Publications by authors named "Theo van den Broek"

21 Publications

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How I started a journal for postdoctoral researchers.

Nature 2020 Dec 10. Epub 2020 Dec 10.

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http://dx.doi.org/10.1038/d41586-020-03498-5DOI Listing
December 2020

Follicular Dendritic Cells Modulate Germinal Center B Cell Diversity through FcγRIIB.

Cell Rep 2019 11;29(9):2745-2755.e4

Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Follicular dendritic cells (FDCs), a rare and enigmatic stromal cell type in the B cell follicles of secondary lymphoid organs, store and present antigen to B cells. While essential for germinal center (GC) responses, their exact role during GC B cell selection remains unknown. FDCs upregulate the inhibitory IgG Fc receptor FcγRIIB during GC formation. We show that the stromal deficiency of FcγRIIB does not affect GC B cell frequencies compared to wild-type mice. However, in the absence of FcγRIIB on FDCs, GCs show aberrant B cell selection during autoreactive and selective foreign antigen responses. These GCs are more diverse as measured by the AidCre -confetti system and show the persistence of IgM clones with decreased numbers of IgH mutations. Our results show that FDCs can modulate GC B cell diversity by the upregulation of FcγRIIB. Permissive clonal selection and subsequent increased GC diversity may affect epitope spreading during autoimmunity and foreign responses.
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http://dx.doi.org/10.1016/j.celrep.2019.10.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015177PMC
November 2019

INNO-LiPA DNA line probe assay misidentification of M. smegmatis as Mycobacterium fortuitum complex.

Diagn Microbiol Infect Dis 2019 Nov 24;95(3):114858. Epub 2019 Jun 24.

Department of Medical Microbiology, University Medical Center Utrecht, 3508, GA, Utrecht, The Netherlands.

Seven weeks after being kicked in the face by a cow, a 34-year-old male patient developed a posttraumatic mycobacterial lymphadenitis. A rapidly growing mycobacterial isolate cultured from a surgically drained lymphadenitis pus specimen was identified as Mycobacterium smegmatis by matrix-assisted laser desorption/ionization mass spectrometry and a combination of ITS-, hsp65-, and 16S rRNA-DNA sequence analysis, but as Mycobacterium fortuitum complex using the commercial INNO-LiPA Mycobacteria v2 line probe assay. As it is unclear if the misidentification of this strain is an exception, more research is required.
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http://dx.doi.org/10.1016/j.diagmicrobio.2019.06.010DOI Listing
November 2019

The full spectrum of human naive T cells.

Nat Rev Immunol 2018 06;18(6):363-373

Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.
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http://dx.doi.org/10.1038/s41577-018-0001-yDOI Listing
June 2018

Human neonatal thymectomy induces altered B-cell responses and autoreactivity.

Eur J Immunol 2017 11 6;47(11):1970-1981. Epub 2017 Sep 6.

Laboratory of Translational Immunology, University Medical Center Utrecht/Wilhelmina Children's Hospital, Utrecht, The Netherlands.

An association between T-cell lymphopenia and autoimmunity has long been proposed, but it remains to be elucidated whether T-cell lymphopenia affects B-cell responses to autoantigens. Human neonatal thymectomy (Tx) results in a decrease in T-cell numbers and we used this model to study the development of autoreactivity. Two cohorts of neonatally thymectomized individuals were examined, a cohort of young (1-5 years post-Tx, n = 10-27) and older children (>10 years, n = 26), and compared to healthy age-matched controls. T-cell and B-cell subsets were assessed and autoantibody profiling performed. Early post-Tx, a decrease in T-cell numbers (2.75 × 10 /L vs. 0.71 × 10 /L) and an increased proportion of memory T cells (19.72 vs. 57.43%) were observed. The presence of autoantibodies was correlated with an increased proportion of memory T cells in thymectomized children. No differences were seen in percentages of different B-cell subsets between the groups. The autoantigen microarray showed a skewed autoantibody response after Tx. In the cohort of older individuals, autoantibodies were present in 62% of the thymectomized children, while they were found in only 33% of the healthy controls. Overall, our data suggest that neonatal Tx skews the autoantibody profile. Preferential expansion and preservation of Treg (regulatory T) cell stability and function, may contribute to preventing autoimmune disease development after Tx.
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http://dx.doi.org/10.1002/eji.201746971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697610PMC
November 2017

Discriminative expression of whole blood genes in HIV patients with latent and active TB in Ethiopia.

Tuberculosis (Edinb) 2016 09 13;100:25-31. Epub 2016 Jun 13.

Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Transcriptomic host biomarkers could assist in developing effective diagnostics, vaccines and therapeutics for tuberculosis (TB). However, different biomarkers may be discriminatory in different populations depending on the host and bacillary genetics and HIV infection, and need to be addressed.

Methods: The expression levels of 45 genes that are known to be involved in or affected by TB pathogenesis were analyzed using dual color Reverse Transcriptase Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) assay in whole blood of 106 HIV positive individuals including active TB patients (TB(+)HIV(+), n = 29), and non TB patients that are tuberculin skin test positive (TST+) (TST(+)HIV(+), n = 26), or TST negative (TST(-)HIV(+), n = 51).

Results: Between the two clinical groups (TB(+)HIV(+) vs. TST(-)HIV(+)) 8 genes were differently expressed (CCL19, CD14, CD8A, FPR1, IL7R, CCL22, TNFRSF1A, and FCGR1A); between TB(+)HIV(+) vs. TST(+)HIV(+), 6 genes (CD14, IL7R, TIMP2, CCL22, TNFRSF1A, and FCGR1A) were differently expressed. Since no difference in gene expression was revealed between TST(+)HIV(+) vs. TST(-)HIV(+), we clustered both the TST(+)HIV(+) and TST(-)HIV(+) individuals as one group (TST(+/-)HIV(+)) and compared gene expression with TB(+)HIV(+) patients. Thus, the results revealed that the levels of five genes (CD8A, TIMP2, CCL22, FCGR1A and TNFRSF1A) were the most accurate single gene markers for differentiation between TB(+)HIV(+) and TST(+/-)HIV(+), with AUCs of 0.71, 0.71, 0.79, 0.83 and 0.73, respectively. However, the combination of two genes (CCL22 + FCGR1A) and FCGR1A alone were the most accurate marker for differentiation between the two groups (TB(+)HIV(+) and TST(+/-)HIV(+)) with AUC of 0.85 and 0.83, respectively.

Conclusions: We showed that five genes (CD8A, TIMP2, CCL22, FCGR1A and TNFRSF1A), specifically FCGR1A and CCL22 have the potential to discriminate active TB from non-active TB in HIV patients in Ethiopia and could be used to improve diagnostic tools for active TB in HIV patients, and to understand the pathogenesis of TB/HIV coinfection.
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http://dx.doi.org/10.1016/j.tube.2016.06.003DOI Listing
September 2016

Neonatal thymectomy reveals differentiation and plasticity within human naive T cells.

J Clin Invest 2016 Mar 22;126(3):1126-36. Epub 2016 Feb 22.

The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants.
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http://dx.doi.org/10.1172/JCI84997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767338PMC
March 2016

Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells.

Blood 2016 Jan 19;127(1):91-101. Epub 2015 Oct 19.

Laboratory of Translational Immunology, Department of Paediatric Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;

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 (Tregs) are thought to be important for disease remission after HSCT. However, eliciting the role of donor and host Tregs in autologous HSCT is not possible in humans due to the 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 (TCR) 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 Tregs, graft-derived Tregs 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+) Tregs during BMT. Infusion of Foxp3(GFP+) Tregs 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 Tregs during BMT results in a delayed reconstitution of T-cell compartments. Therefore, Treg therapy may hamper development of long-term tolerance and should be approached with caution in the clinical autologous setting.
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http://dx.doi.org/10.1182/blood-2015-06-649145DOI Listing
January 2016

Cytokine profiling at disease onset: support for classification of young antinuclear antibody-positive patients as a separate category of juvenile idiopathic arthritis.

Ann Rheum Dis 2015 Feb 10;74(2):470-2. Epub 2014 Nov 10.

Laboratory of Translational Immunology, Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2014-206424DOI Listing
February 2015

Splenic TFH expansion participates in B-cell differentiation and antiplatelet-antibody production during immune thrombocytopenia.

Blood 2014 Oct 16;124(18):2858-66. Epub 2014 Sep 16.

Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands;

Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in ITP.
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http://dx.doi.org/10.1182/blood-2014-03-563445DOI Listing
October 2014

A sensitive protocol for FOXP3 epigenetic analysis in scarce human samples.

Eur J Immunol 2014 Oct 25;44(10):3141-3. Epub 2014 Aug 25.

Translational Research Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA; SingHealth Translational Immunology and Inflammation Centre, Duke-NUS Graduate Medical School, Singapore City, Singapore.

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http://dx.doi.org/10.1002/eji.201444627DOI Listing
October 2014

Brief report: Autologous stem cell transplantation restores immune tolerance in experimental arthritis by renewal and modulation of the Teff cell compartment.

Arthritis Rheumatol 2014 Feb;66(2):350-6

University Medical Center Utrecht and Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Objective: 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).

Methods: 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).

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1002/art.38261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131556PMC
February 2014

Differential homeostatic dynamics of human regulatory T-cell subsets following neonatal thymectomy.

J Allergy Clin Immunol 2014 Jan 18;133(1):277-80.e1-6. Epub 2013 Oct 18.

Department of Pediatric Immunology and the Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2013.08.030DOI Listing
January 2014

STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass.

PLoS One 2012 10;7(4):e35070. Epub 2012 Apr 10.

Department of Pediatric Intensive Care, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Background: Cardiopulmonary bypass (CPB) surgery initiates a controlled systemic inflammatory response characterized by a cytokine storm, monocytosis and transient monocyte activation. However, the responsiveness of monocytes to Toll-like receptor (TLR)-mediated activation decreases throughout the postoperative course. The purpose of this study was to identify the major signaling pathway involved in plasma-mediated inhibition of LPS-induced tumor necrosis factor (TNF)-α production by monocytes.

Methodology/principal Findings: Pediatric patients that underwent CPB-assisted surgical correction of simple congenital heart defects were enrolled (n = 38). Peripheral blood mononuclear cells (PBMC) and plasma samples were isolated at consecutive time points. Patient plasma samples were added back to monocytes obtained pre-operatively for ex vivo LPS stimulations and TNF-α and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation by patient plasma was assessed by Western blotting. A cell-permeable peptide inhibitor was used to block STAT3 signaling. We found that plasma samples obtained 4 h after surgery, regardless of pre-operative dexamethasone treatment, potently inhibited LPS-induced TNF-α but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or IκB-α degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-α production in the presence of suppressive patient plasma.

Conclusions/significance: Our findings suggest that STAT3 signaling plays a crucial role in the downregulation of TNF-α synthesis by human monocytes in the course of systemic inflammation in vivo. Thus, STAT3 might be a potential molecular target for pharmacological intervention in clinical syndromes characterized by systemic inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035070PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323636PMC
October 2012

Heat shock protein-derived T-cell epitopes contribute to autoimmune inflammation in pediatric Crohn's disease.

PLoS One 2009 Nov 2;4(11):e7714. Epub 2009 Nov 2.

Department of Medicine/Pediatrics, University of California San Diego, La Jolla, California, United States of America.

Pediatric Crohn's disease is a chronic auto inflammatory bowel disorder affecting children under the age of 17 years. A putative etiopathogenesis of Crohn's disease (CD) is associated with disregulation of immune response to antigens commonly present in the gut microenvironment. Heat shock proteins (HSP) have been identified as ubiquitous antigens with the ability to modulate inflammatory responses associated with several autoimmune diseases. The present study tested the contribution of immune responses to HSP in the amplification of autoimmune inflammation in chronically inflamed mucosa of pediatric CD patients. Colonic biopsies obtained from normal and CD mucosa were stimulated with pairs of Pan HLA-DR binder HSP60-derived peptides (human/bacterial homologues). The modulation of RNA and protein levels of induced proinflammatory cytokines were measured. We identified two epitopes capable of sustaining proinflammatory responses, specifically TNF< and IFN induction, in the inflamed intestinal mucosa in CD patients. The responses correlated positively with clinical and histological measurements of disease activity, thus suggesting a contribution of immune responses to HSP in pediatric CD site-specific mucosal inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007714PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765612PMC
November 2009

Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial.

Arthritis Rheum 2009 Nov;60(11):3207-16

University of California, San Diego, La Jolla, CA, USA.

Objective: Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.

Methods: One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.

Results: The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo.

Conclusion: Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.
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http://dx.doi.org/10.1002/art.24916DOI Listing
November 2009

Caveolin-1 influences vascular protease activity and is a potential stabilizing factor in human atherosclerotic disease.

PLoS One 2008 Jul 2;3(7):e2612. Epub 2008 Jul 2.

Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center, Utrecht, The Netherlands.

Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice. This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002612PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2432041PMC
July 2008

Arterial occlusion after repetitive angio-seal device closure.

Vasc Endovascular Surg 2007 Aug-Sep;41(4):346-7

Department of Surgery, Rivierenland Hospital, Tiel, University Medical Centre Utrecht, Utrecht, the Netherlands.

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http://dx.doi.org/10.1177/1538574407303174DOI Listing
October 2007

Gender-associated differences in plaque phenotype of patients undergoing carotid endarterectomy.

J Vasc Surg 2007 Feb;45(2):289-96; discussion 296-7

Department of Vascular Surgery, University Medical Center, Utrecht, The Netherlands.

Background: Carotid endarterectomy to prevent a stroke is less beneficial for women compared with men. This benefit is lower in asymptomatic women compared with asymptomatic men or symptomatic patients. A possible explanation for this gender-associated difference in outcome could be found in the atherosclerotic carotid plaque phenotype. We hypothesize that women, especially asymptomatic women, have more stable plaques than men, resulting in a decreased benefit of surgical plaque removal.

Methods: Carotid endarterectomy specimens of 450 consecutive patients (135 women, 315 men) were studied. The culprit lesions were semi-quantitatively analyzed for the presence of macrophages, smooth muscle cells, collagen, calcifications, and luminal thrombus. Plaques were categorized in three phenotypes according to overall presentation and the amount of fat. Protein was isolated from the plaques for determination of interleukin-6 (IL-6) and IL-8 concentrations and matrix metalloproteinase-8 (MMP-8) and MMP-9 activities.

Results: Atheromatous plaques (>40% fat) were less frequently observed in women than in men (22% vs 40%; P < .001). In addition, plaques obtained from women more frequently revealed low macrophage staining (11% vs 18%; P = .05) and strong smooth muscle cell staining (38% vs 24%; P = .001). Compared with men, women had a lower plaque concentration of IL-8 (P = .001) and lower MMP-8 activity (P = .01). The observed differences were most pronounced in asymptomatic women, who showed the most stable plaques, with an atheromatous plaque in only 9% of cases compared with 39% in asymptomatic men (P = .02). In addition, a large proportion of plaques obtained from asymptomatic women showed high smooth muscle cell content (53% vs 30%; P = .03) and high collagen content (55% vs 24%; P = .003). All relations between gender and plaque characteristics, except for MMP-8, remained intact in a multivariate analysis, including clinical presentation and other cardiovascular risk factors.

Conclusion: Carotid artery plaques obtained from women have a more stable, less inflammatory phenotype compared with men, independent of clinical presentation and cardiovascular risk profile. Asymptomatic women demonstrate the highest prevalence of stable plaques. These findings could explain why women benefit less from carotid endarterectomy compared with men.
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http://dx.doi.org/10.1016/j.jvs.2006.09.051DOI Listing
February 2007