Publications by authors named "Wilco de Jager"

81 Publications

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

Rheumatology (Oxford) 2021 Feb;60(2):785-801

Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Objectives: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD.

Methods: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA.

Results: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction.

Conclusion: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.
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http://dx.doi.org/10.1093/rheumatology/keaa270DOI Listing
February 2021

Neonatal Antibiotic Treatment Is Associated With an Altered Circulating Immune Marker Profile at 1 Year of Age.

Front Immunol 2019 10;10:2939. Epub 2020 Jan 10.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Neonatal antibiotics disturb the developing gut microbiome and are therefore thought to influence the developing immune system, but exact mechanisms and health consequences in later life still need to be elucidated. Therefore, we investigated whether neonatal antibiotics influence inflammatory markers at 1 year of age. In addition, we determined whether health problems during the first year of life, e.g., allergic disorders (eczema and wheezing) or infantile colics, were associated with changes in the circulating immune marker profile at 1 year of age. In a subgroup ( = 149) of the INCA-study, a prospective birth-cohort study, a blood sample was drawn from term born infants at 1 year of age and analyzed for 84 immune related markers using Luminex. Associations of antibiotic treatment, eczema, wheezing, and infantile colics with immune marker concentrations were investigated using a linear regression model. The trial is registered as NCT02536560. The use of broad-spectrum antibiotics in the first week of life, was significantly associated with different levels of inflammatory markers including sVCAM-1, sCD14, sCD19, sCD27, IL-1RII, sVEGF-R1, and HSP70 at 1 year of age. Eczema was associated with decreased concentrations of IFNα, IFNγ, TSLP, CXCL9, and CXCL13, but increased concentrations of CCL18 and Galectin-3. Wheezing, independent of antibiotic treatment, was positively associated to TNF-R2 and resistin. Infantile colics were positively associated to IL-31, LIGHT, YKL-40, CXCL13, sPD1, IL1RI, sIL-7Ra, Gal-1, Gal-9, and S100A8 at 1 year of age, independent of early life antibiotic treatment. In this explorative study, we identified that neonatal antibiotics are associated with immunological alterations at 1 year of age and that, independent of the antibiotic treatment, infantile colics were associated with alterations within gut associated markers. These findings support the importance of the first host microbe interaction in early life immune development.
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http://dx.doi.org/10.3389/fimmu.2019.02939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970186PMC
December 2020

Cardiometabolic health in offspring of women with PCOS compared to healthy controls: a systematic review and individual participant data meta-analysis.

Hum Reprod Update 2020 01;26(1):103-117

Department of Reproductive Medicine, Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Background: Women diagnosed with polycystic ovary syndrome (PCOS) suffer from an unfavorable cardiometabolic risk profile, which is already established by child-bearing age.

Objective And Rationale: The aim of this systematic review along with an individual participant data meta-analysis is to evaluate whether cardiometabolic features in the offspring (females and males aged 1-18 years) of women with PCOS (OPCOS) are less favorable compared to the offspring of healthy controls.

Search Methods: PubMed, Embase and gray literature databases were searched by three authors independently (M.N.G., M.A.W and J.C.) (last updated on 1 February 2018). Relevant key terms such as 'offspring' and 'PCOS' were combined. Outcomes were age-specific standardized scores of various cardiometabolic parameters: BMI, blood pressure, glucose, insulin, lipid profile and the sum scores of various cardiometabolic features (metabolic sum score). Linear mixed models were used for analyses with standardized beta (β) as outcome.

Outcomes: Nine relevant observational studies could be identified, which jointly included 1367 children: OPCOS and controls, originating from the Netherlands, Chile and the USA. After excluding neonates, duplicate records and follow-up screenings, a total of 885 subjects remained. In adjusted analyses, we observed that OPCOS (n = 298) exhibited increased plasma levels of fasting insulin (β = 0.21(95%CI: 0.01-0.41), P = 0.05), insulin-resistance (β = 0.21(95%CI: 0.01-0.42), P = 0.04), triglycerides (β = 0.19(95%CI: 0.02-0.36), P = 0.03) and high-density lipoprotein (HDL)-cholesterol concentrations (β = 0.31(95%CI: 0.08-0.54), P < 0.01), but a reduced birthweight (β = -116(95%CI: -195 to 38), P < 0.01) compared to controls (n = 587). After correction for multiple testing, however, differences in insulin and triglycerides lost their statistical significance. Interaction tests for sex revealed differences between males and females when comparing OPCOS versus controls. A higher 2-hour fasting insulin was observed among female OPCOS versus female controls (estimated difference for females (βf) = 0.45(95%CI: 0.07 to 0.83)) compared to the estimated difference between males ((βm) = -0.20(95%CI: -0.58 to 0.19)), with interaction-test: P = 0.03. Low-density lipoprotein-cholesterol differences in OPCOS versus controls were lower among females (βf = -0.39(95%CI: -0.62 to 0.16)), but comparable between male OPCOS and male controls (βm = 0.27(95%CI: -0.03 to 0.57)), with interaction-test: P < 0.01. Total cholesterol differences in OPCOS versus controls were also lower in females compared to the difference in male OPCOS and male controls (βf = -0.31(95%CI: -0.57 to 0.06), βm = 0.28(95%CI: -0.01 to 0.56), interaction-test: P = 0.01). The difference in HDL-cholesterol among female OPCOS versus controls (βf = 0.53(95%CI: 0.18-0.88)) was larger compared to the estimated mean difference among OPCOS males and the male controls (βm = 0.13(95%CI: -0.05-0.31), interaction-test: P < 0.01). Interaction test in metabolic sum score revealed a significant difference between females (OPCOS versus controls) and males (OPCOS versus controls); however, sub analyses performed in both sexes separately did not reveal a difference among females (OPCOS versus controls: βf = -0.14(95%CI: -1.05 to 0.77)) or males (OPCOS versus controls: βm = 0.85(95%CI: -0.10 to 1.79)), with P-value < 0.01.

Wider Implications: We observed subtle signs of altered cardiometabolic health in OPCOS. Therefore, the unfavorable cardiovascular profile of women with PCOS at childbearing age may-next to a genetic predisposition-influence the health of their offspring. Sensitivity analyses revealed that these differences were predominantly observed among female offspring aged between 1 and 18 years. Moreover, studies with minimal risk of bias should elucidate the influence of a PCOS diagnosis in mothers on both sexes during fetal development and subsequently during childhood.
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http://dx.doi.org/10.1093/humupd/dmz036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007319PMC
January 2020

Combined Exposure of Activated Intestinal Epithelial Cells to Nondigestible Oligosaccharides and CpG-ODN Suppresses Th2-Associated CCL22 Release While Enhancing Galectin-9, TGF, and Th1 Polarization.

Mediators Inflamm 2019 25;2019:8456829. Epub 2019 Jul 25.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.

Background: Short-chain galacto- and long-chain fructo-oligosaccharides (scGOS/lcFOS) and CpG-ODN affect intestinal epithelial cells (IEC). Epithelial IL1 may contribute to allergic sensitization via autocrine mediator release affecting dendritic cells (DC). We studied whether IL1 contributes to Th2-associated mediator release by activated IEC and IEC/DC cocultures and possible modulation by scGOS/lcFOS±CpG-ODN.

Methods: Solid phase or transwell cultured IEC were preincubated with IL1 and/or IFN/TNF for 6 h. The transwell IEC were also apically exposed to scGOS/lcFOS±CpG-ODN for 6 h, washed, and re-exposed, while cocultured with immature moDC (ccDC) for 48 h. These ccDC were subsequently added to allogeneic naïve T cells (MLR). IEC- and/or DC-derived mediators and T cell cytokines were measured.

Results: IL1 tended to enhance IL25 and enhanced IL33 and CCL20 release by IEC, while IL1 or TNF or IFN enhanced CCL22. These were all further increased upon combined exposure of IFN/TNF±IL1 coinciding with increased IL33 secretion in the solid phase culture. In the transwell, IL25 and IL33 remained under detection, while CCL20 and CCL22 were induced by IL1 or IFN/TNF, respectively, and a synergistic increase was observed upon combined exposure of IFN/TNF and IL1. Furthermore, IFN was found to enhance galectin-9 secretion, which was more pronounced in IFN/TNF±IL1-exposed IEC and coincided with TGF increase. Epithelial CpG-ODN exposure further increased CCL20, while reducing CCL22 release by IFN/TNF/IL1-activated IEC; however, scGOS/lcFOS suppressed both. Combined scGOS/lcFOS and CpG-ODN reduced CCL22, while CCL20 and regulatory galectin-9 and TGF remained high in the supernatant of IFN/TNF/IL1-activated IEC and the following IEC/DC coculture. ccDC of scGOS/lcFOS- and CpG-ODN-exposed IFN/TNF/IL1-activated IEC increased IFN, IL10, TGF, and galectin-9 secretion in the MLR compared to ccDC exposed to control-activated IEC.

Conclusion: IL1 enhanced CCL20 and Th2-associated CCL22 release by IFN/TNF-activated IEC. Combined scGOS/lcFOS and CpG-ODN exposure suppressed CCL22, while maintaining high CCL20, TGF, and galectin-9 concentrations. In addition, ccDC derived from this IEC/DC coculture enhanced Th1 and regulatory mediator secretion mimicking known effects.
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http://dx.doi.org/10.1155/2019/8456829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683774PMC
January 2020

Galectin-9 and CXCL10 as Biomarkers for Disease Activity in Juvenile Dermatomyositis: A Longitudinal Cohort Study and Multicohort Validation.

Arthritis Rheumatol 2019 08 12;71(8):1377-1390. Epub 2019 Mar 12.

University Medical Centre Utrecht, Utrecht, The Netherlands.

Objective: Objective evaluation of disease activity is challenging in patients with juvenile dermatomyositis (DM) due to a lack of reliable biomarkers, but it is crucial to avoid both under- and overtreatment of patients. Recently, we identified 2 proteins, galectin-9 and CXCL10, whose levels are highly correlated with the extent of juvenile DM disease activity. This study was undertaken to validate galectin-9 and CXCL10 as biomarkers for disease activity in juvenile DM, and to assess their disease specificity and potency in predicting the occurrence of flares.

Methods: Levels of galectin-9 and CXCL10 were measured by multiplex immunoassay in serum samples from 125 unique patients with juvenile DM in 3 international cross-sectional cohorts and a local longitudinal cohort. The disease specificity of both proteins was examined in 50 adult patients with DM or nonspecific myositis (NSM) and 61 patients with other systemic autoimmune diseases.

Results: Both cross-sectionally and longitudinally, galectin-9 and CXCL10 outperformed the currently used laboratory marker, creatine kinase (CK), in distinguishing between juvenile DM patients with active disease and those in remission (area under the receiver operating characteristic curve [AUC] 0.86-0.90 for galectin-9 and CXCL10; AUC 0.66-0.68 for CK). The sensitivity and specificity for active disease in juvenile DM was 0.84 and 0.92, respectively, for galectin-9 and 0.87 and 1.00, respectively, for CXCL10. In 10 patients with juvenile DM who experienced a flare and were prospectively followed up, continuously elevated or rising biomarker levels suggested an imminent flare up to several months before the onset of symptoms, even in the absence of elevated CK levels. Galectin-9 and CXCL10 distinguished between active disease and remission in adult patients with DM or NSM (P = 0.0126 for galectin-9 and P < 0.0001 for CXCL10) and were suited for measurement in minimally invasive dried blood spots (healthy controls versus juvenile DM, P = 0.0040 for galectin-9 and P < 0.0001 for CXCL10).

Conclusion: In this study, galectin-9 and CXCL10 were validated as sensitive and reliable biomarkers for disease activity in juvenile DM. Implementation of these biomarkers into clinical practice as tools to monitor disease activity and guide treatment might facilitate personalized treatment strategies.
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http://dx.doi.org/10.1002/art.40881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973145PMC
August 2019

Treatment to Target Using Recombinant Interleukin-1 Receptor Antagonist as First-Line Monotherapy in New-Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five-Year Follow-Up Study.

Arthritis Rheumatol 2019 07 25;71(7):1163-1173. Epub 2019 May 25.

University Medical Center Utrecht and Utrecht University, Utrecht, The Netherlands.

Objective: Systemic juvenile idiopathic arthritis (JIA) is a multifactorial autoinflammatory disease with a historically poor prognosis. With current treatment regimens, approximately half of patients still experience active disease after 1 year of therapy. This study was undertaken to evaluate a treat-to-target approach using recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) as first-line monotherapy to achieve early inactive disease and prevent damage.

Methods: In this single-center, prospective study, patients with new-onset systemic JIA with an unsatisfactory response to nonsteroidal antiinflammatory drugs received rIL-1Ra monotherapy according to a treat-to-target strategy. Patients with an incomplete response to 2 mg/kg rIL-1Ra subsequently received 4 mg/kg rIL-1Ra or additional prednisolone, or switched to alternative therapy. For patients in whom inactive disease was achieved, rIL-1Ra was tapered after 3 months and subsequently stopped.

Results: Forty-two patients, including 12 who had no arthritis at disease onset, were followed up for a median of 5.8 years. The median time to achieve inactive disease was 33 days. At 1 year, 76% had inactive disease, and 52% had inactive disease while not receiving medication. High neutrophil counts at baseline and a complete response after 1 month of rIL-1Ra were highly associated with inactive disease at 1 year. After 5 years of follow-up, 96% of the patients included had inactive disease, and 75% had inactive disease while not receiving medication. Articular or extraarticular damage was reported in <5%, and only 33% of the patients received glucocorticoids. Treatment with rIL-1Ra was equally effective in systemic JIA patients without arthritis at disease onset.

Conclusion: Treatment to target, starting with first-line, short-course monotherapy with rIL-1Ra, is a highly efficacious strategy to induce and sustain inactive disease and to prevent disease- and glucocorticoid-related damage in systemic JIA.
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http://dx.doi.org/10.1002/art.40865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617757PMC
July 2019

Salivary gland secretome: a novel tool towards molecular stratification of patients with primary Sjögren's syndrome and non-autoimmune sicca.

RMD Open 2019 11;5(1):e000772. Epub 2019 Jan 11.

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

Objective: To explore the potential of salivary gland biopsy supernatants (the secretome) as a novel tool to aid in stratification of patients with sicca syndrome and to study local immunopathology in Sjögren's syndrome.

Methods: Labial salivary gland biopsies were incubated in saline for 1 hour. In these tissue supernatants from a discovery cohort (n=16) of patients with primary Sjögren's syndrome (pSS) and non-Sjögren's sicca (nSS), 101 inflammatory mediators were measured by Luminex. Results were validated in a replication cohort (n=57) encompassing patients with pSS, incomplete SS and nSS.

Results: The levels of 23 cytokines were significantly increased in patients with pSS versus nSS in the discovery cohort. These 23 and 3 additional cytokines were measured in a second cohort. Elevated concentrations of 11 cytokines were validated and the majority correlated with clinical parameters. Classification tree analysis indicated that the concentrations of CXCL13, IL-21, sIL-2R and sIL-7Rα could be used to classify 95.8% of patients with pSS correctly.

Conclusion: Labial salivary gland secretomes can be used to reliably assess mediators involved in immunopathology of patients with pSS, potentially contributing to patient classification. As such, this method represents a novel tool to identify therapeutic targets and markers for diagnosis, prognosis and treatment response.
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http://dx.doi.org/10.1136/rmdopen-2018-000772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340539PMC
April 2020

Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome.

Ann Rheum Dis 2018 12 5;77(12):1810-1814. Epub 2018 Sep 5.

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

Objective: The interferon (IFN) signature is related to disease activity and vascular disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and represents a promising therapeutic target. Quantification of the IFN signature is currently performed by gene expression analysis, limiting its current applicability in clinical practice. Therefore, the objective of this study was to establish an easy to measure biomarker for the IFN signature.

Methods: Serum levels of galectin-9, CXCL-10 (IP-10) and tumour necrosis factor receptor type II (TNF-RII) were measured in patients with SLE, SLE+APS and primary APS (PAPS) and healthy controls (n=148) after an initial screening of serum analytes in a smaller cohort (n=43). Analytes were correlated to measures of disease activity and the IFN signature. The performance of galectin-9, CXCL-10 and TNF-RII as biomarkers to detect the IFN signature was assessed by receiver operating characteristic curves.

Results: Galectin-9, CXCL-10 and TNF-RII were elevated in patients with SLE, SLE+APS and PAPS (p<0.05) and correlated with disease activity and tissue factor expression. Galectin-9 correlated stronger than CXCL-10 or TNF-RII with the IFN score (r=0.70, p<0.001) and was superior to CXCL-10 or TNF-RII in detecting the IFN signature (area under the curve (AUC) 0.86). Importantly, in patients with SLE(±APS), galectin-9 was also superior to anti-dsDNA antibody (AUC 0.70), or complement C3 (AUC 0.70) and C4 (AUC 0.78) levels in detecting the IFN signature.

Conclusion: Galectin-9 is a novel, easy to measure hence clinically applicable biomarker to detect the IFN signature in patients with systemic autoimmune diseases such as SLE and APS.
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http://dx.doi.org/10.1136/annrheumdis-2018-213497DOI Listing
December 2018

First trimester placental vascularization and angiogenetic factors are associated with adverse pregnancy outcome.

Pregnancy Hypertens 2018 Jul 11;13:87-94. Epub 2018 Apr 11.

Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), Wilhelmina Children's Hospital, University Medical Centre Utrecht, 3584 EA Utrecht, The Netherlands.

Background: Hypertensive disorders, fetal growth restriction and preterm birth are major obstetrical complications and are related to impaired placentation. Early identification of impaired placentation can advance clinical care by preventing or postpone adverse pregnancy outcome.

Objectives: Determine whether sonographic assessed placental vascular development and concomitant changes in inflammation- and/or angiogenesis-related serumproteins differ in the first trimester between uncomplicated pregnancies and pregnancies with adverse outcome.

Study Design: This prospective longitudinal study defines adverse pregnancy outcome as conditions associated with impaired placentation; fetal growth restriction, hypertensive disorder, preterm birth and placental abruption. The vascularization index, flow index, vascularization flow index and placental volume were determined at 8, 10 and 12 weeks pregnancy from 64 women using 3D power Doppler. Serum levels were analyzed for Angiopoetin-1 and -2, Leptin, VEGF-R, VEGF, and EGF.

Results: The vascularization index and vascular flow index increased in uneventful pregnancies with almost 50% between 8 and 12 weeks, resulting in a ∼50% higher vascularization index at 12 weeks compared to women with an adverse pregnancy outcome. Women with an adverse pregnancy outcome (n = 13) had significantly lower indices and placental volumes at all time points measured and these indices did not increase between 8 and 12 weeks. Reduced vascular development was associated with increased Angiopoietin-1 levels at 8 and 12 weeks and increased Leptin levels at 8 weeks.

Conclusions: Pregnancies with an adverse outcome caused by conditions associated with impaired placentation differ from uneventful pregnancies in having reduced placental vascularization accompanied by elevated circulating levels of Angiopoietin-1 and Leptin already in the first trimester.
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http://dx.doi.org/10.1016/j.preghy.2018.04.008DOI Listing
July 2018

Exploring Immune Development in Infants With Moderate to Severe Atopic Dermatitis.

Front Immunol 2018 29;9:630. Epub 2018 Mar 29.

Emma Children's Hospital Academic Medical Centre, Department of Paediatric Respiratory Medicine and Allergy, University of Amsterdam, Amsterdam, Netherlands.

Background: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in infancy with a complex pathology. In adults, the clinical severity of AD has been associated with increases in T helper cell type (Th) 2, Th22, and Th17 serum markers, including high levels of CC chemokine ligand (CCL) 17 and CCL22 chemokines.

Objective: To explore the possible association between serum chemokine levels and AD severity in infants with moderate-to-severe AD and elevated immunoglobulin E (IgE).

Subjects And Methods: Serum samples ( = 41) obtained from a randomized, double-blind, and clinical dietary intervention study were used to study biomarkers in infants with AD. Baseline- and post-intervention samples (4 months) were used, six chemokines and nine ratios thereof were analyzed using Luminex and correlated to AD severity. In the initial study, the infants were randomized to receive extensively hydrolyzed whey-based formula without (control) or with short-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (9:1) and M-16V (active).

Results: 31 Infants up to 11 months of age, with an objective-SCORAD score (oSCORAD) ≥ 20 and elevated total-IgE and/or specific-IgE levels were included. In time, the median oSCORAD decreased in both groups by -8 (control,  < 0.05; active,  < 0.01). Irrespective of dietary intervention, several changes in Th2 chemokines (CCL17 and CCL22), inflammatory chemokine (CCL20), and the Th1 chemokine, CXC chemokine ligand (CXCL) 9, were detected over time. Overall CCL17 correlated to oSCORAD ( = 0.446,  < 0.01). After 4 months of dietary intervention, CXCL9 was higher ( < 0.01) in the active group compared with control [active, 2.33 (1.99-2.89); controls, 1.95 (1.77-2.43) log 10 median (range)]. In addition, a reduction in Th2/Th1 chemokine ratios for CCL17/CXCL9, CCL22/CXCL9, CCL20/CXCL10, and CCL20/CXCL11 was detected associated with the active intervention.

Conclusion: While this study is small and exploratory in nature, these data contribute to immune biomarker profiling and understanding of AD in infants.
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http://dx.doi.org/10.3389/fimmu.2018.00630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884950PMC
June 2019

Reversal of Sepsis-Like Features of Neutrophils by Interleukin-1 Blockade in Patients With Systemic-Onset Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2018 06 7;70(6):943-956. Epub 2018 May 7.

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

Objective: Neutrophils are the most abundant innate immune cells in the blood, but little is known about their role in (acquired) chronic autoinflammatory diseases. This study was undertaken to investigate the role of neutrophils in systemic-onset juvenile idiopathic arthritis (JIA), a prototypical multifactorial autoinflammatory disease that is characterized by arthritis and severe systemic inflammation.

Methods: Fifty patients with systemic-onset JIA who were receiving treatment with recombinant interleukin-1 receptor antagonist (rIL-1Ra; anakinra) were analyzed at disease onset and during remission. RNA sequencing was performed on fluorescence-activated cell-sorted neutrophils from 3 patients with active systemic-onset JIA and 3 healthy controls. Expression of activation markers, apoptosis, production of reactive oxygen species (ROS), and degranulation of secretory vesicles from neutrophils were assessed by flow cytometry in serum samples from 17 patients with systemic-onset JIA and 15 healthy controls.

Results: Neutrophil counts were markedly increased at disease onset, and this correlated with the levels of inflammatory mediators. The neutrophil counts normalized within days after the initiation of rIL-1Ra therapy. RNA-sequencing analysis revealed a substantial up-regulation of inflammatory processes in neutrophils from patients with active systemic-onset JIA, significantly overlapping with the transcriptome of sepsis. Correspondingly, neutrophils from patients with active systemic-onset JIA displayed a primed phenotype that was characterized by increased ROS production, CD62L shedding, and secretory vesicle degranulation, which was reversed by rIL-1Ra treatment in patients who had achieved clinical remission. Patients with a short disease duration had high neutrophil counts, more immature neutrophils, and a complete response to rIL-1Ra, whereas patients with symptoms for >1 month had normal neutrophil counts and an unsatisfactory response to rIL-1Ra. In vitro, rIL-1Ra antagonized the priming effect of IL-1β on neutrophils from healthy subjects.

Conclusion: These results strongly support the notion that neutrophils play an important role in systemic-onset JIA, especially in the early inflammatory phase of the disease. The findings also demonstrate that neutrophil numbers and the inflammatory activity of systemic-onset JIA are both susceptible to IL-1 blockade.
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http://dx.doi.org/10.1002/art.40442DOI Listing
June 2018

Effect of anticoagulants on 162 circulating immune related proteins in healthy subjects.

Cytokine 2018 06 28;106:114-124. Epub 2017 Oct 28.

Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; Multiplex Core Facility, Laboratory of Translational Immunology, University Medical center Utrecht, Utrecht, The Netherlands. Electronic address:

Diagnosis of complex disease and response to treatment is often associated with multiple indicators, both clinical and laboratorial. With the use of biomarkers, various mechanisms have been unraveled which can lead to better and faster diagnosis, predicting and monitoring of response to treatment and new drug development. With the introduction of multiplex technology for immunoassays and the growing awareness of the role of immune-monitoring during new therapeutic interventions it is now possible to test large numbers of soluble mediators in small sample volumes. However, standardization of sample collection and laboratory assessments remains suboptimal. We developed a multiplex immunoassay for detection of 162 immune related proteins in human serum and plasma. The assay was split in panels depending on natural occurring concentrations with a maximum of 60 proteins. The aim of this study was to evaluate precision, accuracy, reproducibility and stability of proteins when repeated freeze-thaw cycles are performed of this in-house developed panel, as well as assessing the protein signature in plasma and serum using various anticoagulants. Intra-assay variance of each mediator was <10%. Inter-assay variance ranged between 1.6 and 37% with an average of 12.2%. Recoveries were similar for all mediators (mean 99.8 ± 2.6%) with a range between 89-107%. Next we measured all mediators in serum, EDTA plasma and sodium heparin plasma of 43 healthy control donors. Of these markers only 19 showed similar expression profiles in the 3 different matrixes. Only 5 mediators were effected by multiple freeze-thawing cycles. Principal component analysis revealed different coagulants cluster separately and that sodium heparin shows the most consistent profile.
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http://dx.doi.org/10.1016/j.cyto.2017.10.021DOI Listing
June 2018

Differential adipokine receptor expression on circulating leukocyte subsets in lean and obese children.

PLoS One 2017 26;12(10):e0187068. Epub 2017 Oct 26.

Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Childhood obesity prevalence has increased worldwide and is an important risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). The production of inflammatory adipokines by obese adipose tissue contributes to the development of T2D and CVD. While levels of circulating adipokines such as adiponectin and leptin have been established in obese children and adults, the expression of adiponectin and leptin receptors on circulating immune cells can modulate adipokine signalling, but has not been studied so far. Here, we aim to establish the expression of adiponectin and leptin receptors on circulating immune cells in obese children pre and post-lifestyle intervention compared to normal weight control children.

Methods: 13 obese children before and after a 1-year lifestyle intervention were compared with an age and sex-matched normal weight control group of 15 children. Next to routine clinical and biochemical parameters, circulating adipokines were measured, and flow cytometric analysis of adiponectin receptor 1 and 2 (AdipoR1, AdipoR2) and leptin receptor expression on peripheral blood mononuclear cell subsets was performed.

Results: Obese children exhibited typical clinical and biochemical characteristics compared to controls, including a higher BMI-SD, blood pressure and circulating leptin levels, combined with a lower insulin sensitivity index (QUICKI). The 1-year lifestyle intervention resulted in stabilization of their BMI-SD. Overall, circulating leukocyte subsets showed distinct adipokine receptor expression profiles. While monocytes expressed high levels of all adipokine receptors, NK and iNKT cells predominantly expressed AdipoR2, and B-lymphocytes and CD4+ and CD8+ T-lymphocyte subsets expressed AdipoR2 as well as leptin receptor. Strikingly though, leukocyte subset numbers and adipokine receptor expression profiles were largely similar in obese children and controls. Obese children showed higher naïve B-cell numbers, and pre-intervention also higher numbers of immature transition B-cells and intermediate CD14++CD16+ monocytes combined with lower total monocyte numbers, compared to controls. Furthermore, adiponectin receptor 1 expression on nonclassical CD14+CD16++ monocytes was consistently upregulated in obese children pre-intervention, compared to controls. However, none of the differences in leukocyte subset numbers and adipokine receptor expression profiles between obese children and controls remained significant after multiple testing correction.

Conclusions: First, the distinct adipokine receptor profiles of circulating leukocyte subsets may partly explain the differential impact of adipokines on leukocyte subsets. Second, the similarities in adipokine receptor expression profiles between obese children and normal weight controls suggest that adipokine signaling in childhood obesity is primarily modulated by circulating adipokine levels, instead of adipokine receptor expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658151PMC
November 2017

Proteins in Preservation Fluid as Predictors of Delayed Graft Function in Kidneys from Donors after Circulatory Death.

Clin J Am Soc Nephrol 2017 May;12(5):817-824

Departments of Nephrology and Hypertension and.

Background And Objectives: Kidney transplantation is the preferred treatment for ESRD, and donor kidney shortage urges proper donor-recipient matching. Zero-hour biopsies provide predictive values for short- and long-term transplantation outcomes, but are invasive and may not reflect the entire organ. Alternative, more representative methods to predict transplantation outcome are required. We hypothesized that proteins accumulating in preservation fluid during cold ischemic storage can serve as biomarkers to predict post-transplantation graft function.

Design, Setting, Participants, & Measurements: Levels of 158 proteins were measured in preservation fluids from kidneys donated after circulatory death (Maastricht category III) collected in two Dutch centers (University Medical Center Utrecht and Erasmus Medical Center Rotterdam) between 2013 and 2015. Five candidate biomarkers identified in a discovery set of eight kidneys with immediate function (IF) versus eight with delayed graft function (DGF) were subsequently analyzed in a verification set of 40 additional preservation fluids to establish a prediction model.

Results: Variables tested for their contribution to a prediction model included five proteins (leptin, periostin, GM-CSF, plasminogen activator inhibitor-1, and osteopontin) and two clinical parameters (recipient body mass index [BMI] and dialysis duration) that distinguished between IF and DGF in the discovery set. Stepwise multivariable logistic regression provided a prediction model on the basis of leptin and GM-CSF. Receiver operating characteristic analysis showed an area under the curve (AUC) of 0.87, and addition of recipient BMI generated a model with an AUC of 0.89, outperforming the Kidney Donor Risk Index and the DGF risk calculator, showing AUCs of 0.55 and 0.59, respectively.

Conclusions: We demonstrate that donor kidney preservation fluid harbors biomarkers that, together with information on recipient BMI, predict short-term post-transplantation kidney function. Our approach is safe, easy, and performs better than current prediction algorithms, which are only on the basis of clinical parameters.
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http://dx.doi.org/10.2215/CJN.10701016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477220PMC
May 2017

Biomarker Profiles in Women with PCOS and PCOS Offspring; A Pilot Study.

PLoS One 2016 2;11(11):e0165033. Epub 2016 Nov 2.

Laboratory of Translational Immunology, Division of Pediatrics, Wilhelmina Children's Hospital, Utrecht, the Netherlands.

Objective: To study metabolic/inflammatory biomarker risk profiles in women with PCOS and PCOS offspring.

Design: Cross-sectional comparison of serum biomarkers.

Setting: University Medical Center Utrecht.

Patients: Hyperandrogenic PCOS women (HA-PCOS, n = 34), normoandrogenic PCOS women (NA-PCOS, n = 34), non-PCOS reference population (n = 32), PCOS offspring (n = 14, age 6-8 years), and a paedriatic reference population (n = 30).

Main Outcome Measure(s): Clustering profile of adipocytokines (IL-1b, IL-6, IL-13, IL-17, IL-18, TNF-α, adiponectin, adipsin, leptin, chemerin, resistin, RBP4, DPP-IV/sCD26, CCL2/MCP-1), growth factors (PIGF, VEGF, sVEGF-R1), soluble cell adhesion molecules (sICAM-1/sCD54, sVCAM-1/sCD106), and other inflammatory related proteases (MMP-9, S100A8, Cathepsin S). Differences in median biomarker concentrations between groups, and associations with the free androgen index (FAI; Testosterone/SHBG x100).

Results: The cluster analysis identified leptin, RBP-4, DPP-IV and adiponectin as potential discriminative markers for HA-PCOS with a specifically strong correlation in cases with increased BMI. Leptin (R2 = 0.219) and adiponectin (R2 = 0.182) showed the strongest correlation with the FAI. When comparing median protein concentrations adult PCOS women with or without hyperandrogenemia, the most profound differences were observed for leptin (P < 0.001), DPP-IV (P = 0.005), and adiponectin (P < 0.001). Adjusting for age, BMI and multiple testing attenuated all differences. In PCOS offspring, MMP-9 (P = 0.001) and S100A8 (P < 0.001) concentrations were significantly higher compared to a healthy matched reference population, even after correcting for age and BMI and adjustment for multiple testing.

Conclusion: In this preliminary investigation we observed significant differences in adipocytokines between women with or without hyperandrogenic PCOS and non-PCOS controls, mostly influenced by BMI. Leptin and adiponectin showed the strongest correlation with the FAI in adult women with PCOS. In PCOS offspring other inflammatory biomarkers (MMP-9, S100A8) were increased, suggesting that these children may exhibit increased chronic low-grade inflammation. Additional research is required to confirm results of the current exploratory investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091782PMC
June 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

APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients.

Cell Stress Chaperones 2016 07 30;21(4):735-44. Epub 2016 May 30.

Biomedical Research Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Havana, 11300, Cuba.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a chronic relapsing-remitting joint inflammation. Perturbations in the balance between CD4 + T cells producing IL-17 and CD4 + CD25(high)FoxP3 + Tregs correlate with irreversible bone and cartilage destruction in RA. APL1 is an altered peptide ligand derived from a CD4+ T-cell epitope of human HSP60, an autoantigen expressed in the inflamed synovium, which increases the frequency of CD4 + CD25(high)FoxP3+ Tregs in peripheral blood mononuclear cells from RA patients. The aim of this study was to evaluate the suppressive capacity of Tregs induced by APL1 on proliferation of effector CD4+ T cells using co-culture experiments. Enhanced Treg-mediated suppression was observed in APL1-treated cultures compared with cells cultured only with media. Subsequent analyses using autologous cross-over experiments showed that the enhanced Treg suppression in APL1-treated cultures could reflect increased suppressive function of Tregs against APL1-responsive T cells. On the other hand, APL1-treatment had a significant effect reducing IL-17 levels produced by effector CD4+ T cells. Hence, this peptide has the ability to increase the frequency of Tregs and their suppressive properties whereas effector T cells produce less IL-17. Thus, we propose that APL1 therapy could help to ameliorate the pathogenic Th17/Treg balance in RA patients.
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http://dx.doi.org/10.1007/s12192-016-0698-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908004PMC
July 2016

Inflammatory mediators in human epilepsy: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2016 Apr 11;63:177-90. Epub 2016 Feb 11.

Brain Center Rudolf Magnus, Department of Pediatric Neurology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Background: Accumulating evidence suggests a role for inflammation in the pathophysiology of epilepsy.

Methods: We performed a systematic review and meta-analysis of studies that investigated inflammatory mediators in human epilepsy. Studies reporting on inflammatory mediators in serum, cerebrospinal fluid or brain tissue of epilepsy patients were included. Studies comparing patients to controls were included in a meta-analysis.

Results: 66 articles reporting on 1934 patients were included. IL-1ra, IL-1β, IL-6, IL-10, IFN-γ and TNF-α were the most extensively investigated proteins. Elevated levels for IL-1ra, IL-1β, IL-6 and CXCL8/IL-8 were reported in several different epilepsy etiologies and media, while other proteins were specifically increased for one etiology. IL-1α, IL-7 and IL-13, as well as the chemokines CCL2-5, -19 and -22, were increased exclusively in brain tissue. In an aggregate meta-analysis, we found significantly different protein levels for serum IL-6, IL-17 and CSF IL-1β and IL-10.

Conclusion: Inflammatory pathways are involved in epilepsy. Future studies may further clarify their role, and prove potential of targeted anti-inflammatory treatment.
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http://dx.doi.org/10.1016/j.neubiorev.2016.02.007DOI Listing
April 2016

Ocular Fluid Analysis in Children Reveals Interleukin-29/Interferon-λ1 as a Biomarker for Juvenile Idiopathic Arthritis-Associated Uveitis.

Arthritis Rheumatol 2016 07;68(7):1769-79

Utrecht University Medical Center, Utrecht, The Netherlands.

Objective: Childhood uveitis is a vision-threatening inflammatory eye disease commonly attributed to juvenile idiopathic arthritis (JIA). The pathogenesis is poorly understood, which makes clinical management challenging. We analyzed soluble mediators in ocular fluid (aqueous humor [AqH]) and serum from children with JIA-associated uveitis and common childhood uveitis to identify potential biomarkers and investigate the ocular microenvironment of this sight-threatening eye disease.

Methods: AqH (n = 73) and paired serum (n = 66) samples were analyzed for 51 soluble mediators of inflammation by multiplex immunoassay. Twenty-one children with JIA-associated uveitis were compared to 15 children with chronic anterior uveitis without arthritis, 29 children with noninfectious idiopathic uveitis, and 8 children with noninflammatory conditions (controls). For visualization of the joint effect of multiple mediators, we used the radial coordinate visualization (Radviz) method. Optimal biomarker level cutoffs were also determined.

Results: The levels of interleukin-29 (IL-29)/interferon-λ1 (IFNλ1) were decreased (P < 0.001) and the levels of latency-associated peptide and osteoprotegerin were increased (P = 0.002 and P = 0.001, respectively) in samples of AqH, but not serum, from patients with JIA-associated uveitis. Multivariate analysis correcting for disease activity and treatment revealed that intraocular levels of IL-29/IFNλ1 were specifically decreased in patients with JIA-associated uveitis as compared to those with idiopathic uveitis. Indeed, JIA-associated uveitis patients and idiopathic uveitis patients showed distinct profiles of intraocular soluble mediators. IL-29/IFNλ1 showed a high area under the curve value (0.954), with 23.5 pg/ml as the optimal cutoff value.

Conclusion: We identified IL-29/IFNλ1 as an intraocular biomarker for JIA-associated uveitis, which suggests that aberrant IFNλ signaling might be important in JIA-associated uveitis and distinct from other forms of childhood uveitis.
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http://dx.doi.org/10.1002/art.39621DOI Listing
July 2016

Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes.

PLoS One 2016 11;11(1):e0146649. Epub 2016 Jan 11.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.

Background: Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation.

Methods: Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (<6 months) insulin independence. A panel of 94 proteins including cytokines and adipokines was measured in sera taken before and at one year after transplantation using a validated multiplex immunoassay platform.

Results: Ninety serum proteins were detectable in concentrations varying markedly among patients at either time point. Thirteen markers changed after transplantation, while another seven markers changed in a clinical subpopulation. All other markers remained unaffected after transplantation under generalized immunosuppression. Patterns of cytokines could distinguish good graft function from insufficient function including IFN-α, LIF, SCF and IL-1RII before and after transplantation, by IL-16, CCL3, BDNF and M-CSF only before and by IL-22, IL-33, KIM-1, S100A12 and sCD14 after transplantation. Three other proteins (Leptin, Cathepsin L and S100A12) associated with loss of temporary graft function before or after transplantation.

Conclusions: Distinct cytokine signatures could be identified in serum that predict or associate with clinical outcome. These serum markers may help guiding patient selection and choice of immunotherapy, or act as novel drug targets in islet transplantation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713434PMC
July 2016

Serum inflammatory mediators correlate with disease activity in electrical status epilepticus in sleep (ESES) syndrome.

Epilepsia 2016 Feb 14;57(2):e45-50. Epub 2015 Dec 14.

Department of Pediatric Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

We aimed to study serum cytokine levels in 11 electrical status epilepticus in sleep (ESES) patients and 20 healthy control children. Patients showed significantly higher levels of interleukin (IL)-1α, IL-6, IL-10, chemokine (C-C motif) ligand (CCL)2 and chemokine (C-X-C motif) ligand (CXCL)8/IL-8 than controls, while macrophage migration inhibitory factor (MIF) and CCL3 were significantly lower. Follow-up analyses in five patients revealed a significant decrease of IL-6 levels after immunomodulating treatment. IL-6 changes were accompanied by clear improvement of electroencephalography (EEG) patterns and neuropsychological evaluation. We hypothesize that IL-6 correlates with disease activity and immunomodulating treatment efficacy.
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http://dx.doi.org/10.1111/epi.13274DOI Listing
February 2016

The effect of HIV coinfection, HAART and TB treatment on cytokine/chemokine responses to Mycobacterium tuberculosis (Mtb) antigens in active TB patients and latently Mtb infected individuals.

Tuberculosis (Edinb) 2016 Jan 30;96:131-40. Epub 2015 Sep 30.

Department of Internal Medicine and Infectious Diseases, Laboratory of Transitional Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Identification of Mtb specific induced cytokine/chemokine host biomarkers could assist in developing novel diagnostic, prognostic and therapeutic tools for TB. Levels of IFN-γ, IL-2, IL-17, IL-10, IP-10 and MIP-1α were measured in supernatants of whole blood stimulated with Mtb specific fusion protein ESAT-6/CFP-10 using xMAP technology. The study groups were HIV positive TB patients (HIV(+)TB(+)), HIV negative TB patients (HIV(-)TB(+)), HIV positive tuberculin skin test positive (TST+) (HIV(+)TST(+)), HIV negative TST+ (HIV(-)TST(+)), and HIV(-)TST(-) individuals. Compared to HIV(-)TST(-), latent TB infection led to increased levels of IP-10, IFN-γ and IL-17, while levels of IL-2 and IP-10 were increased with active TB. Levels of IFN-γ, IL-17, MIP-1α, and IL-10 were increased in HIV(-)TST(+) individuals compared to HIV(-)TB(+) patients. HIV coinfection decreased the level of IFN-γ, IL-17, IP-10 and IL-2. After six months (M6) of anti-TB treatment (ATT) in HIV(-)TB(+) patients, IFN-γ, IL-10, and MIP-1α levels normalized. After M6 and M18 of ATT plus HAART in HIV(+)TB(+) patients, levels of MIP-1α and IL-10 normalized, while this was not the case for IFN-γ, IL-2, IL-17, and IP-10 levels. In HIV(+)TST(+) patients on HAART, levels of IFN-γ, IL-17, IL-10 and MIP-1α normalized, while no change in the levels of IL-2 and IP-10 were observed. In conclusion, the simultaneous measurement of IFN-γ, IL-17 and IP-10 may assist in diagnosing LTBI; IL-2 and IP-10 may assist in diagnosing active TB; while IFN-γ, IL-17, MIP-1α, and IL-10 levels could help to discriminate LTBI and active TB. In addition, IL-10 and MIP-1α levels could help to monitor responses to TB treatment and HAART.
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http://dx.doi.org/10.1016/j.tube.2015.05.015DOI Listing
January 2016

Developing clinically relevant biomarkers in inflammatory arthritis: A multiplatform approach for serum candidate protein discovery.

Proteomics Clin Appl 2016 06 9;10(6):691-8. Epub 2015 Nov 9.

School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland.

Purpose: To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel.

Experimental Design: Serum samples from 32 patients (PsA; n = 16 and RA; n = 16) defined as active, early onset, and treatment naïve were analyzed using unbiased label-free LC-MS/MS, a microsphere bead-based immunoassay (Luminex xMAP) and an aptamer-based assay (SOMAscan).

Results: LC-MS/MS was used to quantify 324 proteins, while the Luminex xMAP targeted 48 proteins and SOMAscan supported the measurement of 1129 proteins. The combined data from these techniques gave reproducible quantification of 1501 proteins in total. Of these, 42 (LC-MS/MS), 3 (Luminex xMAP), and 127 (SOMAscan) proteins were found to be differentially expressed between PsA and RA (p < 0.05).

Conclusion And Clinical Relevance: Using three different and potentially complementary proteomic platforms we identified a total of 172 proteins that are differentially expressed in patients with PsA compared to RA. These proteins collectively represent candidates for inclusion in a protein signature that could be developed as a diagnostic test to discriminate patients with PsA from RA and therefore be of clinical utility.
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http://dx.doi.org/10.1002/prca.201500046DOI Listing
June 2016

Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases.

J Allergy Clin Immunol 2015 Nov 27;136(5):1337-45. Epub 2015 May 27.

Institute of Immunology, University of Muenster, Muenster, Germany; Interdisciplinary Centre for Clinical Research IZKF, University Hospital Muenster, University of Muenster, Muenster, Germany. Electronic address:

Background: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin).

Objective: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc.

Methods: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA.

Results: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 μg/mL) compared with those with PAPA syndrome (116 ± 74 μg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1.

Conclusion: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.
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http://dx.doi.org/10.1016/j.jaci.2015.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591125PMC
November 2015

Inflammatory characteristics of distinct abdominal adipose tissue depots relate differently to metabolic risk factors for cardiovascular disease: distinct fat depots and vascular risk factors.

Atherosclerosis 2015 Apr 2;239(2):419-27. Epub 2015 Feb 2.

Department of Vascular Medicine, University Medical Center Utrecht (UMC Utrecht), Utrecht, The Netherlands. Electronic address:

Objective: Abdominal obesity is associated with insulin resistance and metabolic syndrome. However, specific contributions of distinct adipose tissue (AT) depots to metabolic complications of obesity are still unclear. In this study, the inflammatory profile of four distinct abdominal AT-depots and the relation between AT-characteristics and obesity-induced metabolic complications was evaluated.

Methods: In 28 men undergoing abdominal aortic surgery, biopsies were collected from subcutaneous fat (SAT), and 3 visceral AT-depots: mesenteric (MAT), omental (OAT) and periaortic (PAT). The AT biopsies were characterized morphologically (adipocyte size, capillary density, CD68 + macrophages and crown-like-structures (CLS)) and the ex vivo adipokine secretion profile was determined by multiplex-immunoassay. The relation between depot-specific inflammatory characteristics and clinical parameters (waist circumference, insulin resistance and metabolic syndrome) was assessed by multivariable linear regression analysis.

Results: PAT contained the smallest adipocytes, highest capillary density and secreted abundant amounts of adipokines. SAT contained the lowest amount of macrophages and adipokines, while MAT and OAT displayed a similar inflammatory profile. In contrast to the other depots, MAT inflammation was most strongly related to metabolic complications of obesity, as adipocyte size and CLS were related to insulin resistance (β2.0; 95%CI1.15-2.85 and β0.24; 95%CI0.06-0.43) and MAT adipocyte size was associated with 79% higher odds of having metabolic syndrome (OR1.79; 95% CI1.13-2.89).

Conclusions: There are significant differences in the inflammatory profile of distinct abdominal fat depots, of which MAT characteristics were mostly associated with metabolic complications of obesity. These findings suggest a differential contribution of AT-depots to systemic metabolic dysfunction which precedes type 2 diabetes and vascular diseases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.035DOI Listing
April 2015

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

Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells.

Obesity (Silver Spring) 2014 Oct 17;22(10):2216-23. Epub 2014 Jul 17.

Department of Vascular Medicine, University Medical Center Utrecht (UMC Utrecht), Utrecht, The Netherlands; Molecular Cancer Research, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.

Objective: Insulin resistance (IR) is a key mechanism in obesity-induced cardiovascular disease. To unravel mechanisms whereby human adipose tissue (AT) contributes to systemic IR, the effect of human AT-extracellular vesicles (EVs) on insulin signaling in liver and muscle cells was determined.

Methods: EVs released from human subcutaneous (SAT) and omental AT (OAT)-explants ex vivo were used for stimulation of hepatocytes and myotubes in vitro. Subsequently, insulin-induced Akt phosphorylation and expression of gluconeogenic genes (G6P, PEPCK) was determined. AT-EV adipokine levels were measured by multiplex immunoassay, and AT-EVs were quantified by high-resolution flow cytometry.

Results: In hepatocytes, AT-EVs from the majority of patients inhibited insulin-induced Akt phosphorylation, while EVs from some patients stimulated insulin-induced Akt phosphorylation. In myotubes AT-EVs exerted an ambiguous effect on insulin signaling. Hepatic Akt phosphorylation related negatively to G6P-expression by both SAT-EVs (r = -0.60, P = 0.01) and OAT-EVs (r = -0.74, P = 0.001). MCP-1, IL-6, and MIF concentrations were higher in OAT-EVs compared to SAT-EVs and differently related to lower Akt phosphorylation in hepatocytes. Finally, the number of OAT-EVs correlated positively with liver enzymes indicative for liver dysfunction.

Conclusions: Human AT-EVs can stimulate or inhibit insulin signaling in hepatocytes- possibly depending on their adipokine content- and may thereby contribute to systemic IR.
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http://dx.doi.org/10.1002/oby.20847DOI Listing
October 2014

Effectiveness of first-line treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study.

Arthritis Rheumatol 2014 Apr;66(4):1034-43

University Medical Centre Utrecht, Utrecht, The Netherlands.

Objective: To conduct a prospective cohort study using anakinra, a recombinant IL-1 receptor antagonist (IL-1Ra), as first-line therapy in patients with new-onset systemic juvenile idiopathic arthritis (JIA).

Methods: Therapy with recombinant IL-1Ra (2 mg/kg) was initiated in 20 patients who fulfilled the International League of Associations for Rheumatology criteria for systemic JIA, before systemic steroid treatment was administered. Patients were monitored clinically and immunologically. The protocol contained a stop strategy for patients who met at least the adapted American College of Rheumatology 90% criteria for improvement in JIA (ACR Pediatric 90 [ACR Pedi 90]) after 3 months.

Results: We included consecutive patients with new-onset systemic JIA. The mean followup period was 32 months (range 12-54 months). At the 3-month time point, 85% of the patients showed an adapted ACR Pedi 90 response or had inactive disease; 75% of the patients achieved this response while receiving recombinant IL-1Ra alone. After 1 year, 17 of the 20 patients met the criteria for clinically inactive disease, and 13 of these patients met these criteria while receiving monotherapy with recombinant IL-1Ra. However, because of persistent disease activity, 7 of the 20 patients required additional therapy besides recombinant IL-1Ra. According to our stop strategy, 73% of patients with at least an adapted ACR Pedi 90 response at 3 months could stop recombinant IL-1Ra treatment within 1 year. After 2 years, 12 (86%) of 14 patients met the criteria for disease remission, either while receiving (n = 4) or not receiving (n = 8) medication. After 3 years, 10 (91%) of 11 patients met the criteria for disease remission, either while receiving (n = 2) or not receiving (n = 8) medication.

Conclusion: This is the first prospective study in which recombinant IL-1Ra was used as first-line therapy in patients with systemic JIA. We observed excellent responses in nearly all patients within 3 months. In the majority of responding patients, treatment with recombinant IL-1Ra could be stopped within 1 year, with remission being preserved during followup. In approximately one-third of patients, concomitant therapy was required for maintenance of clinical response.
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http://dx.doi.org/10.1002/art.38296DOI Listing
April 2014

Interleukin-7 and Toll-like receptor 7 induce synergistic B cell and T cell activation.

PLoS One 2014 16;9(4):e94756. Epub 2014 Apr 16.

Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands.

Objectives: To investigate the potential synergy of IL-7-driven T cell-dependent and TLR7-mediated B cell activation and to assess the additive effects of monocyte/macrophages in this respect.

Methods: Isolated CD19 B cells and CD4 T cells from healthy donors were co-cultured with TLR7 agonist (TLR7A, Gardiquimod), IL-7, or their combination with or without CD14 monocytes/macrophages (T/B/mono; 1 : 1 : 0,1). Proliferation was measured using 3H-thymidine incorporation and Ki67 expression. Activation marker (CD19, HLA-DR, CD25) expression was measured by FACS analysis. Immunoglobulins were measured by ELISA and release of cytokines was measured by Luminex assay.

Results: TLR7-induced B cell activation was not associated with T cell activation. IL-7-induced T cell activation alone and together with TLR7A synergistically increased numbers of both proliferating (Ki67+) B cells and T cells, which was further increased in the presence of monocytes/macrophages. This was associated by up regulation of activation markers on B cells and T cells. Additive or synergistic induction of production of immunoglobulins by TLR7 and IL-7 was associated by synergistic induction of T cell cytokines (IFNγ, IL-17A, IL-22), which was only evident in the presence of monocytes/macrophages.

Conclusions: IL-7-induced CD4 T cell activation and TLR7-induced B cell activation synergistically induce T helper cell cytokine and B cell immunoglobulin production, which is critically dependent on monocytes/macrophages. Our results indicate that previously described increased expression of IL-7 and TLR7 together with increased numbers of macrophages at sites of inflammation in autoimmune diseases like RA and pSS significantly contributes to enhanced lymphocyte activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989236PMC
February 2015

TCR bias and affinity define two compartments of the CD1b-glycolipid-specific T Cell repertoire.

J Immunol 2014 May 28;192(9):4054-60. Epub 2014 Mar 28.

Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

Current views emphasize TCR diversity as a key feature that differentiates the group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 systems. Whereas TCR sequence motifs define CD1d-reactive NKT cells, the available data do not allow a TCR-based organization of the group 1 CD1 repertoire. The observed TCR diversity might result from donor-to-donor differences in TCR repertoire, as seen for MHC-restricted T cells. Alternatively, diversity might result from differing CD1 isoforms, Ags, and methods used to identify TCRs. Using CD1b tetramers to isolate clones recognizing the same glycolipid, we identified a previously unknown pattern of V gene usage (TRAV17, TRBV4-1) among unrelated human subjects. These TCRs are distinct from those present on NKT cells and germline-encoded mycolyl lipid-reactive T cells. Instead, they resemble the TCR of LDN5, one of the first known CD1b-reactive clones that was previously thought to illustrate the diversity of the TCR repertoire. Interdonor TCR conservation was observed in vitro and ex vivo, identifying LDN5-like T cells as a distinct T cell type. These data support TCR-based organization of the CD1b repertoire, which consists of at least two compartments that differ in TCR sequence motifs, affinity, and coreceptor expression.
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http://dx.doi.org/10.4049/jimmunol.1400158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019959PMC
May 2014