Kim L L Habets

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (20)98.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. Atherosclerosis is a chronic inflammatory process with features of autoimmune disease. We therefore investigated impact of hematopoietic Bim deficiency on plaque formation. Hypothesis: Bim deficient leukocytes will be highly (auto)reactive in a hyperlipidemic setting, increasing plaque apoptosis and necrosis and thus contributing to plaque destabilization.
    Cardiovascular research. 07/2014; 103(suppl 1):S134.
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    ABSTRACT: Patients suffering from cardiovascular disease have well-established atherosclerotic lesions, rendering lesion regression of therapeutic interest. The OX40 (TNFRSF4)-OX40 ligand (OX40L; TNFSF4) pathway is important for the proliferation and survival of T cells, stimulates B cells, and is associated with cardiovascular disease. We hypothesized that interference with the OX40-OX40L pathway, in combination with decreases in cholesterol, may induce regression of atherosclerosis. LDLr(-/-) mice were fed a Western-type diet for 10 wk, after which they received chow diet and were treated with anti-OX40L or PBS for 10 wk. A significant regression of lesions was observed in the aorta and aortic arch of anti-OX40L-treated mice compared with control mice. Interference of the OX40-OX40L pathway reduced Th2 responses, as shown by decreases in GATA-3 and IL-4 levels. Also, IgE levels were decreased, as demonstrated by reduced mast cell presence and activation. Notably, IL-5 production by T and B1 cells was increased, thus enhancing atheroprotective oxidized low-density lipoprotein-specific IgM production. The increase in IL-5 production and IgM was mediated by IL-33 production by APCs upon OX40L blockade. We conclude that interruption of the OX40-OX40L signaling pathway, combined with decreases in dietary cholesterol, induces the regression of atherosclerosis through induction of IL-5-producing T cells and oxidized low-density lipoprotein-specific IgM and reductions in Th2 and mast cells.
    The Journal of Immunology 09/2013; · 5.52 Impact Factor
  • Kim L L Habets, Tom W J Huizinga, René E M Toes
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    ABSTRACT: Vascular injury is the initial manifestation of inflammation resulting in the recruitment and activation of various cell types. The integrity of the vascular wall is monitored by platelets that become activated in the presence of exposed subendothelium. Besides their well-established role in haemostasis, ample data are now emerging on the many immunoregulatory functions of platelets. Platelets store and release a large plethora of cytokines, chemokines and growth factors. They also represent the largest circulating pool of many inflammatory mediators like P-selectin, CD40L and non-neuronal serotonin. Furthermore, complement activation occurs on the platelet surface and deposition of complement results in platelet activation. Overall, platelets have multiple functions in both innate and adaptive immunity. Further insight into the multifaceted role of platelets could therefore provide important clues into how we could implement current platelet therapy to reduce both platelet-induced thrombosis and inflammation. In this review, we discuss the current perceptions of platelet involvement in various autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and multiple sclerosis.
    European Journal of Clinical Investigation 04/2013; · 3.37 Impact Factor
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    ABSTRACT: The role of toll-like receptors (TLRs) in vascular remodeling is well established. However, the involvement of the endosomal TLRs is unknown. Here, we study the effect of combined blocking of TLR7 and TLR9 on postinterventional remodeling and accelerated atherosclerosis. In hypercholesterolemic apolipoprotein E*3-Leiden mice, femoral artery cuff placement led to strong increase of TLR7 and TLR9 presence demonstrated by immunohistochemistry. Blocking TLR7/9 with a dual antagonist in vivo reduced neointimal thickening and foam cell accumulation 14 days after surgery by 65.6% (P=0.0079). Intima/media ratio was reduced by 64.5% and luminal stenosis by 62.8%. The TLR7/9 antagonist reduced the arterial wall inflammation, with reduced macrophage infiltration, decreased cytoplasmic high-mobility group box 1 expression, and altered serum interleukin-10 levels. Stimulation of cultured macrophages with TLR7 and TLR9 ligands enhanced tumor necrosis factor-α expression, which is decreased by TLR7/9 antagonist coadministration. Additionally, the antagonist abolished the TLR7/9-enhanced low-density lipoprotein uptake. The antagonist also reduced oxidized low-density lipoprotein-induced foam cell formation, most likely not via decreased influx but via increased efflux, because CD36 expression was unchanged whereas interleukin-10 levels were higher (36.1 ± 22.3 pg/mL versus 128.9 ± 6.6 pg/mL; P=0.008). Blocking TLR7 and TLR9 reduced postinterventional vascular remodeling and foam cell accumulation indicating TLR7 and TLR9 as novel therapeutic targets.
    Arteriosclerosis Thrombosis and Vascular Biology 05/2012; 32(8):e72-80. · 6.34 Impact Factor
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    ABSTRACT: AimsThe importance of transforming growth factor beta (TGFβ) as an immune regulatory cytokine in atherosclerosis has been established. However, the role of TGFβ signalling in dendritic cells (DCs) and in DC-mediated T cell proliferation and differentiation in atherosclerosis is unknown.Methods and resultsHere, we investigated the effect of disrupted TGFβ signalling in DCs on atherosclerosis by using mice carrying a transgene resulting in functional inactivation of TGFβ receptor II (TGFβRII) signalling in CD11c(+) cells (Apoe(-/-)CD11cDNR). Apoe(-/-)CD11cDNR mice exhibited an over two-fold increase in the plaque area compared with Apoe(-/-) mice. Plaques of Apoe(-/-)CD11cDNR mice showed an increase in CD45(+) leucocyte content, and specifically in CD3(+), CD4(+) and CD8(+) cells, whereas macrophage content was not affected. In lymphoid organs, Apoe(-/-)CD11cDNR mice had equal amounts of CD11c(+) cells, and CD11c(+)CD8(+) and CD11c(+)CD8(-) subsets, but showed a subtle shift in the CD11c(+)CD8(-) population towards the more inflammatory CD11c(+)CD8(-)CD4(-) DC subset. In addition, the number of plasmacytoid-DCs decreased. Maturation markers such as MHCII, CD86 and CD40 on CD11c(hi) cells did not change, but the CD11cDNR DCs produced more TNFα and IL-12. CD11c(+) cells from CD11cDNR mice strongly induced T-cell proliferation and activation, resulting in increased amounts of effector T cells producing high amounts of Th1 (IFN-γ), Th2 (IL-4, IL-10), Th17 (IL-17), and Treg (IL-10) cytokines.Conclusion Here, we show that loss of TGFβRII signalling in CD11c(+) cells induces subtle changes in DC subsets, which provoke uncontrolled T cell activation and maturation. This results in increased atherosclerosis and an inflammatory plaque phenotype during hypercholesterolaemia.
    European Heart Journal 05/2012; · 14.10 Impact Factor
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    ABSTRACT: [This corrects the article on p. e30984 in vol. 7.].
    PLoS ONE 01/2012; 7(5). · 3.73 Impact Factor
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    ABSTRACT: ABCA7, a close relative of ABCA1 which facilitates cholesterol efflux to lipid-poor apoproteins, has been implicated in macrophage lipid efflux and clearance of apoptotic cells in in vitro studies. In the current study, we investigated the in vivo effects of macrophage ABCA7 deficiency on lipid metabolism and atherosclerosis. Chimeras with dysfunctional ABCA7 in macrophages and other blood cells were generated by transplantation of bone marrow from ABCA7 knockout (KO) mice into irradiated low-density lipoprotein receptor (LDLr) KO mice. Unexpectedly, macrophage ABCA7 deficiency did not significantly affect atherosclerosis susceptibility of LDLr KO mice after 10 weeks Western-type diet feeding. However, ABCA7 deficiency was associated with 2-fold (p<0.05) higher macrophage ABCA1 mRNA expression levels. Combined disruption of ABCA1 and ABCA7 in bone-marrow-derived cells increased atherosclerotic lesion development (1.5-fold (p>0.05) as compared to wild type transplanted mice. However, single deletion of ABCA1 had a similar effect (1.8-fold, p<0.05). Macrophage foam cell accumulation in the peritoneal cavity was reduced in ABCA1/ABCA7 dKO transplanted animals as compared to single ABCA1 KO transplanted mice, which was associated with increased ABCG1 expression. Interestingly, spleens of ABCA1/ABCA7 double KO transplanted mice were significantly larger as compared to the other 3 groups and showed massive macrophage lipid accumulation, a reduction in CD3+ T-cells, and increased expression of key regulators of erythropoiesis. In conclusion, deletion of ABCA7 in bone marrow-derived cells does not affect atherogenesis in the arterial wall neither in the absence or presence of ABCA1. Interestingly, combined deletion of bone marrow ABCA1 and ABCA7 causes severe splenomegaly associated with cellular lipid accumulation, a reduction in splenic CD3+ T cells, and induced markers of erythropoeisis. Our data indicate that ABCA7 may play a role in T cell proliferation and erythropoeisis in spleen.
    PLoS ONE 01/2012; 7(3):e30984. · 3.73 Impact Factor
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    ABSTRACT: Bifunctional, pH-activatable BODIPY dyes were developed and incorporated in mannose cluster-containing activity-based probes for cysteine proteases. Mannose receptor-dependent uptake of the probes in dendritic cells, followed by trafficking to acidic cellular compartments resulted in fluorescence as seen by live-cell imaging, and subsequent cathepsin inhibition.
    Chemical Communications 09/2011; 47(33):9363-5. · 6.38 Impact Factor
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    ABSTRACT: Regulatory T cells (Tregs) play an important role in the regulation of T cell-mediated immune responses through suppression of T cell proliferation and cytokine production. In atherosclerosis, a chronic autoimmune-like disease, an imbalance between pro-inflammatory cells (Th1/Th2) and anti-inflammatory cells (Tregs) exists. Therefore, increased Treg numbers may be beneficial for patients suffering from atherosclerosis. In the present study, we determined the effect of a vast expansion of Tregs on the initiation and regression of well-established lesions. For in vivo Treg expansion, LDL receptor deficient (LDLr(-/-)) mice received repeated intraperitoneal injections of a complex of IL-2 and anti-IL-2 mAb. This resulted in a 10-fold increase in CD4(+)CD25(hi)Foxp3(+) T cells, which potently suppressed effector T cells ex vivo. During initial atherosclerosis, IL-2 complex treatment of LDLr(-/-) mice fed a Western-type diet reduced atherosclerotic lesion formation by 39%. The effect on pre-existing lesions was assessed by combining IL-2 complex treatment with a vigorous lowering of blood lipid levels in LDLr(-/-) mice. This did not induce regression of atherosclerosis, but significantly enhanced lesion stability. Our data show differential roles for Tregs during atherosclerosis: Tregs suppress inflammatory responses and attenuate initial atherosclerosis development, while during regression Tregs can improve stabilization of the atherosclerotic lesions.
    Atherosclerosis 05/2011; 218(1):53-60. · 3.71 Impact Factor
  • Atherosclerosis 11/2010; 213(1):e18. · 3.71 Impact Factor
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    ABSTRACT: To determine the role of macrophage ATP-binding cassette transporter A5 (ABCA5) in cellular cholesterol homeostasis and atherosclerotic lesion development. Chimeras with dysfunctional macrophage ABCA5 (ABCA5(-M/-M)) were generated by transplantation of bone marrow from ABCA5 knockout (ABCA5(-/-)) mice into irradiated LDLr(-/-) mice. In vitro, bone marrow-derived macrophages from ABCA5(-M/-M) chimeras exhibited a 29% (P<0.001) decrease in cholesterol efflux to HDL, whereas a 21% (P=0.07) increase in cholesterol efflux to apoA-I was observed. Interestingly, expression of ABCA1, but not ABCG1, was up-regulated in absence of functional ABCA5 in macrophages. To induce atherosclerosis, the transplanted LDLr(-/-) mice were fed a high-cholesterol Western-type diet (WTD) for 6, 10, or 18weeks, allowing analysis of effects on initial as well as advanced lesion development. Atherosclerosis development was not affected in male ABCA5(-M/-M) chimeras after 6, 10, and 18weeks WTD feeding. However, female ABCA5(-M/-M) chimeras did develop significantly (P<0.05) larger aortic root lesions as compared with female controls after 6 and 10weeks WTD feeding. ABCA5 influences macrophage cholesterol efflux, and selective disruption of ABCA5 in macrophages leads to increased atherosclerotic lesion development in female LDLr(-/-) mice.
    Biochemical and Biophysical Research Communications 04/2010; 395(3):387-94. · 2.41 Impact Factor
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    ABSTRACT: Modification of lipoproteins plays an important role in the development of atherosclerosis. Oxidatively modified low-density lipoprotein (oxLDL) has a number of pro-inflammatory effects, whereas immunization with various forms of oxLDL is able to reduce atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatory effects of LDL. In this study, we transferred oxLDL-pulsed mature DCs (mDCs) to LDL receptor-null (LDLr(-/-)) mice and examined the effects on atherosclerosis. Bone marrow-derived DCs were cultured for 10 days in the presence of granulocyte-macrophage colony-stimulating factor. Immature DCs were matured by lipopolysaccharide and pulsed with copper-oxidized LDL. These mDCs were transferred three times to LDLr(-/-) mice before the induction of atherosclerosis by Western-type diet feeding. The transfer of oxLDL-pulsed mDCs resulted in an 87% reduction in carotid artery lesion size (P < 0.001) with a concurrent increase in plaque stability, whereas treatment using mDCs pulsed with the atherosclerosis-irrelevant antigen, ovalbumin, did not influence lesion size or stability. Furthermore, the vaccination procedure resulted in the induction of oxLDL-specific T cells with a reduced Th1 profile and an increase in oxLDL-specific IgG levels, which contributed to a reduction in foam cell formation. These data indicate that vaccination with oxLDL-pulsed mDCs provides a novel and powerful strategy for the immunomodulation of atherosclerosis.
    Cardiovascular research 10/2009; 85(3):622-30. · 5.80 Impact Factor
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    ABSTRACT: Regulatory T cells are crucial for immune homeostasis and an impaired regulatory T cell function results in many pathological conditions. Regulatory T cells have already been described to be protective in atherosclerosis. However the exact contribution of Foxp3-expressing natural regulatory T cells in atherosclerosis has not been elucidated yet. In this study we vaccinated LDL receptor deficient mice with dendritic cells which are transfected with Foxp3 encoding mRNA and studied the effect on initial atherosclerosis. Vaccination against Foxp3 resulted in a reduction of Foxp3(+) regulatory T cells in several organs and in an increase in initial atherosclerotic lesion formation. Furthermore we observed an increase in plaque cellularity and increased T cell proliferation in the Foxp3 vaccinated mice. We further establish the protective role of Tregs in atherosclerosis. The results illustrate the important role for Foxp3-expressing regulatory T cells in atherosclerosis, thereby providing a potential opportunity for therapeutic intervention against this disease.
    Atherosclerosis 08/2009; 209(1):74-80. · 3.71 Impact Factor
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    ABSTRACT: Tag for professionals: A fluorescently tagged clustered mannoside DCG-04 analogue (see structure) is designed and synthesized using a modular approach. Uptake of the probe in professional antigen presenting cells and subsequent labeling of cathepsins proceeded in a mannose-receptor dependent manner.
    Angewandte Chemie International Edition 02/2009; 48(9):1629-32. · 13.73 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2009; 10(2).
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    ABSTRACT: TIE2(+) cells play a crucial role in processes that are involved in atherosclerosis, such as angiogenesis. Therefore, the specific deletion of TIE2(+) cells by means of DNA vaccination may affect atherosclerosis. Cellular immunity against cells that overexpress TIE2 was established in LDLr(-/-) mice by a novel oral DNA vaccination technique, in which an attenuated Salmonella typhimurium strain was used as a carrier for plasmid pcDNA3.1 encoding TIE2. After three oral vaccinations with 2-week time intervals LDLr(-/-) mice were put on a Western type diet and atherosclerosis was induced. Eight weeks after vaccination FACS analysis of circulating peripheral blood mononuclear cells (PBMCs) revealed a significant decrease (33%, p<0.05) in TIE2(+) cells upon vaccination against TIE2, indicating the successful induction of cellular immunity following vaccination against TIE2. Six weeks after collar placement vaccination against TIE2 resulted in significantly decreased carotid atherosclerosis, as indicated by 30% (p<0.05) reduced intima area and 27% (p<0.05) reduced intima/lumen ratios. Furthermore, atherosclerosis was attenuated in the aortic root by 42% (p<0.05), further underlining the anti-atherosclerotic effect of vaccination against TIE2. Adventitial angiogenesis was reduced by 61% (p<0.05) upon vaccination against TIE2 providing a mechanism via which vaccination against TIE2 inhibits lesion formation. Histochemical analysis of the atherosclerotic lesion composition revealed a 1.6-fold (carotid artery, p<0.05) and 1.9-fold (aortic root, p<0.05) increase in collagen content upon vaccination against TIE2, indicating a more stable plaque phenotype. We demonstrate that vaccination against TIE2 induces cellular immunity against cells that overexpress TIE2 and results in smaller atherosclerotic lesions with a more stable phenotype. Therefore, vaccination strategies that target cells that contribute to atherosclerosis, may be of potential use in the development of novel treatments of atherosclerosis.
    Atherosclerosis 10/2008; 204(2):365-71. · 3.71 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis. LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156+/-19x10(3) microm2 after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226+/-30x10(3) microm2; P<0.05) and not significantly different from single ABCG1 KO (117+/-22x10(3) microm2) and WT transplanted mice (112+/-15x10(3) microm2). Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts.
    Arteriosclerosis Thrombosis and Vascular Biology 02/2008; 28(2):258-64. · 6.34 Impact Factor
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    ABSTRACT: HSP60-specific T cells contribute to the development of the immune responses in atherosclerosis. This can be dampened by regulatory T cells activated via oral tolerance induction, and we explored the effect of oral tolerance induction to HSP60 and the peptide HSP60 (253 to 268) on atherosclerosis. HSP60 and HSP60 (253 to 268) were administered orally to LDLr(-/-) mice before induction of atherosclerosis and resulted in a significant 80% reduction in plaque size in the carotid arteries and in a 27% reduction in plaque size at the aortic root. Reduction in plaque size correlated with an increase in CD4(+)CD25(+)Foxp3(+) regulatory T cells in several organs and in an increased expression of Foxp3, CD25, and CTLA-4 in atherosclerotic lesions of HSP60-treated mice. The production of interleukin (IL)-10 and transforming growth factor (TGF)-beta by lymph node cells in response to HSP60 was observed after tolerance induction. Oral tolerance induction to HSP60 and a small HSP60-peptide leads to an increase in the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells, resulting in a decrease in plaque size as a consequence of increased production of IL-10 and TGF-beta. We conclude that these beneficial results of oral tolerance induction to HSP60 and HSP60 (253 to 268) may provide new therapeutic approaches for the treatment of atherosclerosis.
    Arteriosclerosis Thrombosis and Vascular Biology 01/2008; · 6.34 Impact Factor
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    ABSTRACT: Cardiovascular disease, as manifested in the formation of atherosclerotic lesions, can be described as a chronic inflammatory autoimmune-like disease that proceeds in the context of enhanced plasma lipid levels. Modulation of the immune response may therefore form a valuable therapy in addition to standardized cholesterol and blood pressure-lowering therapies. The purpose of this review is to describe a number of recent approaches to immunomodulate atherosclerosis: immunization against mediators involved in atherosclerosis, such as cytokines and modified low-density lipoprotein; intervention in cytokine pathways; intervention in co-stimulatory pathways; activation of regulatory T cells; and modulation of natural killer T cells. The most recent findings point to an important role for regulatory T cells in atherosclerotic lesion formation. The function of the regulatory T cells is modulated by chemokines and by co-stimulatory pathways, whereas the function of these cells can be strongly upregulated by anti-CD3 treatment and tolerance induction. In the near future the first exponents of this approach, such as immunization and enhancement of the function of regulatory T cells, may enter the first phase of clinical trials, and may ultimately add to the current therapies in atherosclerosis.
    Current Opinion in Lipidology 11/2007; 18(5):521-6. · 5.84 Impact Factor
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    ABSTRACT: Abstract Background. Modification of lipoproteins plays an important role in the development,of atherosclerosis. Oxidatively modified low-density lipoprotein (oxLDL) has a number of pro-inflammatory effects, whereas immunization,with various forms of oxLDL is able to reduce,atherosclerosis. The uptake of modified LDL by dendritic cells (DCs) and the presentation of epitopes thereof may form an important step in the immunomodulatoryeffects of LDL. In this study we transferred oxLDL-pulsed DCs to LDLr, mice ,every other day before induction of atherosclerosis by Western-type diet feeding. Transfer of oxLDL-pulsed DCs resulted in a 92% and 87% reduction in carotid artery lesion size compared to the PBS-treated or mature DCs-treated groups, respectively (P< 0.001). Lesion size in the aortic valves was not affected but we observed,at both sites an increase in plaque stability. The reduction in atherosclerosis was accompanied,by a 3.8 fold increase (P< 0.05) in Cu-oxLDL specific IgG levels whereas the levels of anti-malondialdehyde-LDL (MDA-LDL) specific IgG and IgM were not significantly affected. In addition, we also showed that the sera of mice treated with oxLDL-pulsed DCs reduced the formation of foam cells as compared to sera from PBS or mDCs- treated mice. Conclusions. Weconclude,that oxLDL-pulsed DCs induce an enhanced production of anti-oxLDL IgG

Publication Stats

292 Citations
98.44 Total Impact Points

Institutions

  • 2013–2014
    • Leiden University Medical Centre
      • Department of Rheumatology
      Leyden, South Holland, Netherlands
  • 2008–2013
    • Leiden University
      • Leiden Amsterdam Center for Drug Research
      Leiden, South Holland, Netherlands