Taco W Kuijpers

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (204)1141.42 Total impact

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    ABSTRACT: Aicardi-Goutières syndrome (AGS) is a monogenic inflammatory encephalopathy caused by mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or MDA5. Mutations in those genes affect normal RNA/DNA intracellular metabolism and detection, triggering an autoimmune response with an increase in cerebral IFN-α production by astrocytes. Microangiopathy and vascular disease also contribute to the neuropathology in AGS. In this study, we report that AGS gene silencing of TREX1, SAMHD1, RNASEH2A, and ADAR1 by short hairpin RNAs in human neural stem cell-derived astrocytes, human primary astrocytes, and brain-derived endothelial cells leads to an antiviral status of these cells compared with nontarget short hairpin RNA-treated cells. We observed a distinct activation of the IFN-stimulated gene signature with a substantial increase in the release of proinflammatory cytokines (IL-6) and chemokines (CXCL10 and CCL5). A differential impact of AGS gene silencing was noted; silencing TREX1 gave rise to the most dramatic in both cell types. Our findings fit well with the observation that patients carrying mutations in TREX1 experience an earlier onset and fatal outcome. We provide in the present study, to our knowledge for the first time, insight into how astrocytic and endothelial activation of antiviral status may differentially lead to cerebral pathology, suggesting a rational link between proinflammatory mediators and disease severity in AGS. Copyright © 2015 by The American Association of Immunologists, Inc.
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    ABSTRACT: The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.This article is protected by copyright. All rights reserved
    European Journal of Immunology 02/2015; 45(2). DOI:10.1002/eji.201445070 · 4.52 Impact Factor
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    ABSTRACT: Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.
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    ABSTRACT: Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.
    Frontiers in Immunology 01/2015; 6:11. DOI:10.3389/fimmu.2015.00011
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    ABSTRACT: Background: Despite the declined incidence of severe neurological complications such as HIV‐encephalopathy, HIV‐infection in children is still associated with a range of cognitive problems. Studies comparing HIV‐infected children to socioeconomically (SES)‐matched controls are lacking, while most HIV‐infected children in industrialized countries are immigrants with a relatively low SES. Methods: This cross‐sectional study included perinatally HIV‐infected children and controls matched for age, gender, ethnicity and SES, who completed a neuropsychological assessment (NPA) evaluating intelligence, information processing speed, attention, memory, executive‐ and visual‐motor functioning. Multivariate normative comparison (MNC) was used to assess the prevalence of cognitive impairment in the HIV‐infected group. Multivariable regression analyses were performed to identify HIV‐ and cART‐related factors associated with cognitive performance. Results: In total, 35 perinatally HIV‐infected (median age: 13.8 years, median CD4+ T‐cells: 770*106/L, 83% with an undetectable HIV VL) and 37 healthy children (median age: 12.1 years) were included. HIV‐infected children scored lower than the healthy controls on all cognitive domains (e.g. intelligence quotient (IQ): 76 [SD 15.7] and 87.5 [SD 13.6] for HIV‐infected versus healthy children; P=0.002). Cognitive impairment was found in 6 HIV‐infected children (17%). The CDC clinical category at HIV diagnosis was inversely associated with verbal IQ (CDC C: coefficient ‐22.98, P=0.010). Conclusion: Our results show that cognitive performance of HIV‐infected children is poor as compared to SES‐matched healthy controls. Gaining insight in these cognitive deficits is essential as subtle impairments may progress to more pronounced complications, that will influence future intellectual performance, job opportunities and community participation of HIV‐infected children.
    Clinical Infectious Diseases 12/2014; DOI:10.1093/cid/ciu1144 · 9.42 Impact Factor
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    ABSTRACT: REVIEW ARTICLE published: 12December2014 doi: 10.3389/fimmu.2014.00629 Isdosingoftherapeuticimmunoglobulinsoptimal?Areviewofathree-decadelongdebateinEurope JacquelineKerr 1, IsabellaQuinti 2, MarthaEibl 3, HelenChapel 4, PeterJ.Späth5,W.A.CarrockSewell 6, AbdulgabarSalama7, IvoN.vanSchaik 8,TacoW.Kuijpers9 and Hans-HartmutPeter 10* 1 Section Poly-andMonoclonalAntibodies,PaulEhrlichInstitut,Langen,Germany 2 Department ofMolecularMedicine,SapienzaUniversityofRome,Rome,Italy 3 ImmunologischeTagesklinik,Vienna,Austria 4 NuffieldDepartmentofMedicine,UniversityofOxford,Oxford,UK 5 InstituteofPharmacology,UniversityofBern,Bern,Switzerland 6 Hull YorkMedicalSchool,UniversityofLincoln,Lincoln,UK 7 ZentrumfürTransfusionsmedizinu.Zelltherapie,Charité,Berlin,Germany 8 Department ofNeurology,AcademicMedicalCenter(AMC),UniversityofAmsterdam,Amsterdam,Netherlands 9 Department ofPediatricHematology,ImmunologyandInfectiousdisease,AcademicMedicalCenter(AMC),UniversityofAmsterdam,Amsterdam,Netherlands 10 CentrumfürchronischeImmunodeficienz(CCI),UniversityMedicalCentre,UniversityofFreiburg,FreiburgimBreisgau,Germany Editedby: Albert Farrugia,UniversityofWestern Australia,Australia Reviewedby: Antonio Condino-Neto,Universityof São Paulo,Brazil Alessandro Plebani,Universityof Brescia, Italy *Correspondence: Hans-Hartmut Peter,Centrumfür chronischeImmundefizienz(CCI), Engesserstr.4,D-79108Freiburgim Breisgau, Germany e-mail: hans-hartmut.peter@ uniklinik-freiburg.de Theconsumptionofimmunoglobulins(Ig)isincreasingduetobetterrecognitionofantibodydeficiencies,anagingpopulation,andnewindications.Thisreviewaimstoexaminethevariousdosingregimensandresearchdevelopmentsintheestablishedandinsomeoftherelevantoff-labelindicationsinEurope.ThebackgroundtothecurrentregulatorysettingsinEuropeisprovidedasabackdropforthelatestdevelopmentsinprimaryandsecondaryimmunodefiienciesandinimmunomodulatoryindications.Intheseheterogeneousareas,clinicaltrialsencompassingdifferentroutesofadministration,varyingintervals,andinfusionratesarepavingthewaytowardmoreindividualizedtherapyregimens.Inprimaryantibodydeficiencies,adjustmentsindosingandintervalswilldependontheclinicalpresentation,effectiveIgGtroughlevelsandIgGmetabolism.Ideally,individualpharmacokineticpro-filesinconjunctionwiththeclinicalphenotypecouldleadtohighlytailoredtreatment.Inpractice,incrementaldosageincreasesarenecessarytotitratetheoptimaldoseformoreseverelyillpatients.Higherintravenousdosesinthesepatientsalsohavebenefi-cialimmunomodulatoryeffectsbeyondmereIgGreplacement.BetterunderstandingofthepharmacokineticsofIgtherapyisleadingtoamoveawayfromsimplistic“perkg”dosing.Defectiveantibodyproductioniscommoninmanysecondaryimmunodeficien-ciesirrespectiveofwhetherthecausativefactorwaslymphoidmalignancies(establishedindications),certainautoimmunedisorders,immunosuppressiveagents,orbiologics.Thisantibodyfailure,asshownbytestimmunization,maybeamenabletotreatmentwithreplacementIgtherapy.Incertainimmunomodulatorysettings[e.g.,idiopathicthrombo-cytopenicpurpura(ITP)],selectionofpatientsforIgtherapymaybeenhancedbyrelevantbiomarkersinordertoexcludenon-respondersandthusobtainhigherresponserates.Inthisreview,thedevelopmentsindosingoftherapeuticimmunoglobulinshavebeenlimitedtohighandsomemediumpriorityindicationssuchasITP,Kawasaki’disease,Guillain–Barrésyndrome,chronicinflammatorydemyelinatingpolyradiculoneuropathy,myastheniagravis,multifocalmotorneuropathy,fetalalloimmunethrombocytopenia,fetalhemolyticanemia,anddermatologicaldiseases. Keywords:IVIG,SCIG,replacementtherapy,immunomodulation,dosing INTRODUCTION Indicationsforintravenous(IVIG)andsubcutaneous(SCIG) immunoglobulin(Ig)therapiesaresteadilyincreasingandthe annualdemandhastripledinthelast15yearsreachingaworld- wideconsumptionof~130metrictonsin2012(1). Shortagesin supplyhaveoccurredinthepastandcostpressureonhealthsys- temsworldwideisgrowingTheincreaseddemandfortherapeutic Ighasbeenmetbyincreasingthenumberofplasmadonorsand byintroducingnewhigh-yieldfractionationprocedures,which in somecaseshavebeenaccompaniedbyincreasesinratesof hemolyticanemia. ReportsinvolvingalternativedosesgiveninbothIgreplace- mentandimmunomodulatoryindicationsarequestioningcur- rentpractice.These,togetherwithemergingbiomarkersassociated withIg-responderandnon-responderstatus,inviteclosescrutiny ofindicationsfor,andmethodsofadministering,IVIGandSCIG use inthefuture.TraditionaldosingofIghasreliedheavily ona“perkgofbodyweight”calculation,whichhasnowbeen www.frontiersin.org December 2014|Volume5|Article629| 1
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    ABSTRACT: BACKGROUND:: Immigrant HIV-infected adults in industrialized countries show a poorer clinical and virological outcome compared to native patients. We aimed to investigate potential differences in clinical, immunological and virological outcome in Dutch HIV-infected children born in the Netherlands (NL) versus born in Sub-Saharan Africa (SSA) in a national cohort-analysis. METHODS:: We included all HIV-infected children registered between 1996 and 2013. Descriptive statistics, mixed-effects models and Cox proportional hazard models were used to investigate differences between groups. RESULTS:: In total, 319 HIV-infected children were registered. The majority of these children were born in SSA (n=148, 47%) or NL (n=113, 36%) and most were black (n=158, 61%). Children born in NL were diagnosed at a median age of 1.2 years and initiated combination antiretroviral therapy (cART) at a median age of 2.6 years, compared to 3.7 and 5.3 years respectively for children born in SSA (HIV-diagnosis: P<0.001; cART initiation: P<0.001). Despite a lower initial CD4 T-cell Z-score in children born in SSA, their immunological reconstitution was similar to children from NL. Virological suppression was achieved in the majority of all cART-treated children (NL:96%, SSA:94%). There was no difference in the occurrence or timing of virological failure. CONCLUSIONS:: The majority of immigrant HIV-infected children living in NL were born in SSA. Children born in SSA were diagnosed and initiated cART at an older age than children born in NL. Despite initial differences in CD4 T-cell counts and HIV viral load, the long-term immunological and virological response to cART was similar in both groups.
    JAIDS Journal of Acquired Immune Deficiency Syndromes 11/2014; Nov. DOI:10.1097/QAI.0000000000000431 · 4.39 Impact Factor
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    ABSTRACT: Group B streptococcus is the most common cause of neonatal infections. We studied the clinical and molecular epidemiology of invasive group B streptococcus infection in children younger than 3 months in the Netherlands over 25 years. We assessed the effect of the Dutch guidelines, introduced in 1999, for prevention of group B streptococcus, consisting of intravenous antibiotic prophylaxis during labour in cases of premature labour, prolonged rupture of membranes, or fever during delivery. We did this nationwide surveillance study with data from 1987 to 2011, from the Netherlands Reference Laboratory for Bacterial Meningitis. We included data for patients aged 3 months or younger with positive blood culture or cerebrospinal fluid culture for group B streptococcus and Escherichia coli infection. Early onset was defined as less than 7 days after birth and late onset was defined as 7 or more days after birth. We did multilocus sequence typing of a random subset of group B streptococcus samples to assess changes in sequence type (Mann-Kendall trend test) and the distribution of clonal complexes (χ(2) and Fisher exact test) before the introduction of prevention guidelines (1987-99) and afterwards (2000-11). We compared incidences and the distribution of clonal complexes before and after the introduction of guidelines. Most cases of group B streptococcus had early onset (696/1075; 65%). The incidence of invasive group B streptococcus infection increased from 0·20 per 1000 livebirths in 1987, to 0·32 per 1000 livebirths in 2011 (p<0·0001). The incidence of early-onset disease increased from 0·11 per 1000 livebirths to 0·19 per 1000 livebirths (p<0·0001). The incidence of invasive Escherichia coli infection was 0·05 in 1987, and 0·16 in 2011 (p=0·17). Early-onset group B streptococcus infection caused by isolates belonging to clonal complex 17 was more common in the post-implementation period than in the pre-implementation period (p=0·002). The introduction of prevention guidelines for invasive group B streptococcus disease in 1999 did not reduce the incidence of disease in neonates. The guidelines should be reassessed and alternative approaches to prevent infant invasive group B streptococcus disease should be sought. National Institute of Public Health and the Environment, the European Union's seventh framework programme, Netherlands Organization for Health Research and Development, Academic Medical Center, and the European Research Council. Copyright © 2014 Elsevier Ltd. All rights reserved.
    The Lancet Infectious Diseases 11/2014; 14(11):1083-9. DOI:10.1016/S1473-3099(14)70919-3 · 19.45 Impact Factor
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    ABSTRACT: In immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA), circulating IgG-opsonized blood cells are cleared from the circulation by macrophages. Administration of intravenous immunoglobulin (IVIg) can prevent uptake, but the exact working mechanism is not known. The prevailing theory from murine studies, which states that Fc-sialylated IgG alters the balance between activating and inhibitory Fc-gamma receptors (FcγRs) by inducing upregulation of the inhibitory FcγRIIb on effector macrophages, is currently debated. We studied phagocytosis of IgG-opsonized blood cells in a human system, assessing the effect of IVIg and blocking anti-FcγR F(ab')2 fragments on uptake by monocyte-derived macrophages (both M1 and M2 macrophages). Phagocytosis was remarkably sensitive to administration of IVIg but unexpectedly, recombinant Fc-sialylated IgG or sialic acid-enriched IVIg were equally active as unsialylated IgG fractions in mediating this inhibition - independent of FcγRIIb expression. Instead, IVIg inhibited phagocytosis by direct blockade of FcγRs. IgG fractions enriched for IgG-dimers with enhanced avidity for FcγRs showed increased inhibition compared to monomeric IgG fractions. Together, our data demonstrate that inhibition of IgG-mediated phagocytosis in human macrophages by IVIg is dependent on the capacity to directly bind FcγRs but independent of FcγRIIb or sialylation of the Fc fragment in the human setting.
    Blood 10/2014; 124(25). DOI:10.1182/blood-2014-05-576835 · 9.78 Impact Factor
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    ABSTRACT: Absolute numbers of lymphocytes are decreased in uninfected infants born to HIV-1-infected women (HIV-1-exposed). Although the exact mechanism is unknown, fetal exposure to maternal HIV-1-infection could prime the immune system and affect T cell trafficking. We compared the expression of chemokine receptors on cord blood CD4(+) T cells from HIV-1-exposed children and healthy controls. At baseline CD4(+) T cells had a largely naïve phenotype. However, stimulation with cytokines resulted in an upregulation of inflammatory response-related chemokine receptors on CD4(+) T cells, with HIV-1-exposed infants having a significantly higher frequency of CD4(+) T cells expressing, in particularly Th2 associated chemokine receptors (CCR3 p < 0.01, CCR8 p = 0.03). Numbers of naive CCR7(+) CD4(+) T cells were reduced (p = 0.01) in HIV-1-exposed infants. We further assessed whether the inflammatory phenotype was associated with susceptibility to HIV-1 and detected higher levels of p24 upon in in vitro infection of stimulated CD4(+) T cells of HIV-1-exposed infants. In summary, fetal exposure to HIV-1 primes the immune system in the infant leading to an enhanced immune activation and altered T cell homing, with potential ramifications regarding T cell responses and the acquisition of HIV-1 as an infant.
    Scientific Reports 10/2014; 4:6690. DOI:10.1038/srep06690 · 5.08 Impact Factor
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    ABSTRACT: Uptake of oxLDL and foam cell formation by macrophages is one of the first steps in the development of atherosclerosis. Recently, PKCδ has been implicated as a regulator of oxLDL uptake and foam cell formation via down-regulation of PKCβ and scavenger receptors CD36 and SR-A expression. Here we describe studies in which we have re-evaluated the role of PKCδ in oxLDL uptake and foam cell formation.
    Cardiovascular Research 09/2014; DOI:10.1093/cvr/cvu213 · 5.81 Impact Factor
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    ABSTRACT: To assess the sequence and type of active joints in a cohort of newly diagnosed juvenile idiopathic arthritis (JIA) patients with full access to current treatment at first visit and during a follow-up period of 5-years, in order to identify an index joint/group of joints for magnetic resonance imaging in JIA. Patient charts of all consecutive newly diagnosed JIA patients with a follow-up duration of at least 5 years were analyzed. Patients were derived from two tertiary pediatric rheumatology centers. Patient characteristics and data concerning the presence of joints with arthritis and the use of medication were recorded. Findings from 95 JIA patients [39 (41 %) oligoarticular and 56 (59 %) polyarticular] were analyzed. At first visit, distribution of active joints among patients was as follows: knee (n = 70, 74 %), ankle (n = 55, 58 %), elbow (n = 23, 24 %), wrist (n = 23, 24 %), metacarpophalangeal (MCP) (n = 20, 21 %), proximal interphalangeal (PIP) (n = 13, 14 %), hip (n = 6, 6 %), shoulder (n = 5, 5 %), and distal interphalangeal (DIP) (n = 4, 4 %) joints. After a follow-up period of 5 years, the cumulative percentage of patients with specific joint involvement changed into: knee (n = 88, 93 %), ankle (n = 79, 83 %), elbow (n = 43, 45 %), wrist (n = 38, 40 %), MCP (n = 36, 38 %), PIP (n = 29, 31 %), shoulder (n = 20, 21 %), hip (n = 17, 19 %), and DIP (n = 9, 10 %) joints. Despite changes in treatment strategies over the years, the knee remains the most commonly involved joint at onset and during follow-up in JIA, followed by the ankle, elbow, and wrist. For the evaluation of outcome with MRI, the knee appears the most appropriate joint in JIA.
    Rheumatology International 08/2014; DOI:10.1007/s00296-014-3108-x · 1.63 Impact Factor
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    ABSTRACT: A chronic illness, such as Juvenile Idiopathic Arthritis (JIA), has an impact on the whole family, especially on parents caring for the ill child. Therefore the aim of this study is to evaluate parental Health Related Quality of Life (HRQOL) and parental perceptions of child vulnerability (PPCV) and associated variables in parents of a child with JIA.
    Pediatric Rheumatology 08/2014; 12:34. DOI:10.1186/1546-0096-12-34 · 1.62 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Myeloid antigen-presenting cells (APCs) tailor immune responses to the pathogen involved through the production of specific pro- and anti-inflammatory cytokines. It is becoming increasingly clear that the ultimate cytokine profile produced by myeloid APCs crucially depends on interaction between multiple pathogen recognizing receptors. In this respect, we recently identified an important role for cross-talk between Fc gamma receptor IIa (FcγRIIa) and Toll-like receptors (TLRs) in human dendritic cells (DCs), which induces anti-bacterial immunity through the selective induction of TNFα and Th17-promoting cytokines. Here, we show that FcγRIIa-TLR cross-talk is not restricted to DCs, but is a common feature of various human myeloid APC subsets including monocytes and macrophages. Interestingly, FcγRIIa-TLR cross-talk in monocytes resulted in the induction of a cytokine profile distinct from that in DCs and macrophages, indicating that FcγRIIa stimulation induces cell-type and tissue specific responses. Surprisingly, we show that the FCGR2A H131R single nucleotide polymorphism (SNP), which is known to greatly affect FcγRIIa-mediated uptake of IgG2-opsonized bacteria, did not affect FcγRIIa-dependent cytokine production, indicating that these processes are differently regulated. In addition, we demonstrate that FcγRIIa selectively synergized with TLRs, IL-1R, and IFNγR, but did not affect cytokine production induced by other receptors such as C-type lectin receptor Dectin-1. Taken together, these data demonstrate that FcγRIIa-dependent modulation of cytokine production is more widespread than previously considered, and indicate that cross-talk of FcγRIIa with various receptors and in multiple cell types contributes to the induction of pathogen and tissue-specific immunity.
    Immunobiology 07/2014; 220(2). DOI:10.1016/j.imbio.2014.07.016 · 2.81 Impact Factor
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    ABSTRACT: The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation. Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI. The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding. Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3. Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading. Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2. Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis.
    Journal of Experimental Medicine 06/2014; 211(7). DOI:10.1084/jem.20130477 · 13.91 Impact Factor
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    ABSTRACT: Invasive fungal infections, accompanied by high rates of mortality, represent an increasing problem in medicine. Neutrophils are the major effector immune cells in fungal killing. Based on studies with neutrophils from patients with defined genetic defects, we provide evidence that human neutrophils use two distinct and independent phagolysosomal mechanisms to kill Candida albicans. The first mechanism for the killing of unopsonized Candida albicans was found to be dependent on Complement Receptor 3 (CR3), the signaling proteins phosphatidylinositol-3-kinase (PI3K) and CARD9, but was independent of NADPH oxidase activity. The second mechanism for the killing of opsonized Candida albicans was strictly dependent on Fc-gamma receptors, protein kinase C (PKC) and Reactive Oxygen Species (ROS) production by the NADPH oxidase system. Each of the two pathways of Candida killing required Syk tyrosine kinase activity, but dectin-1 was dispensible for both of them. These data provide an explanation for the variable clinical presentation of fungal infection in patients suffering from different immune defects, including dectin-1 deficiency, CARD9 deficiency or Chronic Granulomatous Disease (CGD).
    Blood 06/2014; 124(4). DOI:10.1182/blood-2014-01-551473 · 9.78 Impact Factor
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    ABSTRACT: Objectives Aicardi–Goutières syndrome (AGS) is an autoimmune disorder that shares similarities with systemic lupus erythematous. AGS inflammatory responses specially target the cerebral white matter. However, it remains uncertain why the brain is the most affected organ, and little is known about the presence of autoantibodies in AGS. Here, we aim to profile specific autoantibodies in AGS and to determine whether these autoantibodies target cerebral epitopes. Methods Using a multiplex microarray, we assessed the spectrum of serum autoantibodies in 56 genetically confirmed patients with AGS. We investigated the presence of immunoglobulins in AGS brain specimens using immunohistochemistry and studied the reactivity of sera against brain epitopes with proteomics. Results Serum from patients exhibited high levels of IgGs against nuclear antigens (gP210, Nup62, PCNA, Ro/SSA, Sm/RNP complex, SS-A/SS-B), components of the basement membrane (entactin, laminin), fibrinogen IV and gliadin. Upon testing whether antibodies in AGS could be found in the central nervous system, IgGs were identified to target in vivo endothelial cells in vivo and astrocytes in brain sections of deceased patients with AGS. Using a proteomics approach, we were able to confirm that IgGs in serum samples from AGS patients bind epitopes present in the cerebral white matter. Conclusions Patients with AGS produce a broad spectrum of autoantibodies unique from other autoimmune diseases. Some of these autoantibodies target endothelial cells and astrocytes in the brain of the affected patients, perhaps explaining the prominence of neurological disease in the AGS phenotype.
    Annals of the Rheumatic Diseases 06/2014; DOI:10.1136/annrheumdis-2014-205396 · 9.27 Impact Factor
  • EULAR 2014, Paris, France; 06/2014
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    ABSTRACT: OBJECTIVE. The aim of this study in clinically active juvenile idiopathic arthritis (JIA) was to assess the frequency and distribution pattern of synovitis as hallmark of disease and additional soft-tissue and bony abnormalities on MRI in the knee and wrist as two target joints. MATERIALS AND METHODS. MRI datasets of 153 clinically active JIA patients (110 with knee and 43 with wrist involvement) were evaluated independently by two readers for the presence of literature-based imaging features: "synovial hypertrophy," "bone marrow changes," "bone erosions," "tenosynovitis" (only in the wrist), and "cartilage lesions" (only in the knee) in accordance with validated definitions and scoring locations. RESULTS. Synovial hypertrophy was most frequently observed-both in the knee and in the wrist (61.8-65.1% of cases). For the knee, the most frequently involved locations were the cruciate ligaments (46/183 locations [25.1%] affected with synovial hypertrophy) and medial patella (18/62 locations [29.0%] with bone marrow changes). Cartilage lesions and bone erosions were rare (5.5-7.3% of cases). For the wrist, most frequently involved were the radiocarpal joint (21/64 locations [32.8%] with synovial hypertrophy), lunate (7/46 locations [15.2%] with bone marrow changes), and capitate or triquetrum (6/28 locations [21.4%] with bone erosions). Tenosynovitis was a common wrist-specific feature (46.5% of cases). MRI showed no abnormalities in a subgroup of patients with clinically active knee (23.6%) and wrist (16.3%) involvement. CONCLUSION. The distribution pattern of MRI abnormalities in the knee and wrist of active JIA patients provides a practical tool to detect a signature of JIA disease activity in target joints.
    American Journal of Roentgenology 05/2014; 202(5):W439-46. DOI:10.2214/AJR.13.11314 · 2.74 Impact Factor
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    ABSTRACT: Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies.
    PLoS Genetics 05/2014; 10(5):e1004371. DOI:10.1371/journal.pgen.1004371 · 8.52 Impact Factor

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Institutions

  • 2001–2015
    • University of Amsterdam
      • • Faculty of Medicine AMC
      • • Department of Paediatrics
      Amsterdamo, North Holland, Netherlands
  • 2002–2014
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
  • 2001–2014
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Academic Medical Center
      • • Department of Paediatrics
      Amsterdamo, North Holland, Netherlands
  • 2012
    • University of Freiburg
      • Faculty of Biology
      Freiburg, Baden-Württemberg, Germany
  • 2010–2011
    • Genome Institute of Singapore
      Tumasik, Singapore
    • Sanquin Blood Supply Foundation
      • Phagocyte Laboratory
      Amsterdamo, North Holland, Netherlands
  • 2006
    • VU University Amsterdam
      • Department of Clinical Chemistry
      Amsterdamo, North Holland, Netherlands
    • Hong Kong Red Cross Blood Transfusion Service
      Hong Kong, Hong Kong