20 results on '"Csomor E"'
Search Results
2. POS0407 TYPE I INTERFERON PATHWAY IS UPREGULATED IN GLOMERULAR AND TUBULOINTERSTITIAL KIDNEY COMPARTMENTS OF PATIENTS WITH LUPUS NEPHRITIS AND OTHER RENAL DISEASES
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Ferrari, N., primary, Mysler, E., additional, Tumlin, J., additional, Rovin, B. H., additional, Anders, H. J., additional, Csomor, E., additional, Gavin, P. G., additional, Platt, A., additional, Woollard, K., additional, Agren, R., additional, and Lindholm, C., additional
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- 2024
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3. P082 The CCR9/CCL25 axis is specific to the ileum and is correlated with stricturing disease
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Gehrmann, U, primary, Csomor, E, additional, Monkley, S, additional, Georgi, B, additional, Tian, S, additional, Cairns, J, additional, Angermann, B, additional, Khan, E, additional, Nys, J, additional, and Marks, D, additional
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- 2023
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4. P025 Colonic rather than ileal expression of ITGA4/ITGB7 correlates with local intestinal inflammation in IBD
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Csomor, E, primary, Gehrmann, U, additional, Monkley, S, additional, Tian, S, additional, Cairns, J, additional, Angermann, B, additional, Khan, E, additional, Nys, J, additional, and Marks, D, additional
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- 2023
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5. Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis
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Denton, C.P., Galdo, F. Del, Khanna, D., Vonk, M.C., Chung, L., Johnson, S.R., Varga, J., Furst, D.E., Temple, J., Zecchin, C., Csomor, E., Lee, A, Wisniacki, N., Flint, S.M., Reid, J., Denton, C.P., Galdo, F. Del, Khanna, D., Vonk, M.C., Chung, L., Johnson, S.R., Varga, J., Furst, D.E., Temple, J., Zecchin, C., Csomor, E., Lee, A, Wisniacki, N., Flint, S.M., and Reid, J.
- Abstract
Item does not contain fulltext, OBJECTIVES: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process. METHODS: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint. RESULTS: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups. CONCLUSION: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95.
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- 2022
6. 465 Identification of Atopic Dermatitis endotypes based on serum biomarker analysis
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Thijs, J., primary, Strickland, I., additional, Bruijnzeel-Koomen, C., additional, Nierkens, S., additional, Giovanonne, B., additional, Csomor, E., additional, Sellman, B., additional, Mustelin, T., additional, Sleeman, M., additional, de Bruin-Weller, M., additional, Herath, A., additional, Drylewicz, J., additional, May, R., additional, and Hijnen, D., additional
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- 2017
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7. Inhibitor of complement, Compstatin, prevents polymer-mediated Mac-1 up-regulation of human neutrophils independent of biomaterial type tested
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Schmidt, S., primary, Haase, G., additional, Csomor, E., additional, Lütticken, R., additional, and Peltroche-Llacsahuanga, H., additional
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- 2003
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8. Epithelial Interleukin-1 Receptor-Like-1 Activation Is Contingent on Interleukin-33 Isoforms and Asthma-Related Receptor Variation.
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Portelli MA, Ketelaar ME, Bates S, Csomor E, Shaw D, Emsley J, Brightling C, Hall I, Affleck K, Edwards M, Nawijn MC, Koppelman GH, Van Oosterhout AJ, and Sayers I
- Abstract
Introduction: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway., Method: In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33
112-270 (50 ng/mL) and induced IL-8 mRNA expression measured., Results: HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395-270 and IL33106-270 had the greatest effect and the IL33113-270 , and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes., Conclusions: Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395-270 and IL33106-270 may be more amenable to IL33/IL1RL1 targeting., (© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)- Published
- 2024
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9. A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale.
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Khanna D, Denton CP, Assassi S, Kuwana M, Allanore Y, Domsic RT, Kleoudis C, Xu J, Csomor E, Seo C, Albulescu M, Tummala R, Al-Mossawi H, Kalyani RN, and Del Galdo F
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- Humans, Double-Blind Method, Treatment Outcome, Receptor, Interferon alpha-beta, Clinical Trials, Phase III as Topic, Randomized Controlled Trials as Topic, Male, Multicenter Studies as Topic, Adult, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized adverse effects, Scleroderma, Systemic drug therapy, Scleroderma, Systemic immunology
- Abstract
Objectives: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY)., Methods: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, including mycophenolate mofetil, at a stable dose prior to randomisation is permitted in addition to weekly subcutaneous anifrolumab or placebo. Efficacy will be assessed at Week 52 via Revised-Composite Response Index in SSc (CRISS)-25 response (primary endpoint). Lung function and skin thickness will be assessed via change from baseline in forced vital capacity in patients with SSc-associated interstitial lung disease and modified Rodnan Skin Score, respectively (key secondary endpoints)., Conclusions: The DAISY trial will evaluate the efficacy and safety of anifrolumab as a first-in-class treatment option for patients with both limited and diffuse cutaneous SSc and will provide insight into the contributions of type I interferon to SSc pathogenesis. Revised-CRISS-25 can account for improvement and worsening in a broad set of validated clinical measures beyond lung function and skin thickness, including clinician- and patient-reported outcomes, capturing the heterogeneity of SSc.
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- 2024
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10. Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials.
- Author
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Baker T, Sharifian H, Newcombe PJ, Gavin PG, Lazarus MN, Ramaswamy M, White WI, Ferrari N, Muthas D, Tummala R, Morand EF, Furie RA, Vital EM, Chamberlain C, Platt A, Al-Mossawi H, Brohawn PZ, and Csomor E
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- Humans, Female, Male, Adult, Middle Aged, Receptor, Interferon alpha-beta genetics, Transcriptome, Lupus Erythematosus, Systemic drug therapy, Lupus Erythematosus, Systemic genetics, Lupus Erythematosus, Systemic immunology, Antibodies, Monoclonal, Humanized therapeutic use, Proteomics, Interferon Type I
- Abstract
Introduction: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials., Methods: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels., Results: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52, and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular traps-(NET)osis-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment., Discussion: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis., Competing Interests: Competing interests: TB is an employee and stock holder of AstraZeneca; HS is an employee and stock holder of AstraZeneca; PJN was an employee of AstraZeneca at the time the study was being conducted and is an employee and stock holder of GSK; PGG is an employee and stock holder of AstraZeneca; MNL was an employee of AstraZeneca at the time the study was being conducted; MR was an employee and stock holder of AstraZeneca at the time the study was being conducted and is an employee and stock holder of GSK; WIW is an employee and stock holder of AstraZeneca; is applying for two patents (No. 17/999257; No. 18/556733); NF is an employee and stock holder of AstraZeneca; DM is an employee and stock holder of AstraZeneca; RT is an employee and stock holder of AstraZeneca; EFM received grants/contracts from AbbVie, Amgen, AstraZeneca, Biogen, BMS, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, Novartis, Takeda and UCB; received consulting feed from AbbVie, AstraZeneca, Capella, Eli Lilly, EMD Serono, Galapagos, IGM, Novartis, Servier, Wolf, and Zenas; received payment/honoraria from AstraZeneca, BMS, GSK, and Roche; received support for meetings/travel from AstraZeneca and Roche; participated on Data Safety Monitoring/Advisory Boards of AstraZeneca, EMD Serono, Galapagos, Janssen, Novartis, and Takeda; is the Board Director of Rare Voices Australia and Exosome Biosciences Pty; RAF received grants/contracts, consulting fees, payment/honoraria, and support for attending meetings/travel from AstraZeneca and participated on a Data Safety Monitoring/Advisory Board of AstraZeneca; EMV received grants/contracts from AstraZeneca and Sandoz; consulting fees from AbbVie, AstraZeneca, CESAS, Elli Lilly, Novartis, Otsuka, Pfizer, Roche, UCB; payment/honoraria from AstraZeneca, Novastis and Otsuka; support for attending meetings/travel from Otsuka; participated on Data Safety Monitoring/Advisory Boards of Aurinia; is the General Secretary in SLEuro; CC is an employee and stock holder of AstraZeneca; AP is an employee and stockholder of AstraZeneca; HA-M was an employee and stock holder of AstraZeneca at the time the study was being conducted; PZB is an employee and stock holder of AstraZeneca; EC is an employee and stock holder of AstraZeneca., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)
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- 2024
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11. Biological and clinical insights from a randomized phase 2 study of an anti-oncostatin M monoclonal antibody in systemic sclerosis.
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Denton CP, Del Galdo F, Khanna D, Vonk MC, Chung L, Johnson SR, Varga J, Furst DE, Temple J, Zecchin C, Csomor E, Lee A, Wisniacki N, Flint SM, and Reid J
- Subjects
- Humans, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Inflammation drug therapy, Fibrosis, Double-Blind Method, Scleroderma, Systemic drug therapy, Scleroderma, Systemic chemically induced
- Abstract
Objectives: The cytokine oncostatin M (OSM) is implicated in the pathology of SSc. Inhibiting OSM signalling using GSK2330811 (an anti-OSM monoclonal antibody) in patients with SSc has the potential to slow or stop the disease process., Methods: This multicentre, randomized, double-blind, placebo-controlled study enrolled participants ≥18 years of age with active dcSSc. Participants were randomized 3:1 (GSK2330811:placebo) in one of two sequential cohorts to receive GSK2330811 (cohort 1: 100 mg; cohort 2: 300 mg) or placebo s.c. every other week for 12 weeks. The primary endpoint was safety; blood and skin biopsy samples were collected to explore mechanistic effects on inflammation and fibrosis. Clinical efficacy was an exploratory endpoint., Results: Thirty-five participants were randomized to placebo (n = 8), GSK2330811 100 mg (n = 3) or GSK2330811 300 mg (n = 24). Proof of mechanism, measured by coordinate effects on biomarkers of inflammation or fibrosis, was not demonstrated following GSK2330811 treatment. There were no meaningful differences between GSK2330811 and placebo for any efficacy endpoints. The safety and tolerability of GSK2330811 were not favourable in the 300 mg group, with on-target, dose-dependent adverse events related to decreases in haemoglobin and platelet count that were not observed in the 100 mg or placebo groups., Conclusion: Despite a robust and novel experimental medicine approach and evidence of target engagement, anticipated SSc-related biologic effects of GSK2330811 were not different from placebo and safety was unfavourable, suggesting OSM inhibition may not be a useful therapeutic strategy in SSc., Trial Registration Number: ClinicalTrials.gov, NCT03041025; EudraCT, 2016-003417-95., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2022
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12. Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study.
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Clark KEN, Csomor E, Campochiaro C, Galwey N, Nevin K, Morse MA, Teo YV, Freudenberg J, Ong VH, Derrett-Smith E, Wisniacki N, Flint SM, and Denton CP
- Abstract
Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma., Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months., Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype., Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability., Funding: GlaxoSmithKline and UK Medical Research Council., Competing Interests: CPD reports consulting fees or honoraria from Janssen, GlaxoSmithKline, Roche, Boehringer Ingelheim, Sanofi, Galapagos, Inventiva, Corbus, Acceleron, Horizon, Gesynta, and ARXX Therapeutics; and from research grants to their institution from GlaxoSmithKline, ARXX Therapeutics, Servier, and Horizon Therapeutics. NW, SMF, YVT, JF, NG, EC, KN, and MAM are employees of GlaxoSmithKline. NG, EC, JF, NW, MAM, SMF, and KN are shareholders in GlaxoSmithKline. All other authors declare no competing interests, (© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)
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- 2022
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13. Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.
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Clark KEN, Campochiaro C, Csomor E, Taylor A, Nevin K, Galwey N, Morse MA, Singh J, Teo YV, Ong VH, Derrett-Smith E, Wisniacki N, Flint SM, and Denton CP
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- Adult, Aged, Aged, 80 and over, Autoantibodies immunology, Case-Control Studies, Disease Progression, Female, Gene Expression Profiling, Humans, Hyaluronic Acid blood, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Peptide Fragments blood, Procollagen blood, Prospective Studies, Proteomics, Scleroderma, Diffuse blood, Scleroderma, Diffuse drug therapy, Tissue Inhibitor of Metalloproteinase-1 blood, Transcriptome, Young Adult, Antibodies, Antinuclear immunology, DNA Topoisomerases, Type I immunology, RNA Polymerase III immunology, Scleroderma, Diffuse immunology
- Abstract
Objectives: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities., Results: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis., Conclusions: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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14. Long intergenic non-coding RNAs regulate human lung fibroblast function: Implications for idiopathic pulmonary fibrosis.
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Hadjicharalambous MR, Roux BT, Csomor E, Feghali-Bostwick CA, Murray LA, Clarke DL, and Lindsay MA
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- Cells, Cultured, Epigenesis, Genetic, Female, Fibroblasts metabolism, Humans, Idiopathic Pulmonary Fibrosis pathology, Lung metabolism, Male, Middle Aged, Transcriptome, Fibroblasts pathology, Idiopathic Pulmonary Fibrosis genetics, Lung pathology, RNA, Long Noncoding genetics
- Abstract
Phenotypic changes in lung fibroblasts are believed to contribute to the development of Idiopathic Pulmonary Fibrosis (IPF), a progressive and fatal lung disease. Long intergenic non-coding RNAs (lincRNAs) have been identified as novel regulators of gene expression and protein activity. In non-stimulated cells, we observed reduced proliferation and inflammation but no difference in the fibrotic response of IPF fibroblasts. These functional changes in non-stimulated cells were associated with changes in the expression of the histone marks, H3K4me1, H3K4me3 and H3K27ac indicating a possible involvement of epigenetics. Following activation with TGF-β1 and IL-1β, we demonstrated an increased fibrotic but reduced inflammatory response in IPF fibroblasts. There was no significant difference in proliferation following PDGF exposure. The lincRNAs, LINC00960 and LINC01140 were upregulated in IPF fibroblasts. Knockdown studies showed that LINC00960 and LINC01140 were positive regulators of proliferation in both control and IPF fibroblasts but had no effect upon the fibrotic response. Knockdown of LINC01140 but not LINC00960 increased the inflammatory response, which was greater in IPF compared to control fibroblasts. Overall, these studies demonstrate for the first time that lincRNAs are important regulators of proliferation and inflammation in human lung fibroblasts and that these might mediate the reduced inflammatory response observed in IPF-derived fibroblasts.
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- 2019
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15. Serum biomarker profiles suggest that atopic dermatitis is a systemic disease.
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Thijs JL, Strickland I, Bruijnzeel-Koomen CAFM, Nierkens S, Giovannone B, Knol EF, Csomor E, Sellman BR, Mustelin T, Sleeman MA, de Bruin-Weller MS, Herath A, Drylewicz J, May RD, and Hijnen D
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- Adult, Animals, Asthma blood, Female, Humans, Inflammation blood, Male, Mice, Mice, Transgenic, Biomarkers blood, Dermatitis, Atopic blood
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- 2018
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16. Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.
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Thijs JL, Strickland I, Bruijnzeel-Koomen CAFM, Nierkens S, Giovannone B, Csomor E, Sellman BR, Mustelin T, Sleeman MA, de Bruin-Weller MS, Herath A, Drylewicz J, May RD, and Hijnen D
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- Adult, Allergens immunology, Asthma blood, Asthma epidemiology, Biomarkers blood, Comorbidity, Cytokines blood, Dermatitis, Atopic epidemiology, Female, Humans, Immunoglobulin E blood, Immunoglobulin E immunology, Male, Rhinitis blood, Rhinitis epidemiology, Dermatitis, Atopic blood, Dermatitis, Atopic classification
- Abstract
Background: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level., Objective: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators., Methods: Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components., Results: Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-β, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin., Conclusion: AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2017
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17. Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1.
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Benlahrech A, Harris J, Meiser A, Papagatsias T, Hornig J, Hayes P, Lieber A, Athanasopoulos T, Bachy V, Csomor E, Daniels R, Fisher K, Gotch F, Seymour L, Logan K, Barbagallo R, Klavinskis L, Dickson G, and Patterson S
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- AIDS Vaccines immunology, Adenoviridae genetics, Antibodies, Viral immunology, CD4-Positive T-Lymphocytes cytology, Dendritic Cells cytology, Dendritic Cells immunology, Genetic Vectors genetics, Genetic Vectors immunology, HIV Infections immunology, HIV-1 pathogenicity, Humans, Integrin alpha4 immunology, Integrin beta Chains immunology, Lymphocyte Activation immunology, Mucous Membrane immunology, Phenotype, Receptors, CCR immunology, Receptors, CCR4 immunology, Adenoviridae immunology, CD4-Positive T-Lymphocytes immunology, HIV-1 immunology, Immunity, Mucosal immunology, Immunologic Memory immunology, Vaccination
- Abstract
In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.
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- 2009
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18. Complement production and regulation by dendritic cells: molecular switches between tolerance and immunity.
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van Kooten C, Fiore N, Trouw LA, Csomor E, Xu W, Castellano G, Daha MR, and Gelderman KA
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- Animals, Complement C1q immunology, Complement C3 immunology, Humans, Macrophages immunology, Models, Immunological, Complement System Proteins immunology, Dendritic Cells immunology, Immune Tolerance immunology, Immunity immunology
- Abstract
In recent years it has become clear that the innate and adaptive immune systems are highly integrated and interact at several levels. Dendritic cells (DCs) are on the one hand instrumental for directing and controlling adaptive immunity and on the other hand are specialized in detecting and integrating signals from the microenvironment. In view of the strong link between deficiencies in certain complement components and the development of autoimmunity, interaction between complement and DCs seems to be of fundamental importance. We will discuss the role of C1q, C3, as well as complement regulators in DC biology.
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- 2008
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19. Complement protein C1q induces maturation of human dendritic cells.
- Author
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Csomor E, Bajtay Z, Sándor N, Kristóf K, Arlaud GJ, Thiel S, and Erdei A
- Subjects
- Animals, Cells, Cultured, Coculture Techniques, Humans, Rabbits, Cell Differentiation immunology, Complement C1q physiology, Dendritic Cells cytology, Dendritic Cells immunology
- Abstract
Maturation of dendritic cells (DCs) is known to be induced by several stimuli, including microbial products, inflammatory cytokines and immobilized IgG, as demonstrated recently. Since immune complexes formed in vivo also contain C1q, moreover apoptotic cells and several pathogens fix C1q in the absence of antibodies, we undertook to investigate whether this complement protein has an impact on various functions of human DCs. Maturation of monocyte-derived immature DCs (imMDCs) cultured on immobilized C1q was followed by monitoring expression of CD80, CD83, CD86, MHCII and CCR7. The functional activity of the cells was assessed by measuring cytokine secretion and their ability to activate allogeneic T lymphocytes. Cytokine production by T cells co-cultured with C1q-matured DCs was also investigated. C1q, but not the structurally related mannose-binding lectin was found to bind to imMDC in a dose-dependent manner and induced NF-kappaB translocation to the nucleus. Immobilized C1q induced maturation of MDCs and enhanced secretion of IL-12 and TNF-alpha, moreover, elevated their T-cell stimulating capacity. As IFN-gamma levels were increased in supernatants of MDC-T cell co-cultures, our data suggest that C1q-induced DC maturation generates a Th1-type response. Interestingly, IL-10 levels were elevated by C1q-treated MDCs but not in the supernatant of their co-cultures with allogeneic T cells. Taken together, these results indicate that C1q-opsonized antigens may play a role in the induction and regulation of immune response. Moreover our data are relevant in view of the role of C1q in removal of apoptotic cells and the association between C1q-deficiency and autoimmunity.
- Published
- 2007
- Full Text
- View/download PDF
20. Expression and role of Fc- and complement-receptors on human dendritic cells.
- Author
-
Bajtay Z, Csomor E, Sándor N, and Erdei A
- Subjects
- Humans, Immunoglobulins immunology, Dendritic Cells immunology, Receptors, Complement metabolism, Receptors, Fc metabolism
- Abstract
Dendritic cells (DCs) are professional antigen presenting cells, which take up pathogens/foreign structures in peripheral tissues, then migrate to secondary lymphoid organs where they initiate adaptive immune responses by activating naive T-cells. In the early phase of antigen uptake pattern recognition receptors (including mannose-, scavenger- and toll-like receptors) that recognize pathogen-associated molecular patterns play an important role. Later receptors binding opsonized antigen are also involved in phagocytosis. These cell membrane molecules include various Fc-receptors, recognizing different isotypes of antibodies and various complement-receptors, such as CR3, CR4 and the C1q-binding complex of calreticulin and CD91. Here we aim to summarize how these immunecomplex binding receptors are involved in the initiation of DC maturation, and how they influence antigen presentation as well as some additional functions of these cells.
- Published
- 2006
- Full Text
- View/download PDF
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