المؤلفون: Makrygiannakis, Dimitrios

مصطلحات موضوعية: Arthritis, rheumatoid -- genetics, Arthritis, rheumatoid -- drug therapy, Antirheumatic agents -- administration & dosage, Glucocorticoids -- administration & dosage, Injections, intra-articular, Synovial membrane -- drug effects, Reumatologi

Degree: Diss. (sammanfattning) Stockholm : Karolinska institutet, 2008

المؤلفون: Hermansson, Monika, Artemenko, Konstantin, Ossipova, Elena, Eriksson, Hanna, Lengqvist, Johan, Makrygiannakis, Dimitrios, Catrina, Anca I., Nicholas, Anthony P., Klareskog, Lars, Savitski, Mikhail, Zubarev, Roman A., Jakobsson, Per-Johan

المصدر: Proteomics - Clinical Applications. 4(5):511-518

مصطلحات موضوعية: Citrullination, fibrinogen, MS, rheumatoid arthritis, MEDICINE, MEDICIN

الوصف: PurposeCitrullination is a post-translational modification of arginine residues to citrulline catalyzed by peptidyl arginine deiminases. Induced expression of citrullinated proteins are frequently detected in various inflammatory states including arthritis; however, direct detection of citrullination in arthritic samples has not been successfully performed in the past.Experimental designCitrullination of human fibrinogen, a candidate autoantigen in arthritis, was studied. Accurate identification of citrullinated fibrinogen peptides from rheumatoid arthritis synovial tissue specimens was performed using accurate mass and retention time analysis.ResultsA peptide with the sequence ESSSHHPGIAEFPSRGK corresponding to amino acids 559-575 of fibrinogen a-chain was identified to be citrullinated with an occupancy rate between 1.4 and 2.5%. Citrullination of the peptide KREEAPSLRPAPPPISGGGYRARPAK corresponding to amino acids 52-77 of the fibrinogen beta-chain was identified with an occupancy rate of 1.2%.Conclusions and clinical relevanceWe report a proof of principle study for the identification of citrullinated proteins and within them, identification of citrullination sites and quantification of their occupancies in synovial tissue from rheumatoid arthritis patients using high-resolution MS. Detailed studies on which molecules are citrullinated in arthritis can provide information about their role in immune regulation and serve as novel biomarkers and potentially even as therapeutic targets.

وصف الملف: print

URL الوصول: https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-136069

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المؤلفون: Makrygiannakis D; Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden., af Klint E, Catrina SB, Botusan IR, Klareskog E, Klareskog L, Ulfgren AK, Catrina AI

المصدر: Arthritis and rheumatism [Arthritis Rheum] 2006 May; Vol. 54 (5), pp. 1463-72.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 0370605 Publication Model: Print Cited Medium: Print ISSN: 0004-3591 (Print) Linking ISSN: 00043591 NLM ISO Abbreviation: Arthritis Rheum Subsets: MEDLINE

مواضيع طبية MeSH: Adrenal Cortex Hormones/*administration & dosage , Anti-Inflammatory Agents/*administration & dosage , Arthritis/*drug therapy , Arthritis/*metabolism , Carrier Proteins/*biosynthesis , Glycoproteins/*biosynthesis , Membrane Glycoproteins/*biosynthesis , Receptors, Cytoplasmic and Nuclear/*biosynthesis , Receptors, Tumor Necrosis Factor/*biosynthesis , Synovial Membrane/*metabolism , Triamcinolone Acetonide/*analogs & derivatives, Adult ; Aged ; Aged, 80 and over ; Cells, Cultured ; Female ; Humans ; Injections, Intra-Articular ; Male ; Middle Aged ; Osteoprotegerin ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B ; Synovial Membrane/pathology ; Triamcinolone Acetonide/administration & dosage

مستخلص: Objective: Intraarticular corticosteroids are frequently used as successful adjuvant therapy for inflammatory arthritides, but little is known about their effects on molecules that regulate bone biology. We undertook this study to investigate the effect of intraarticular corticosteroids on the synovial expression of RANKL and osteoprotegerin (OPG).
Methods: We evaluated RANKL, OPG, and surface marker expression by immunohistochemical methods in synovial knee biopsy samples obtained from 13 patients with inflammatory arthritis before and 2 weeks following intraarticular injection of triamcinolone hexacetonide. We further investigated the effect of dexamethasone (DEX) on RANKL expression by lymphocytes from rheumatoid arthritis synovial fluids (RA SF), using flow cytometric analysis. Finally, we evaluated the in vitro effect of DEX on RANKL and OPG expression in osteoblast-like cells, by Western blotting.
Results: Intraarticular corticosteroids induced a decrease in the number of synovial T cells without influencing the number of macrophages, evaluated as both CD68+ and CD163+ cells. This change was paralleled by a decrease of synovial RANKL expression with a concomitant reduction of the RANKL:OPG ratio. DEX down-regulated RANKL expression on lymphocytes derived from RA SF. Moreover, in vitro pretreatment of osteoblast-like cells with tumor necrosis factor favored an antiresorptive effect of DEX treatment through a similar down-regulation of RANKL expression.
Conclusion: The decrease in inflammation attributed to intraarticular corticosteroids is accompanied by down-modulation of bone destruction markers. These findings offer a rationale for the beneficial effect of corticosteroids on joint erosion in arthritis.

المؤلفون: Catrina AI; Rheumatology Research Laboratory, Karolinska University Hospital, Karolinska Institutet, S-17176 Stockholm, Sweden. Anca.Catrina@ki.se, af Klint E, Ernestam S, Catrina SB, Makrygiannakis D, Botusan IR, Klareskog L, Ulfgren AK

المصدر: Arthritis and rheumatism [Arthritis Rheum] 2006 Jan; Vol. 54 (1), pp. 76-81.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 0370605 Publication Model: Print Cited Medium: Print ISSN: 0004-3591 (Print) Linking ISSN: 00043591 NLM ISO Abbreviation: Arthritis Rheum Subsets: MEDLINE

مواضيع طبية MeSH: Antibodies, Monoclonal/*therapeutic use , Antirheumatic Agents/*therapeutic use , Arthritis, Rheumatoid/*drug therapy , Carrier Proteins/*biosynthesis , Glycoproteins/*biosynthesis , Immunoglobulin G/*therapeutic use , Membrane Glycoproteins/*biosynthesis , Receptors, Cytoplasmic and Nuclear/*biosynthesis , Receptors, Tumor Necrosis Factor/*biosynthesis , Receptors, Tumor Necrosis Factor/*therapeutic use , Synovial Membrane/*drug effects , Synovial Membrane/*metabolism , Tumor Necrosis Factor-alpha/*antagonists & inhibitors, Adult ; Aged ; Antibodies, Monoclonal/pharmacology ; Antirheumatic Agents/pharmacology ; Etanercept ; Female ; Humans ; Immunoglobulin G/pharmacology ; Infliximab ; Male ; Middle Aged ; Osteoprotegerin ; RANK Ligand ; Receptor Activator of Nuclear Factor-kappa B

مستخلص: Objective: Treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF)-blocking agents, including etanercept and infliximab, has resulted in reductions in the radiographic progression of RA. However, the exact mechanism by which this protection occurs has not been determined. In order to add to such knowledge, we investigated the effect of anti-TNF therapy on the expression of osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) in synovial tissue.
Methods: The expression of OPG and RANKL in synovial biopsy specimens was evaluated by immunohistochemistry. Serial synovial biopsy specimens were obtained from 18 patients with RA, before and after treatment with etanercept (9 patients) or infliximab (9 patients). Biopsy specimens were evaluated by double-blind semiquantitative analysis and image analysis. The in vitro effect of TNF antagonists on the RANKL/OPG expression in osteoblasts and endothelial cells was evaluated by Western blotting. Statistical analysis was performed using Wilcoxon's signed rank test, followed by the Bonferroni correction for multiple comparisons of paired samples. The results of in vitro experiments were evaluated by one-way analysis of variance, with Tukey's post hoc test.
Results: Treatment with both infliximab and etanercept increased the expression of OPG in synovial tissue. After 8 weeks of treatment, neither infliximab nor etanercept influenced RANKL expression. In both groups of patients, the RANKL:OPG ratio decreased following therapy. In vitro, both of the TNF antagonists mimicked the in vivo effect, inducing a decrease in the RANKL:OPG ratio in TNF-primed osteoblasts and endothelial cells.
Conclusion: Therapy with TNF antagonists in RA modulates the OPG/RANKL system, a potential mechanism that could explain the retardation of radiographic damage observed following anti-TNF therapy.

المؤلفون: af Klint E; Karolinska Institutet, Stockholm, Sweden., Grundtman C, Engström M, Catrina AI, Makrygiannakis D, Klareskog L, Andersson U, Ulfgren AK

المصدر: Arthritis and rheumatism [Arthritis Rheum] 2005 Dec; Vol. 52 (12), pp. 3880-9.

نوع المنشور: Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 0370605 Publication Model: Print Cited Medium: Print ISSN: 0004-3591 (Print) Linking ISSN: 00043591 NLM ISO Abbreviation: Arthritis Rheum Subsets: MEDLINE

مواضيع طبية MeSH: Anti-Inflammatory Agents/*administration & dosage , Arthritis, Rheumatoid/*drug therapy , Glucocorticoids/*administration & dosage , Synovitis/*drug therapy , Triamcinolone Acetonide/*analogs & derivatives, Adult ; Aged ; Aged, 80 and over ; Arthritis, Rheumatoid/immunology ; Arthritis, Rheumatoid/pathology ; Biopsy ; Blood Vessels/drug effects ; Blood Vessels/immunology ; Cytokines/genetics ; Female ; Gene Expression/immunology ; HMGB1 Protein/genetics ; HMGB1 Protein/metabolism ; Humans ; Injections, Intra-Articular ; Macrophages/pathology ; Male ; Middle Aged ; RNA, Messenger/analysis ; Signal Transduction/drug effects ; Signal Transduction/immunology ; Synovial Membrane/blood supply ; Synovial Membrane/drug effects ; Synovial Membrane/immunology ; Synovitis/immunology ; Synovitis/pathology ; T-Lymphocytes/pathology ; Triamcinolone Acetonide/administration & dosage

مستخلص: Objective: To investigate whether intraarticular (IA) glucocorticoid (GC) therapy diminishes synovial cell infiltration, vascularity, expression of proinflammatory cytokines, and adhesion molecule levels in patients with chronic arthritides.
Methods: Thirty-one patients with chronic arthritides received a single IA injection of triamcinolone hexacetonide to treat active large-joint inflammation. Synovial biopsy specimens were obtained with arthroscopic guidance before and 9-15 days after injection. The presence of T lymphocytes, macrophages, intercellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor (VEGF), the pan-endothelial marker CD31, and the proinflammatory cytokines interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor (TNF), and high mobility group box chromosomal protein 1 (HMGB-1) was studied by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction.
Results: IA GC treatment resulted in good clinical response in 29 of 31 joints. After therapeutic intervention, the number of synovial T lymphocytes declined, whereas the number of macrophages remained unchanged. Overall synovial protein expression of TNF, IL-1beta, extranuclear HMGB-1, VEGF, and ICAM-1 was reduced at followup tissue sampling, while no significant effects were observed regarding vascularity. In contrast, expression of IL-1alpha, VEGF, and cytoplasmic HMGB-1 protein in vascular endothelial cells was not affected. GC therapy down-regulated levels of messenger RNA encoding IL-1alpha and IL-1beta, but not TNF or HMGB-1.
Conclusion: Synovial cell infiltration and proinflammatory cytokine expression were affected in a multifaceted manner by IA GC treatment. Marked reduction of synovial T lymphocytes, TNF, IL-1beta, extranuclear HMGB-1, ICAM-1, and VEGF occurred in association with beneficial clinical effects. Unexpectedly, macrophage infiltration and proinflammatory endothelial cytokine expression remained unchanged. These findings may reflect mechanisms controlling the transiency of clinical improvement frequently observed after IA GC injection.