of p1, CpG or a combination of p1 and CpG. Antigen-presenting cells were studied in nose-draining lymph nodes (mandibular lymph nodes; MLN) after nasal treatment, and T-cell responses were analysed in joint-draining lymph nodes after arthritis induction. Nasal co-administration of p1/CpG significantly augmented the arthritis-protective effect of p1, while CpG treatment alone did not. Co-treatment of p1/CpG increased both the number and activation status of pDC in draining MLN, which was accompanied by amplified p1-specific T-cell proliferation and interleukin (IL)-10 production. During early arthritis, p1-specific IL-10 production was identified at the site of inflammation. P1 and p1/CpG-treated rats showed a greater amount of CD4+FoxP3+ regulatory T cells in the joint-draining lymph nodes, which correlated with lower arthritis scores. These clinical and immunological data suggest the use of CpG as a potent adjuvant for mucosal peptide-specific immune therapy in arthritis.
    Annals of the rheumatic diseases 05/2012; 71(10):1706-15. · 8.11 Impact Factor

Publication Stats

410 Citations
249.71 Total Impact Points


  • 2007–2014
    • University Medical Center Utrecht
      • Department of Immunology
      Utrecht, Utrecht, Netherlands
  • 2013
    • Sanford-Burnham Medical Research Institute
      La Jolla, California, United States
  • 2009–2013
    • La Jolla Institute for Allergy & Immunology
      • Division of Developmental Immunology
      La Jolla, CA, United States
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
  • 2007–2011
    • Canisius-Wilhelmina Ziekenhuis
      Nymegen, Gelderland, Netherlands
  • 2004–2007
    • Universiteit Utrecht
      • Institute for Risk Assessment Sciences (IRAS)
      Utrecht, Provincie Utrecht, Netherlands