247 results on '"Radstake, Tr"'
Search Results
2. PS5:91 Increased expression of tlr7 in plasmacytoid dendritic cells drives type i ifn mediated immunopathology in sle and aps
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van den Hoogen, LL, primary, Pandit, A, additional, Palla, G, additional, Rossato, M, additional, Fritsch-Stork, RDE, additional, van Roon, JAG, additional, and Radstake, TR, additional
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- 2018
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3. S5A:5 Galectin-9 is produced by dendritic cells and serum levels outperform cxcl10 as a biomarker to detect the ifn signature in sle and aps
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van den Hoogen, LL, primary, van Roon, JAG, additional, Wienke, J, additional, van Wijk, F, additional, Fritsch-Stork, RDE, additional, and Radstake, TR, additional
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- 2018
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4. Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies
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López-Isac E, Martín JE, Assassi S, Simeón CP, Carreira P, Ortego-Centeno N, Freire M, Beltrán E, Narváez J, Alegre-Sancho JJ, Spanish Scleroderma Group, Fernández-Gutiérrez B, Balsa A, Ortiz AM, González-Gay MA, Beretta L, Santaniello A, Bellocchi C, Lunardi C, Moroncini G, Gabrielli A, Witte T, Hunzelmann N, Distler JH, Riekemasten G, van der Helm-van Mil AH, de Vries-Bouwstra J, Magro-Checa C, Voskuyl AE, Vonk MC, Molberg Ø, Merriman T, Hesselstrand R, Nordin A, Padyukov L, Herrick A, Eyre S, Koeleman BP, Denton CP, Fonseca C, Radstake TR, Worthington J, Mayes MD, Martín J, University of Queensland [Brisbane], Rheumatology Service, Hospital Clínico San Carlos, University Hospital La Paz, Madrid, Referral Center for Systemic Autoimmune Diseases, University of Milan, Department of Clinical and Experimental Medicine, University of Verona (UNIVR), Department of Dermatology, University of Cologne, Department of Internal Medicine 3, Institute for Clinical Immunology Erlangen-Nuremberg, Karolinska Institutet [Stockholm], University Medical Center [Utrecht], Laboratory of Translational Immunology [Utrecht, the Netherlands], Institute of Parasitology and Biomedicine (IPB - GRANADA), Spanish National Research Council (CSIC), Immunologie et Pathologie (EA 2216), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Brest, and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche
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[SDV.GEN]Life Sciences [q-bio]/Genetics ,Scleroderma, Systemic ,integumentary system ,[SDV]Life Sciences [q-bio] ,Arthritis, Rheumatoid ,[SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system ,Genetic Loci ,Risk Factors ,Interferon Regulatory Factors ,Humans ,Genetic Predisposition to Disease ,skin and connective tissue diseases ,ComputingMilieux_MISCELLANEOUS ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genome-Wide Association Study - Abstract
Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.
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- 2016
5. Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders
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Miller, FW, Cooper, RG, Vencovský, J, Rider, LG, Danko, K, Wedderburn, LR, Lundberg, IE, Pachman, LM, Reed, AM, Ytterberg, SR, Padyukov, L, Selva-O'Callaghan, A, Radstake, TR, Isenberg, DA, Chinoy, H, Ollier, WE, O'Hanlon, TP, Peng, B, Lee, A, Lamb, JA, Chen, W, Amos, CI, and Gregersen, PK
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Orvostudományok ,Klinikai orvostudományok - Abstract
OBJECTIVE: To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of
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- 2016
6. THU0234 Epigenetic cell counting: a novel tool to quantify immune cells in salivary glands detects robust correlations of tfh cells with immunopathology
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Roon, JA van, primary, Moret, FM, additional, Blokland, SL, additional, Kruize, AA, additional, Bouma, G, additional, Maurik, A van, additional, Olek, S, additional, Hoffmueller, U, additional, and Radstake, TR, additional
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- 2017
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7. THU0223 Elevated MTORC1 signature in B cells from sjÖgren's syndrome patients correlates with B cell hyperactivity that is abrogated by MTOR inhibition: a novel therapeutic strategy to halt B cell hyperactivity in PSS?
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Blokland, SL, primary, Hillen, MR, additional, Kommer-Wichers, CG, additional, Kruize, AA, additional, Broen, JC, additional, Roon, JA van, additional, and Radstake, TR, additional
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- 2017
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8. AB0446 Additive inhibition of interferons, b and t cell activation and tfh-related cytokine cxcl13 by leflunomide and hydroxychloroquine supports rationale for combination therapy in pss patients
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Heijden, EH van der, primary, Hartgring, SA, additional, Kruize, AA, additional, Radstake, TR, additional, and Roon, JA van, additional
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- 2017
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9. OP0306 Downregulation of micrornas in plasmacytoid dendritic cells is associated with a type i interferon signature in systemic lupus erythematosus and antiphospholipid syndrome
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Hoogen, LL Van Den, primary, Roon, JA van, additional, Fritsch-Stork, RD, additional, Bekker, CP, additional, Pandit, A, additional, Rossato, M, additional, and Radstake, TR, additional
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- 2017
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10. THU0241 Decreased circulating CXCR3+CCR9+ th cells are associated with elevated levels of their ligands CXCL10 and CCL25 in the salivary gland of patients with SJÖGREN'S syndrome to potentially facilitate concerted migration
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Blokland, SL, primary, Hillen, MR, additional, Meller, S, additional, Homey, B, additional, Smithson, GM, additional, Kruize, AA, additional, Radstake, TR, additional, and Roon, JA van, additional
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- 2017
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11. AB0054 CXCL4 potentiates TLR-driven polarization of human dendritic cells towards cytokine production, antigen cross-presentation and increases stimulation of CD8+T-cells
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Silva-Cardoso, SC, primary, Affandi, AJ, additional, Spel, L, additional, Cossu, M, additional, Boes, M, additional, and Radstake, TR, additional
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- 2017
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12. SAT0324 Increased frequencies of circulating CXCL10-, CXCL8- and CCL4-producing monocytes and SIGLEC-3-expressing myeloid dendritic cells in systemic sclerosis patients
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Carvalheiro, T, primary, Horta, S, additional, Roon, JA van, additional, Santiago, M, additional, Salvador, MJ, additional, Radstake, TR, additional, Trindade, H, additional, Silva, JA da, additional, and Paiva, A, additional
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- 2017
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13. AB0121 Dysregulated circulating mirna levels are characteristic of both non sjÖgren's sicca and primary sjÖgren's syndrome patients
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Lopes, AP, primary, Hillen, MR, additional, Chouri, E, additional, Blokland, SL, additional, Kruize, AA, additional, Rossato, M, additional, Radstake, TR, additional, and Roon, JA van, additional
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- 2017
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14. OP0303 The salivary gland secretome as a potential new tool to identify biomarkers of dryness and immunopathology in primary sjÖgren's syndrome and non-autoimmune sicca patients
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Blokland, SL, primary, Hillen, MR, additional, Kruize, AA, additional, Jager, W de, additional, Pandit, A, additional, Roon, JA van, additional, and Radstake, TR, additional
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- 2017
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15. Identification of IL12RB1 as a novel systemic sclerosis susceptibility locus
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López Isac E1, Bossini Castillo, L, Guerra, Sg, Denton, C, Fonseca, C, Assassi, S, Zhou, X, Mayes, Md, Simeón, Cp, Ortego Centeno, N, Castellví, I, Carreira, P, Spanish Scleroderma Group, Gorlova, O, Beretta, L, Santaniello, A, Lunardi, Claudio, Hesselstrand, R, Nordin, A, Riemekasten, G, Witte, T, Hunzelmann, N, Kreuter, A, Distler, Jh, Voskuyl, Ae, de Vries Bouwstra, J, Koeleman, Bp, Herrick, A, Worthington, J, Radstake, Tr, Martin, J., Rheumatology, and CCA - Disease profiling
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Logistic Models ,Scleroderma, Systemic ,Gene Frequency ,Case-Control Studies ,loci ,Receptors, Interleukin-12 ,IL12RB1 ,Humans ,Genetic Predisposition to Disease ,Rheumatoid Arthritis ,Polymorphism, Single Nucleotide ,Article - Published
- 2014
16. A7.09 Class 3 semaphorins modulate the invasive capacity of rheumatoid arthritis fibroblast-like synoviocytes
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Perez, S García, primary, Malvar-Fernández, B, additional, Newsom, SP, additional, Tang, MW, additional, Radstake, TR, additional, Baeten, DL, additional, Tak, PP, additional, and Reedquist, KA, additional
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- 2016
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17. Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout
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McKinney, C, Stamp, LK, Dalbeth, N, Topless, RK, Day, RO, Kannangara, DRW, Williams, KM, Janssen, M, Jansen, TL, Joosten, LA, Radstake, TR, Riches, PL, Tausche, AK, Lioté, F, So, A, Merriman, TR, McKinney, C, Stamp, LK, Dalbeth, N, Topless, RK, Day, RO, Kannangara, DRW, Williams, KM, Janssen, M, Jansen, TL, Joosten, LA, Radstake, TR, Riches, PL, Tausche, AK, Lioté, F, So, A, and Merriman, TR
- Abstract
Introduction: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1β (IL-1β) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1β axis for association with gout. Methods: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Maori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. Results: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. Conclusion: There is evidence for association of gout with functional variants in CARD8, IL
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- 2015
18. KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor
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Bossini Castillo, L, Simeon, Cp, Beretta, L, Broen, J, Vonk, Mc, Callejas, Jl, Carreira, P, Rodriguez Rodriguez, L, Garcia Portales, R, Gonzalez Gay MA, Castellvi, I, Camps, Mt, Tolosa, C, Vicente Rabaneda, E, Egurbide, Mv, Ssg, Ss, Schuerwegh, Aj, Hesselstrand, R, Lunardi, Claudio, van Laar JM, Shiels, P, Herrick, A, Worthington, J, Denton, C, Radstake, Tr, Fonseca, C, and Martin, J.
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medicine.medical_specialty ,Pathology ,Linkage disequilibrium ,Genotype ,systemic sclerosis ,Hypertension, Pulmonary ,Immunology ,Population ,Polymorphism, Single Nucleotide ,Gastroenterology ,Linkage Disequilibrium ,White People ,Cohort Studies ,Kv1.5 Potassium Channel ,Gene Frequency ,Rheumatology ,pulmonary arterial hypertension ,Internal medicine ,Odds Ratio ,medicine ,Humans ,Immunology and Allergy ,SNP ,Genetic Predisposition to Disease ,Potassium voltage-gated channel shaker-related subfamily member 5 ,education ,skin and connective tissue diseases ,Allele frequency ,Netherlands ,Rheumatology and Autoimmunity ,Sweden ,education.field_of_study ,Scleroderma, Systemic ,integumentary system ,business.industry ,Autoantibody ,Odds ratio ,medicine.disease ,Pulmonary hypertension ,United Kingdom ,Italy ,Spain ,Genetic marker ,business ,Research Article - Abstract
Introduction Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. Methods The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Results Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. Conclusions Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients., This work was supported by the following grants: JM was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain, and by Fondo Europeo de Desarrollo Regional (FEDER). TRDJR was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). JM and TRDJR were sponsored by the Orphan Disease Program grant from the European League Against Rheumatism (EULAR). BPCK is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). This study was also funded by PI-0590-2010, Consejería de Salud, Junta de Andalucía, Spain.
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- 2012
19. Association study of the RANK locus in white European rheumatoid arthritis families
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Teixeira, Vh, Dieudé, P, Michou, L, Migliorini, Paola, Balsa, A, Westhovens, R, Barrera, P, Alves, H, Vaz, C, Fernandes, M, PASCUAL SALCEDO, D, Bombardieri, Stefano, Dequeker, J, Radstake, Tr, VAN RIEL, P, VAN DE PUTTE, L, LOPES VAZ, A, Bardin, T, Cornélis, F, Ecraf, and PETIT TEIXEIRA, E.
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Arthritis, Rheumatoid ,Receptor Activator of Nuclear Factor-kappa B ,Humans ,Genetic Predisposition to Disease ,White People - Published
- 2009
20. Genetic and expression analysis of CASP7 gene in a European Caucasian population with rheumatoid arthritis
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Teixeira, Vh, Jacq, L, Lasbleiz, S, Hilliquin, P, Oliveira, Cr, Cornelis, F, PETIT TEIXEIRA, E, EUROPEAN CONSORTIUM ON RHEUMATOID ARTHRITIS FAMILIES, Collaborators, Cornélis, F, Bardin, T, Migliorini, Paola, Bombardieri, Stefano, Westhvens, R, Dequeker, J, Balsa, A, PASCUALE SALCEDO, D, Barrera, P, VAN DE PUTTE, L, VAN RIEL, P, Radstake, Tr, Alves, H, LOPES VAZ, A, Fernandes, M, and Vaz, C.
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- 2008
21. Clinical and immunogenetic characteristics of European multicase rheumatoid arthritis families
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Balsa, A, Barrera, P, Westhovens, R, Alves, H, Maenaut, K, Pascual Salcedo, D, Cornélis, F, Bardin, T, Riente, Lucrezia, Radstake, Tr, de Almeida, G, Lepage, V, Stravopoulos, C, Spaepen, M, Lopes Vaz, A, Charron, D, Martinez, M, Prudhomme, Jf, Migliorini, Paola, Fritz, P, and European Consortium on Rheumatoid Arthritis Families
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- 2001
22. Noninherited maternal antigens do not play a role in rheumatoid arthritis susceptibility in Europe
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MAENAUT K, BARRERA P. BALSA A. ALVES H. WESTHOVENS R., LOPES VAZ A, CORNELIS F. FRITZ P. BARDIN T. DE ALMEIDA G., DE LA CONCHA EG RADSTAKE TR VAN DE PUTTE LB, PASCUAL SALCEDO D., Migliorini, Paola, SPAEPEN M, PRUD'HOMME JF CHARRON D. SPYROPOULOU M. MENDES A., and Martinez, M. LEPAGE V. STRAVOPOULOS C.
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- 2000
23. Association of variation in Fcgamma receptor 3B gene copy number with rheumatoid arthritis in Caucasian samples.
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McKinney C, Fanciulli M, Merriman ME, Phipps-Green A, Alizadeh BZ, Koeleman BP, Dalbeth N, Gow PJ, Harrison AA, Highton J, Jones PB, Stamp LK, Steer S, Barrera P, Coenen MJ, Franke B, van Riel PL, Vyse TJ, Aitman TJ, and Radstake TR
- Abstract
Objective: There is increasing evidence that variation in gene copy number (CN) influences clinical phenotype. The low-affinity Fcgamma receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment to sites of inflammation and activation of polymorphonuclear neutrophils (PMNs). Given recent evidence that low FCGR3B CN is a risk factor for systemic but not organ-specific autoimmune disease and the potential importance of PMN in the pathophysiology of rheumatoid arthritis (RA), the authors hypothesised that FCGR3B gene dosage influences susceptibility to RA.Methods: FCGR3B CN was measured in 643 cases of RA and 461 controls from New Zealand (NZ), with follow-up analysis in 768 cases and 702 controls from the Netherlands and 250 cases and 211 controls from the UK. All subjects were of Caucasian ancestry.Results: Significant evidence for an association between CN <2 and RA was observed in the Dutch cohort (OR 2.01 (95% CI 1.37 to 2.94), p=3 x 10-4) but not in the two smaller cohorts (OR 1.45 (95% CI 0.92 to 2.26), p=0.11 and OR 1.33 (95% CI 0.58 to 3.02), p=0.50 for the NZ and UK populations, respectively). The association was evident in a meta-analysis which included a previously published Caucasian sample set (OR 1.67 (95% CI 1.28 to 2.17), p=1.2 x 10-4).Conclusions: One possible mechanism to explain the association between reduced FCGR3B CN and RA is the reduced clearance of immune complex during inflammation. However, it is not known whether the association between RA and FCGR3B CN is aetiological or acts as a proxy marker for another biologically relevant variant. More detailed examination of genetic variation within the FCGR gene cluster is required. [ABSTRACT FROM AUTHOR]- Published
- 2010
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24. Association of STAT4 with rheumatoid arthritis: a replication study in three European populations.
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Orozco G, Alizadeh BZ, Delgado-Vega AM, González-Gay MA, Balsa A, Pascual-Salcedo D, Fernández-Gutierrez B, González-Escribano MF, Petersson IF, van Riel PL, Barrera P, Coenen MJ, Radstake TR, van Leeuwen MA, Wijmenga C, Koeleman BP, Alarcón-Riquelme M, and Martín J
- Abstract
OBJECTIVE: This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. METHODS: Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). CONCLUSION: Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data. [ABSTRACT FROM AUTHOR]
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- 2008
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25. Discovery of new myositis genetic associations through leveraging other immune-mediated diseases.
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Reales G, Amos CI, Benveniste O, Chinoy H, De Bleecker J, De Paepe B, Doria A, Gregersen PK, Lamb JA, Limaye V, Lundberg IE, Machado PM, Maurer B, Miller FW, Molberg Ø, Pachman LM, Padyukov L, Radstake TR, Reed AM, Rider LG, Rothwell S, Selva-O'Callaghan A, Vencovský J, Wedderburn LR, and Wallace C
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- Humans, Polymorphism, Single Nucleotide, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Immune System Diseases genetics, Myositis genetics, Myositis immunology, Genome-Wide Association Study, Genetic Predisposition to Disease
- Abstract
Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD., Competing Interests: Declaration of interests Dr. Wallace receives research funding from GSK and MSD and is a part-time employee of GSK. Neither company had any influence on this work or its publication. Dr. Radstake is an employee of Abbvie and may hold stock. Abbvie had no influence on the content of this work or its publication. Dr. Chinoy has received fees as a speaker for GSK and UCB; consulting for PTC Therapeutics; advisory board member for Astra Zeneca, Pfizer, Argenx, and Galapagos; and as a data and science monitoring board chair for Horizon Therapeutics. Dr. Maurer has grants from Novartis, consulting fees from Novartis, Boehringer Ingelheim, Jannsen-Cilag, and GSK; speaker fees from Boehringer-Ingelheim, GSK, Novartis, Otsuka, and MSD; congress support from Medtalk, Pfizer, Roche, Actelion, Mepha, and MSD; and has a patent mir-29 for the treatment of SSc (US8247389, EP2331143). Dr. Wedderburn has received speaker and consultancy fees from Pfizer paid to UCL, unrelated to this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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26. Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren's syndrome that show potential to predict and monitor clinical response.
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Hamkour S, van der Heijden EH, Lopes AP, Blokland SLM, Bekker CPJ, Van Helden-Meeuwsen CG, Versnel MA, Kruize AA, Radstake TR, Leavis HL, Hillen MR, and van Roon JA
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- Humans, Biomarkers, Hydroxychloroquine therapeutic use, Leflunomide therapeutic use, Leukocytes, Mononuclear metabolism, Proteins, RNA, Interferon Type I metabolism, Sjogren's Syndrome diagnosis, Sjogren's Syndrome drug therapy
- Abstract
Objectives: To assess to what extent leflunomide (LEF) and hydroxychloroquine (HCQ) therapy in patients with primary Sjögren's syndrome (RepurpSS-I) targets type I IFN-associated responses and to study the potential of several interferon associated RNA-based and protein-based biomarkers to predict and monitor treatment., Methods: In 21 patients treated with LEF/HCQ and 8 patients treated with placebo, blood was drawn at baseline, 8, 16 and 24 weeks. IFN-signatures based on RNA expression of five IFN-associated genes were quantified in circulating mononuclear cells and in whole blood. MxA protein levels were measured in whole blood, and protein levels of CXCL10 and Galectin-9 were quantified in serum. Differences between responders and non-responders were assessed and receiver operating characteristic analysis was used to determine the capacity of baseline expression and early changes (after 8 weeks of treatment) in biomarkers to predict treatment response at the clinical endpoint., Results: IFN-signatures in peripheral blood mononuclear cell and whole blood decreased after 24 weeks of LEF/HCQ treatment, however, changes in IFN signatures only poorly correlated with changes in disease activity. In contrast to baseline IFN signatures, baseline protein concentrations of galectin-9 and decreases in circulating MxA and Galectin-9 were robustly associated with clinical response. Early changes in serum Galectin-9 best predicted clinical response at 24 weeks (area under the curve 0.90)., Conclusions: LEF/HCQ combination therapy targets type-I IFN-associated proteins that are associated with strongly decreased B cell hyperactivity and disease activity. IFN-associated Galectin-9 is a promising biomarker for treatment prediction and monitoring in pSS patients treated with LEF/HCQ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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27. Deciphering the role of cDC2s in Sjögren's syndrome: transcriptomic profile links altered antigen processes with IFN signature and autoimmunity.
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Lopes AP, Hillen MR, Hinrichs AC, Blokland SL, Bekker CP, Pandit A, Kruize AA, Radstake TR, and van Roon JA
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- Humans, Transcriptome, Autoimmunity, Interferon-alpha, Epithelial Cells metabolism, Sjogren's Syndrome, Interferon Type I genetics
- Abstract
Objective: Type 2 conventional dendritic cells (cDC2s) are key orchestrators of inflammatory responses, linking innate and adaptative immunity. Here we explored the regulation of immunological pathways in cDC2s from patients with primary Sjögren's syndrome (pSS)., Methods: RNA sequencing of circulating cDC2s from patients with pSS, patients with non-Sjögren's sicca and healthy controls (HCs) was exploited to establish transcriptional signatures. Phenotypical and functional validation was performed in independent cohorts., Results: Transcriptome of cDC2s from patients with pSS revealed alterations in type I interferon (IFN), toll-like receptor (TLR), antigen processing and presentation pathways. Phenotypical validation showed increased CX3CR1 expression and decreased integrin beta-2 and plexin-B2 on pSS cDC2s. Functional validation confirmed impaired capacity of pSS cDC2s to degrade antigens and increased antigen uptake, including self-antigens derived from salivary gland epithelial cells. These changes in antigen uptake and degradation were linked to anti-SSA/Ro (SSA) autoantibodies and the presence of type I IFNs. In line with this, in vitro IFN-α priming enhanced the uptake of antigens by HC cDC2s, reflecting the pSS cDC2 profile. Finally, pSS cDC2s compared with HC cDC2s increased the proliferation and the expression of CXCR3 and CXCR5 on proliferating CD4
+ T cells., Conclusions: pSS cDC2s are transcriptionally altered, and the aberrant antigen uptake and processing, including (auto-)antigens, together with increased proliferation of tissue-homing CD4+ T cells, suggest altered antigen presentation by pSS cDC2s. These functional alterations were strongly linked to anti-SSA positivity and the presence of type I IFNs. Thus, we demonstrate novel molecular and functional pieces of evidence for the role of cDC2s in orchestrating immune response in pSS, which may yield novel avenues for treatment., Competing Interests: Competing interests: TRDJR was the principal investigator in the immune catalyst programme of GlaxoSmithKline, which was an independent research programme. He did not receive any financial support other than the research funding for the current project. Currently, He is an employee of Abbvie, where he holds stock. He had no part in the design and interpretation of the study results after he started at Abbvie.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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28. Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes.
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Acosta-Herrera M, Kerick M, Lopéz-Isac E, Assassi S, Beretta L, Simeón-Aznar CP, Ortego-Centeno N, Proudman SM, Hunzelmann N, Moroncini G, de Vries-Bouwstra JK, Orozco G, Barton A, Herrick AL, Terao C, Allanore Y, Brown MA, Radstake TR, Fonseca C, Denton CP, Mayes MD, and Martin J
- Subjects
- Alleles, Genetic Predisposition to Disease, HLA-DRB1 Chains genetics, Humans, Major Histocompatibility Complex, Genome-Wide Association Study, Scleroderma, Systemic genetics
- Abstract
Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes., Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA)., Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01 , and revealed a novel association of HLA-B*08:01 . Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation., Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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29. Tissue-Resident Memory CD8+ T Cells From Skin Differentiate Psoriatic Arthritis From Psoriasis.
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Leijten EF, van Kempen TS, Olde Nordkamp MA, Pouw JN, Kleinrensink NJ, Vincken NL, Mertens J, Balak DMW, Verhagen FH, Hartgring SA, Lubberts E, Tekstra J, Pandit A, Radstake TR, and Boes M
- Subjects
- Adult, Aminopeptidases genetics, Antigens, CD genetics, Antigens, Differentiation, T-Lymphocyte immunology, Arthritis, Psoriatic genetics, Arthritis, Psoriatic pathology, CD8-Positive T-Lymphocytes metabolism, Case-Control Studies, Female, Forkhead Transcription Factors genetics, GATA3 Transcription Factor genetics, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Humans, Immunologic Memory immunology, Immunophenotyping, Integrin alpha Chains genetics, Interleukin-17 immunology, Interleukins immunology, Male, Middle Aged, Minor Histocompatibility Antigens genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Oligosaccharides metabolism, Psoriasis genetics, Psoriasis pathology, Receptor, Interferon alpha-beta genetics, Receptors, CCR10 metabolism, Receptors, CCR4 metabolism, Sialyl Lewis X Antigen analogs & derivatives, Sialyl Lewis X Antigen metabolism, Skin pathology, Spondylarthropathies genetics, Spondylarthropathies immunology, Spondylarthropathies pathology, Synovial Fluid cytology, T-Lymphocyte Subsets metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Regulatory metabolism, Interleukin-22, Arthritis, Psoriatic immunology, CD8-Positive T-Lymphocytes immunology, Psoriasis immunology, Skin immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Objective: To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA., Methods: In-depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high-throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis., Results: Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin-17A (IL-17A) and IL-22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin-homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue-resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up-regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22-like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function., Conclusion: Tissue-resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)
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- 2021
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30. Genomic Risk Score impact on susceptibility to systemic sclerosis.
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Bossini-Castillo L, Villanueva-Martin G, Kerick M, Acosta-Herrera M, López-Isac E, Simeón CP, Ortego-Centeno N, Assassi S, Hunzelmann N, Gabrielli A, de Vries-Bouwstra JK, Allanore Y, Fonseca C, Denton CP, Radstake TR, Alarcón-Riquelme ME, Beretta L, Mayes MD, and Martin J
- Subjects
- Adult, Aged, Antibodies, Antinuclear immunology, Arthritis, Rheumatoid genetics, Autoantibodies immunology, Case-Control Studies, DNA Topoisomerases immunology, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linear Models, Lupus Erythematosus, Systemic genetics, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Scleroderma, Diffuse immunology, Scleroderma, Limited immunology, Scleroderma, Systemic genetics, Scleroderma, Systemic immunology, Sjogren's Syndrome genetics, White People, Scleroderma, Diffuse genetics, Scleroderma, Limited genetics
- Abstract
Objectives: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time., Methods: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model., Results: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693., Conclusions: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc., Competing Interests: Competing interests: LB-C: none; GV-M: none; MK: none; MA-H: none; ELI: none; International SSc Group: none; PRECISESADS Consortium: none; MEAl-R: none; LB: none; JM: none., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
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31. Neutrophil extracellular traps and low-density granulocytes are associated with the interferon signature in systemic lupus erythematosus, but not in antiphospholipid syndrome.
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van den Hoogen LL, van der Linden M, Meyaard L, Fritsch-Stork RDE, van Roon JA, and Radstake TR
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- Granulocytes, Humans, Interferons, Neutrophils, T-Lymphocytes, Antiphospholipid Syndrome, Extracellular Traps, Lupus Erythematosus, Systemic
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2020
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32. Extracellular SPARC cooperates with TGF-β signalling to induce pro-fibrotic activation of systemic sclerosis patient dermal fibroblasts.
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Carvalheiro T, Malvar Fernández B, Ottria A, Giovannone B, Marut W, Reedquist KA, Garcia S, and Radstake TR
- Subjects
- Case-Control Studies, Cells, Cultured, Extracellular Matrix genetics, Extracellular Matrix Proteins genetics, Fibrosis, Humans, RNA, Messenger genetics, Signal Transduction genetics, Skin cytology, Transcriptional Activation genetics, Fibroblasts metabolism, Osteonectin genetics, Scleroderma, Systemic genetics, Skin pathology, Transforming Growth Factor beta1 genetics
- Abstract
Objectives: SSc is an autoimmune disease characterized by inflammation, vascular injury and excessive fibrosis in multiple organs. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein that regulates processes involved in SSc pathology, such as inflammation and fibrosis. In vivo and in vitro studies have implicated SPARC in SSc, but it is unclear if the pro-fibrotic effects of SPARC on fibroblasts are a result of intracellular signalling or fibroblast interactions with extracellular SPARC hampering further development of SPARC as a potential therapeutic target. This study aimed to analyse the potential role of exogenous SPARC as a regulator of fibrosis in SSc., Methods: Dermal fibroblasts from both healthy controls and SSc patients were stimulated with SPARC alone or in combination with TGF-β1, in the absence or presence of a TGF receptor 1 inhibitor. mRNA and protein expression of extracellular matrix components and other fibrosis-related mediators were measured by quantitative PCR and western blot., Results: Exogenous SPARC induced mRNA and protein expression of collagen I, collagen IV, fibronectin 1, TGF-β and SPARC by dermal fibroblasts from SSc patients, but not from healthy controls. Importantly, exogenous SPARC induced the activation of the tyrosine kinase SMAD2 and pro-fibrotic gene expression induced by SPARC in SSc fibroblasts was abrogated by inhibition of TGF-β signalling., Conclusion: These results indicate that exogenous SPARC is an important pro-fibrotic mediator contributing to the pathology driving SSc but in a TGF-β dependent manner. Therefore, SPARC could be a promising therapeutic target for reducing fibrosis in SSc patients, even in late states of the disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2020
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33. Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients.
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Kabala PA, Malvar-Fernández B, Lopes AP, Carvalheiro T, Hartgring SAY, Tang MW, Conde C, Baeten DL, Sleeman M, Tak PP, Connor J, Radstake TR, Reedquist KA, and García S
- Subjects
- Animals, Arthritis, Experimental pathology, Arthritis, Psoriatic pathology, Arthritis, Rheumatoid pathology, Cytokines metabolism, Humans, Inflammation metabolism, Inflammation pathology, Macrophages metabolism, Mice, Mice, Transgenic, Signal Transduction physiology, Synovial Fluid metabolism, Synovial Membrane pathology, Arthritis, Experimental metabolism, Arthritis, Psoriatic metabolism, Arthritis, Rheumatoid metabolism, Macrophage Activation physiology, Receptor, TIE-2 metabolism, Synovial Membrane metabolism
- Abstract
Objective: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA., Methods: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex., Results: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients., Conclusion: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2020
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34. Induction of Inflammation and Fibrosis by Semaphorin 4A in Systemic Sclerosis.
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Carvalheiro T, Affandi AJ, Malvar-Fernández B, Dullemond I, Cossu M, Ottria A, Mertens JS, Giovannone B, Bonte-Mineur F, Kok MR, Marut W, Reedquist KA, Radstake TR, and García S
- Subjects
- Adult, Blotting, Western, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Extracellular Matrix metabolism, Extracellular Matrix pathology, Female, Fibroblasts immunology, Fibroblasts pathology, Fibrosis pathology, Humans, Inflammation immunology, Male, Microscopy, Confocal, Middle Aged, Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Scleroderma, Systemic immunology, Scleroderma, Systemic pathology, Skin cytology, Th17 Cells immunology, CD4-Positive T-Lymphocytes immunology, Cytokines immunology, Fibroblasts metabolism, Fibrosis metabolism, Inflammation metabolism, Monocytes immunology, Scleroderma, Systemic metabolism, Semaphorins metabolism
- Abstract
Objective: To analyze the potential role of semaphorin 4A (Sema4A) in inflammatory and fibrotic processes involved in the pathology of systemic sclerosis (SSc)., Methods: Sema4A levels in the plasma of healthy controls (n = 11) and SSc patients (n = 20) were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Sema4A and its receptors in monocytes and CD4+ T cells from healthy controls and SSc patients (n = 6-7 per group) was determined by ELISA and flow cytometry. Th17 cytokine production by CD4+ T cells (n = 5-7) was analyzed by ELISA and flow cytometry. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblast cells (n = 6) was analyzed by quantitative polymerase chain reaction, ELISA, Western blotting, confocal microscopy, and ECM deposition assay., Results: Plasma levels of Sema4A, and Sema4A expression by circulating monocytes and CD4+ T cells, were significantly higher in SSc patients than in healthy controls (P < 0.05). Inflammatory mediators significantly up-regulated the secretion of Sema4A by monocytes and CD4+ T cells from SSc patients (P < 0.05 versus unstimulated SSc cells). Functional assays showed that Sema4A significantly enhanced the expression of Th17 cytokines induced by CD3/CD28 in total CD4+ T cells as well in different CD4+ T cell subsets (P < 0.05 versus unstimulated SSc cells). Finally, Sema4A induced a profibrotic phenotype in dermal fibroblasts from both healthy controls and SSc patients, which was abrogated by blocking or silencing the expression of Sema4A receptors., Conclusion: Our findings indicate that Sema4A plays direct and dual roles in promoting inflammation and fibrosis, 2 main features of SSc, suggesting that Sema4A might be a novel therapeutic target in SSc., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)
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- 2019
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35. Low RUNX3 expression alters dendritic cell function in patients with systemic sclerosis and contributes to enhanced fibrosis.
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Affandi AJ, Carvalheiro T, Ottria A, Broen JC, Bossini-Castillo L, Tieland RG, Bon LV, Chouri E, Rossato M, Mertens JS, Garcia S, Pandit A, de Kroon LM, Christmann RB, Martin J, van Roon JA, Radstake TR, and Marut W
- Subjects
- Animals, Core Binding Factor Alpha 3 Subunit biosynthesis, Dendritic Cells pathology, Disease Models, Animal, Disease Progression, Fibroblasts metabolism, Fibroblasts pathology, Fibrosis genetics, Fibrosis metabolism, Fibrosis pathology, Humans, Mice, Scleroderma, Systemic metabolism, Scleroderma, Systemic pathology, Skin metabolism, Core Binding Factor Alpha 3 Subunit genetics, Dendritic Cells metabolism, Gene Expression Regulation, RNA genetics, Scleroderma, Systemic genetics, Skin pathology
- Abstract
Objectives: Systemic sclerosis (SSc) is an autoimmune disease with unknown pathogenesis manifested by inflammation, vasculopathy and fibrosis in skin and internal organs. Type I interferon signature found in SSc propelled us to study plasmacytoid dendritic cells (pDCs) in this disease. We aimed to identify candidate pathways underlying pDC aberrancies in SSc and to validate its function on pDC biology., Methods: In total, 1193 patients with SSc were compared with 1387 healthy donors and 8 patients with localised scleroderma. PCR-based transcription factor profiling and methylation status analyses, single nucleotide polymorphism genotyping by sequencing and flow cytometry analysis were performed in pDCs isolated from the circulation of healthy controls or patients with SSc. pDCs were also cultured under hypoxia, inhibitors of methylation and hypoxia-inducible factors and runt-related transcription factor 3 (RUNX3) levels were determined. To study Runx3 function, Itgax -Cre: Runx3
f/f mice were used in in vitro functional assay and bleomycin-induced SSc skin inflammation and fibrosis model., Results: Here, we show downregulation of transcription factor RUNX3 in SSc pDCs. A higher methylation status of the RUNX3 gene, which is associated with polymorphism rs6672420, correlates with lower RUNX3 expression and SSc susceptibility. Hypoxia is another factor that decreases RUNX3 level in pDC. Mouse pDCs deficient of Runx3 show enhanced maturation markers on CpG stimulation. In vivo, deletion of Runx3 in dendritic cell leads to spontaneous induction of skin fibrosis in untreated mice and increased severity of bleomycin-induced skin fibrosis., Conclusions: We show at least two pathways potentially causing low RUNX3 level in SSc pDCs, and we demonstrate the detrimental effect of loss of Runx3 in SSc model further underscoring the role of pDCs in this disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2019
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36. Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale for combination therapy for Sjögren's syndrome.
- Author
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van der Heijden EH, Hartgring SA, Kruize AA, Radstake TR, and van Roon JA
- Subjects
- Adult, Aged, B-Lymphocytes immunology, B-Lymphocytes pathology, Cytokines immunology, Drug Therapy, Combination, Female, Humans, Immunoglobulin G immunology, Immunoglobulin M immunology, Male, Middle Aged, Sjogren's Syndrome immunology, Sjogren's Syndrome pathology, T-Lymphocytes immunology, T-Lymphocytes pathology, Hydroxychloroquine administration & dosage, Leflunomide administration & dosage, Sjogren's Syndrome drug therapy
- Abstract
Objective : Effective treatment for primary Sjögren's syndrome (pSS) is not available. pSS immunopathology involves a variety of immune-cells and dysregulated pathways; targeting several pathways instead of only one could therefore be effective. Treatment with leflunomide (LEF) and hydroxychloroquine (HCQ) might be successful given their unique immunosuppressive properties. We aimed to study the in vitro effects of LEF, HCQ and their combination on T- and B-cell proliferation, cytokine and immunoglobulin production by activated PBMCs. Methods : PBMCs of six healthy individuals and nine pSS patients were stimulated with superantigen and TLR9 agonist to mimic the hallmark features. LEF, HCQ and their combinations were tested at clinically observed concentrations and proliferation, cytokine and immunoglobulin production were measured. Results : TCR/TLR9 activation of PBMCs induced strong proliferation of T and B-cells and production of CXCL13, IFN-α, IFN-γ, IgG and IgM. LEF dose-dependently inhibited all measured parameters, where HCQ potently and dose-dependently decreased B cell proliferation, CXCL13, IFN-α, IgG and IgM production. At different concentration combinations, HCQ and LEF inhibited several immune hallmark features more potently than each single compound. Conclusion : A combination of LEF and HCQ at clinically applicable concentrations additively inhibits immune activation, supporting a potential implementation of this drug combination in pSS treatment.
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- 2019
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37. Limits of traditional evidence-based medicine methodologies exemplified by the novel era in psoriatic arthritis drug development.
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Leijten EF, Radstake TR, McInnes IB, and Jacobs JW
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- Arthritis, Psoriatic immunology, Arthritis, Psoriatic pathology, Humans, Antirheumatic Agents therapeutic use, Arthritis, Psoriatic drug therapy, Drug Development, Evidence-Based Medicine
- Published
- 2019
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38. RNA sequencing to predict response to TNF-α inhibitors reveals possible mechanism for nonresponse in smokers.
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Cuppen BVJ, Rossato M, Fritsch-Stork RDE, Concepcion AN, Linn-Rasker SP, Bijlsma JWJ, van Laar JM, Lafeber FPJG, and Radstake TR
- Subjects
- Adult, Aged, Antirheumatic Agents pharmacology, Arthritis, Rheumatoid diagnosis, Biomarkers, Pharmacological, Cigarette Smoking, Cohort Studies, Drug Resistance, Female, Follow-Up Studies, Gene Expression Profiling, Humans, Male, Middle Aged, Prognosis, Receptors, G-Protein-Coupled genetics, Receptors, Peptide genetics, Semaphorins genetics, Sequence Analysis, RNA, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy, Leukocytes, Mononuclear physiology, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Background: Several studies have employed microarray-based profiling to predict response to tumor necrosis factor-alpha inhibitors (TNFi) in rheumatoid arthritis (RA); yet efforts to validate these targets have failed to show predictive abilities acceptable for clinical practice., Methods: The eighty most extreme responders and nonresponders to TNFi therapy were selected from the observational BiOCURA cohort. RNA sequencing was performed on mRNA from peripheral blood mononuclear cells (PBMCs) collected before initiation of treatment. The expression of pathways as well as individual gene transcripts between responders and nonresponders was investigated. Promising targets were technically replicated and validated in n = 40 new patients using qPCR assays., Results: Before therapy initiation, nonresponders had lower expression of pathways related to interferon and cytokine signaling, while also showing higher levels of two genes, GPR15 and SEMA6B (p = 0.02). The two targets could be validated, however, additional analyses revealed that GPR15 and SEMA6B did not independently predict response, but were rather dose-dependent markers of smoking (p < 0.0001)., Conclusions: The study did not identify new transcripts ready to use in clinical practice, yet GPR15 and SEMA6B were recognized as candidate explanatory markers for the reduced treatment success in RA smokers.
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- 2018
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39. Endoplasmic reticulum stress cooperates with Toll-like receptor ligation in driving activation of rheumatoid arthritis fibroblast-like synoviocytes.
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Kabala PA, Angiolilli C, Yeremenko N, Grabiec AM, Giovannone B, Pots D, Radstake TR, Baeten D, and Reedquist KA
- Subjects
- Arthritis, Rheumatoid pathology, Cells, Cultured, Humans, Synoviocytes pathology, Arthritis, Rheumatoid metabolism, Endoplasmic Reticulum Stress physiology, Synoviocytes metabolism, Toll-Like Receptors metabolism
- Abstract
Background: Endoplasmic reticulum (ER) stress has proinflammatory properties, and transgenic animal studies of rheumatoid arthritis (RA) indicate its relevance in the process of joint destruction. Because currently available studies are focused primarily on myeloid cells, we assessed how ER stress might affect the inflammatory responses of stromal cells in RA., Methods: ER stress was induced in RA fibroblast-like synoviocytes (FLS), dermal fibroblasts, and macrophages with thapsigargin or tunicamycin alone or in combination with Toll-like receptor (TLR) ligands, and gene expression and messenger RNA (mRNA) stability was measured by quantitative polymerase chain reaction. Cellular viability was measured using cell death enzyme-linked immunosorbent assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and signaling pathway activation was analyzed by immunoblotting., Results: No cytotoxicity was observed in FLS exposed to thapsigargin, despite significant induction of ER stress markers. Screening of 84 proinflammatory genes revealed minor changes in their expression (fold change 90th percentile range 2.8-8.3) by thapsigargin alone, but the vast majority were hyperinduced during combined stimulation with thapsigargin and TLR ligands (35% greater than fivefold vs lipopolysaccharide alone). The synergistic response could not be explained by quantitative effects on nuclear factor-κB and mitogen-activated protein kinase pathways alone, but it was dependent on increased mRNA stability. mRNA stabilization was similarly enhanced by ER stress in dermal fibroblasts but not in macrophages, correlating with minimal cooperative effects on gene induction in macrophages., Conclusions: RA FLS are resistant to apoptosis induced by ER stress, but ER stress potentiates their activation by multiple TLR ligands. Interfering with downstream signaling pathway components of ER stress may be of therapeutic potential in the treatment of RA.
- Published
- 2017
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40. Standardisation of labial salivary gland histopathology in clinical trials in primary Sjögren's syndrome.
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Fisher BA, Jonsson R, Daniels T, Bombardieri M, Brown RM, Morgan P, Bombardieri S, Ng WF, Tzioufas AG, Vitali C, Shirlaw P, Haacke E, Costa S, Bootsma H, Devauchelle-Pensec V, Radstake TR, Mariette X, Richards A, Stack R, Bowman SJ, and Barone F
- Subjects
- Biopsy, Delphi Technique, Humans, Leukocytes pathology, Lip, Reference Standards, Germinal Center pathology, Lymphocytes pathology, Salivary Glands, Minor pathology, Sialadenitis pathology, Sjogren's Syndrome pathology
- Abstract
Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus., Competing Interests: Competing interests: SJB has received honoraria/consultancy fees in the field of Sjögren's syndrome in 2015–2016 for AstraZeneca, Celgene, Glenmark, Eli Lilly, Novartis, Ono and UCB Pharmaceuticals. Roche provided rituximab for the TRACTISS study. BAF has received honoraria/consultancy fees from Novartis, Roche and Medimmune. FB has received honoraria/consultancy fees from Roche, GlaxoSmithKline, Glenmark and Medimmune, and research funding from UCB. Other authors have declared no competing interests., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)
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- 2017
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41. Fcγ receptor expression on splenic macrophages in adult immune thrombocytopenia.
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Audia S, Santegoets K, Laarhoven AG, Vidarsson G, Facy O, Ortega-Deballon P, Samson M, Janikashvili N, Saas P, Bonnotte B, and Radstake TR
- Subjects
- Adult, Aged, Autoimmune Diseases surgery, Autoimmune Diseases therapy, B7-2 Antigen analysis, Female, Flow Cytometry, Humans, Immunoglobulin G blood, Immunoglobulins, Intravenous therapeutic use, Macrophages physiology, Male, Middle Aged, Phagocytosis, Phenotype, Polymorphism, Genetic, Receptors, IgG immunology, Spleen cytology, Splenectomy, Thrombocytopenia surgery, Thrombocytopenia therapy, Autoimmune Diseases immunology, Macrophages immunology, Receptors, IgG analysis, Receptors, IgG genetics, Spleen immunology, Thrombocytopenia immunology
- Abstract
Splenic macrophages play a key role in immune thrombocytopenia (ITP) pathogenesis by clearing opsonized platelets. Fcγ receptors (FcγR) participate in this phenomenon, but their expression on splenic macrophages and their modulation by treatment have scarcely been studied in human ITP. We aimed to compare the phenotype and function of splenic macrophages between six controls and 24 ITP patients and between ITP patients according to the treatments they received prior to splenectomy. CD86, human leucocyte antigen D-related (HLA-DR) and FcγR expression were measured by flow cytometry on splenic macrophages. The major FcγR polymorphisms were determined and splenic macrophage function was assessed by a phagocytosis assay. The expression of the activation markers CD86 and HLA-DR was higher on splenic macrophages during ITP compared to controls. While the expression of FcγR was not different between ITP and controls, the phagocytic function of splenic macrophages was reduced in ITP patients treated with intravenous immunoglobulin (IVIg) within the 2 weeks prior to splenectomy. The FCGR3A (158V/F) polymorphism, known to increase the affinity of FcγRIII to IgG, was over-represented in ITP patients. Thus, these are the first results arguing for the fact that the therapeutic use of IVIg during human chronic ITP does not modulate FcγR expression on splenic macrophages but decreases their phagocytic capabilities., (© 2017 British Society for Immunology.)
- Published
- 2017
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42. The acetyl code in rheumatoid arthritis and other rheumatic diseases.
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Angiolilli C, Baeten DL, Radstake TR, and Reedquist KA
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- Acetylation drug effects, Animals, Arthritis, Rheumatoid drug therapy, Arthritis, Rheumatoid metabolism, Histone Code, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use, Histone Deacetylases metabolism, Humans, Protein Processing, Post-Translational drug effects, Rheumatic Diseases drug therapy, Rheumatic Diseases metabolism, Arthritis, Rheumatoid genetics, Epigenesis, Genetic drug effects, Histones metabolism, Rheumatic Diseases genetics
- Abstract
Growing evidence supports the idea that aberrancies in epigenetic processes contribute to the onset and progression of human immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). Epigenetic regulators of histone tail modifications play a role in chromatin accessibility and transcriptional responses to inflammatory stimuli. Among these, histone deacetylases (HDACs) regulate the acetylation status of histones and nonhistone proteins, essential for immune responses. Broad-spectrum HDAC inhibitors are well-known anti-inflammatory agents and reduce disease severity in animal models of arthritis; however, selective HDAC inhibitors remain poorly studied. In this review, we describe emerging findings regarding the aberrant acetyl code in RA and other rheumatic disorders which may help identify not only novel diagnostic and prognostic clinical biomarkers for RA, but also new targets for epigenetic pharmacological applications.
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- 2017
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43. Hematopoietic stem cell-derived myeloid and plasmacytoid DC-based vaccines are highly potent inducers of tumor-reactive T cell and NK cell responses ex vivo .
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Thordardottir S, Schaap N, Louer E, Kester MG, Falkenburg JH, Jansen J, Radstake TR, Hobo W, and Dolstra H
- Abstract
Because of the potent graft-versus-tumor (GVT) effect, allogeneic stem cell transplantation (alloSCT) can be a curative therapy for hematological malignancies. However, relapse remains the most frequent cause of treatment failure, illustrating the necessity for development of adjuvant post-transplant therapies to boost GVT immunity. Dendritic cell (DC) vaccination is a promising strategy in this respect, in particular, where distinct biologic functions of naturally occurring DC subsets, i.e. myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), are harnessed. However, it is challenging to obtain high enough numbers of primary DC subsets from blood for immunotherapy due to their low frequencies. Therefore, we present here an ex vivo GMP-compliant cell culture protocol for generating different DC subsets from CD34
+ hematopoietic stem and progenitor cells (HSPCs) of alloSCT donor origin. High numbers of BDCA1+ mDCs and pDCs could be generated, sufficient for multiple vaccination cycles. These HSPC-derived DC subsets were highly potent in inducing antitumor immune responses in vitro . Notably, HSPC-derived BDCA1+ mDCs were superior in eliciting T cell responses. They efficiently primed naïve T cells and robustly expanded patient-derived minor histocompatibility antigen (MiHA)-specific T cells. Though the HSPC-pDCs also efficiently induced T cell responses, they exhibited superior capacity in activating NK cells. pDC-primed NK cells highly upregulated TRAIL and possessed strong cytolytic capacity against tumor cells. Collectively, these findings indicate that HSPC-derived DC vaccines, comprising both mDCs and pDCs, may possess superior potential to boost antitumor immunity post alloSCT, due to their exceptional T cell and NK cell stimulatory capacity.- Published
- 2017
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44. An Ocular Protein Triad Can Classify Four Complex Retinal Diseases.
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Kuiper JJ, Beretta L, Nierkens S, van Leeuwen R, Ten Dam-van Loon NH, Ossewaarde-van Norel J, Bartels MC, de Groot-Mijnes JD, Schellekens P, de Boer JH, and Radstake TR
- Subjects
- Adult, Aged, Aged, 80 and over, Algorithms, Aqueous Humor metabolism, Biomarkers, Clinical Decision-Making, Cluster Analysis, Computational Biology methods, Female, Humans, Male, Middle Aged, Proteome, Proteomics methods, Reproducibility of Results, Sensitivity and Specificity, Eye Proteins metabolism, Retinal Diseases diagnosis, Retinal Diseases metabolism
- Abstract
Retinal diseases generally are vision-threatening conditions that warrant appropriate clinical decision-making which currently solely dependents upon extensive clinical screening by specialized ophthalmologists. In the era where molecular assessment has improved dramatically, we aimed at the identification of biomarkers in 175 ocular fluids to classify four archetypical ocular conditions affecting the retina (age-related macular degeneration, idiopathic non-infectious uveitis, primary vitreoretinal lymphoma, and rhegmatogenous retinal detachment) with one single test. Unsupervised clustering of ocular proteins revealed a classification strikingly similar to the clinical phenotypes of each disease group studied. We developed and independently validated a parsimonious model based merely on three proteins; interleukin (IL)-10, IL-21, and angiotensin converting enzyme (ACE) that could correctly classify patients with an overall accuracy, sensitivity and specificity of respectively, 86.7%, 79.4% and 92.5%. Here, we provide proof-of-concept for molecular profiling as a diagnostic aid for ophthalmologists in the care for patients with retinal conditions., Competing Interests: The authors declare no competing financial interests.
- Published
- 2017
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45. Is sex bias orchestrated in the skin?
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Pandit A, Meyaard L, and Radstake TR
- Subjects
- Humans, Sexism, Skin
- Published
- 2017
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46. Embracing Complexity beyond Systems Medicine: A New Approach to Chronic Immune Disorders.
- Author
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Te Velde AA, Bezema T, van Kampen AH, Kraneveld AD, 't Hart BA, van Middendorp H, Hack EC, van Montfrans JM, Belzer C, Jans-Beken L, Pieters RH, Knipping K, Huber M, Boots AM, Garssen J, Radstake TR, Evers AW, Prakken BJ, and Joosten I
- Abstract
In order to combat chronic immune disorders (CIDs), it is an absolute necessity to understand the bigger picture, one that goes beyond insights at a one-disease, molecular, cellular, and static level. To unravel this bigger picture we advocate an integral, cross-disciplinary approach capable of embracing the complexity of the field. This paper discusses the current knowledge on common pathways in CIDs including general psychosocial and lifestyle factors associated with immune functioning. We demonstrate the lack of more in-depth psychosocial and lifestyle factors in current research cohorts and most importantly the need for an all-encompassing analysis of these factors. The second part of the paper discusses the challenges of understanding immune system dynamics and effectively integrating all key perspectives on immune functioning, including the patient's perspective itself. This paper suggests the use of techniques from complex systems science in describing and simulating healthy or deviating behavior of the immune system in its biopsychosocial surroundings. The patient's perspective data are suggested to be generated by using specific narrative techniques. We conclude that to gain more insight into the behavior of the whole system and to acquire new ways of combatting CIDs, we need to construct and apply new techniques in the field of computational and complexity science, to an even wider variety of dynamic data than used in today's systems medicine.
- Published
- 2016
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47. The magnitude of cytokine production by stimulated CD56 + cells is associated with early stages of systemic sclerosis.
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Cossu M, van Bon L, Nierkens S, Bellocchi C, Santaniello A, Dolstra H, Beretta L, and Radstake TR
- Subjects
- Adult, Aged, CD56 Antigen immunology, Female, Humans, Leukocytes, Mononuclear immunology, Male, Middle Aged, Toll-Like Receptor 1 immunology, Toll-Like Receptor 2 immunology, Cytokines immunology, Scleroderma, Systemic immunology
- Abstract
Immune activation is a hallmark of systemic sclerosis (SSc). However, the immunological alterations that occur in preclinical and non-fibrotic SSc and that differentiate these subjects from those with primary Raynaud's phenomenon (PRP) or healthy controls (HC) are poorly defined. We isolated CD56
+ (NK/NKT-like) cells from HC, patients with PRP, early SSc (EaSSc) and definite SSc without skin or lung fibrosis. Cytokine production upon different activating stimuli was measured via a multiplex immuno assay. Clearly discriminative patterns among the different stages of SSc were most markedly observed after TLR1/2 stimulation, with increased IL-6, TNF-α and MIP-1α/CCL3 production in definite SSc patients as compared to HC and/or PRP. Initial alterations were observed in EaSSc patients with an intermediate secretion pattern between HC/PRP and definite SSc. CD56+ cells from patients at different stages of SSc differentially respond to TLR stimulation, highlighting the relevance of natural immunity in the developmental and pre-fibrotic SSc., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2016
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48. Monocyte type I interferon signature in antiphospholipid syndrome is related to proinflammatory monocyte subsets, hydroxychloroquine and statin use.
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van den Hoogen LL, Fritsch-Stork RD, Versnel MA, Derksen RH, van Roon JA, and Radstake TR
- Subjects
- Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Interferon Type I, Lupus Erythematosus, Systemic, Monocytes, Antiphospholipid Syndrome, Hydroxychloroquine
- Published
- 2016
- Full Text
- View/download PDF
49. Drug Survival and Predictors of Drug Survival for Methotrexate Treatment in a Retrospective Cohort of Adult Patients with Localized Scleroderma.
- Author
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Mertens JS, van den Reek JM, Kievit W, van de Kerkhof PC, Thurlings RM, Radstake TR, Seyger MM, and de Jong EM
- Subjects
- Adolescent, Adult, Aged, Antirheumatic Agents administration & dosage, Antirheumatic Agents adverse effects, Child, Child, Preschool, Female, Folic Acid therapeutic use, Humans, Infant, Male, Methotrexate administration & dosage, Methotrexate adverse effects, Middle Aged, Remission Induction, Retrospective Studies, Treatment Outcome, Antirheumatic Agents therapeutic use, Methotrexate therapeutic use, Scleroderma, Localized drug therapy
- Abstract
Data regarding the efficacy and safety of methotrexate (MTX) in adults with localized scleroderma (LoS) is scarce. This study gathered data from a retrospective cohort of adult patients with LoS (n?=?107), treated with MTX (1993-2015). MTX drug survival and predictors thereof were analysed. After 1 and 2 years, 26% and 63% of patients stopped MTX due to disease remission, respectively. Patients with younger age at MTX initiation (hazard ratio (HR) 1.159 (95% confidence interval (CI) 1.052-1.277)) and those with no other autoimmune diseases (HR 3.268 (95% CI 1.334-8.009)) more often stopped MTX due to disease remission. In addition, 24% of patients stopped MTX due to treatment failure within one year. Patients with circumscribed superficial LoS (HR 0.221 (95% CI 0.081-0.601)) experienced treatment failure less often than those with other LoS subtypes. Finally, adding folic acid (HR 0.184 (95% CI 0.079-0.425)) and reducing treatment delay (HR 1.056 (95% CI 1.004-1.112)) could be the most important factors in minimizing MTX treatment failure in LoS in clinical practice.
- Published
- 2016
- Full Text
- View/download PDF
50. High-Dose Intravenous Pulse Methotrexate in Patients With Eosinophilic Fasciitis.
- Author
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Mertens JS, Zweers MC, Kievit W, Knaapen HK, Gerritsen M, Radstake TR, van den Hoogen FH, Creemers MC, and de Jong EM
- Subjects
- Adult, Aged, Female, Hospitals, University, Humans, Immunosuppressive Agents adverse effects, Male, Methotrexate adverse effects, Middle Aged, Prospective Studies, Single-Blind Method, Treatment Outcome, Eosinophilia drug therapy, Fasciitis drug therapy, Immunosuppressive Agents administration & dosage, Methotrexate administration & dosage, Pulse Therapy, Drug methods
- Abstract
Importance: Eosinophilic fasciitis (EF) is a connective tissue disorder in which conventional treatment leads to disappointing results in a proportion of patients. Therefore, we investigated high-dose intravenous (IV) pulse methotrexate (MTX) as a treatment for EF., Objective: To examine safety and effects of monthly high-dose IV pulse MTX in EF., Design, Setting, and Participants: For this prospective single-arm study, we recruited 12 patients diagnosed with biopsy specimen-proven EF between 2006 and 2009 from the Department of Dermatology and Rheumatology at the Radboud University Medical Centre., Interventions: Intravenous MTX (4 mg/kg) monthly for 5 months with folinic acid rescue 24 hours after MTX administration., Main Outcomes and Measures: The primary outcome was improvement of the modified skin score at month 5 vs baseline. Secondary outcomes were durometry, range of motion, visual analog scale scores for disease activity, and 36-Item Short Form Survey health questionnaires., Results: Overall, 12 patients (11 women between 37-69 years old) received a median (range) monthly dose of 288 (230-336) mg MTX. Median (range) modified skin score improved from 17.5 (8.0-24.0) at baseline to 8.5 (1.0-20.0) at month 5 (P = .001). Secondary outcome measures improved significantly, except for durometer scores and range of motion of the elbows. Adverse events included gastrointestinal symptoms (n = 9), mild stomatitis (n = 5), and alopecia (n = 4)., Conclusions and Relevance: High-dose IV pulse MTX is a safe and effective treatment option in EF., Trial Registration: clinicaltrials.gov Identifier: NCT00441961.
- Published
- 2016
- Full Text
- View/download PDF
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