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Systemic-onset Juvenile Idiopathic Arthritis (systemic-onset + juvenile_idiopathic_arthritis)
Selected AbstractsDefective phosphorylation of interleukin-18 receptor , causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Wilco de Jager Objective Systemic-onset juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by arthritis and systemic features. Its pathogenesis is still largely unknown. It is characterized immunologically by natural killer (NK) cell dysfunction and cytokine signatures that predominantly feature interleukin-1 (IL-1), IL-6, and IL-18. Since IL-18 can drive NK cell function, we examined how the high plasma levels of this cytokine are related to the documented NK cell failure in these patients. Methods The phenotype and function of NK cells from 10 healthy control subjects, 15 patients with polyarticular JIA, and 15 patients with systemic-onset JIA were characterized by staining and functional assays in vitro. IL-18 ligand binding was visualized by fluorescence microscopy. Phosphorylation of several MAP kinases and the IL-18 receptor , (IL-18R,) were visualized by Western blotting. Results IL-18 from the plasma of systemic-onset JIA patients stimulated the activation of NK cells from healthy controls and bound its cognate receptor. However, NK cells from systemic-onset JIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-,, after IL-18 stimulation. Furthermore, treatment with IL-18 did not induce the phosphorylation of receptor-activated MAP kinases in NK cells. Alternate activation of NK cells by IL-12 induced NK cell cytotoxicity. We observed no additive effect of IL-18 in combination with IL-12 in systemic-onset JIA patients. Immunoprecipitation of IL-18R, showed that NK cells from systemic-onset JIA could not phosphorylate this receptor after IL-18 stimulation. Conclusion The mechanism of the impaired NK cell function in systemic-onset JIA involves a defect in IL-18R, phosphorylation. This observation has major implications for the understanding and, ultimately, the treatment of systemic-onset JIA. [source] Failure to distinguish systemic-onset juvenile idiopathic arthritis from incomplete Kawasaki disease in an infantJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 10 2007Haruki Komatsu Abstract: In an infant, an initial diagnosis of incomplete Kawasaki disease was made according to the American Heart Association guidelines. However, the diagnosis of systemic-onset juvenile idiopathic arthritis was established later. Physicians need to recognize that systemic-onset juvenile idiopathic arthritis can be mistaken for incomplete Kawasaki disease, even when the guidelines are used. [source] Defective phosphorylation of interleukin-18 receptor , causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Wilco de Jager Objective Systemic-onset juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by arthritis and systemic features. Its pathogenesis is still largely unknown. It is characterized immunologically by natural killer (NK) cell dysfunction and cytokine signatures that predominantly feature interleukin-1 (IL-1), IL-6, and IL-18. Since IL-18 can drive NK cell function, we examined how the high plasma levels of this cytokine are related to the documented NK cell failure in these patients. Methods The phenotype and function of NK cells from 10 healthy control subjects, 15 patients with polyarticular JIA, and 15 patients with systemic-onset JIA were characterized by staining and functional assays in vitro. IL-18 ligand binding was visualized by fluorescence microscopy. Phosphorylation of several MAP kinases and the IL-18 receptor , (IL-18R,) were visualized by Western blotting. Results IL-18 from the plasma of systemic-onset JIA patients stimulated the activation of NK cells from healthy controls and bound its cognate receptor. However, NK cells from systemic-onset JIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-,, after IL-18 stimulation. Furthermore, treatment with IL-18 did not induce the phosphorylation of receptor-activated MAP kinases in NK cells. Alternate activation of NK cells by IL-12 induced NK cell cytotoxicity. We observed no additive effect of IL-18 in combination with IL-12 in systemic-onset JIA patients. Immunoprecipitation of IL-18R, showed that NK cells from systemic-onset JIA could not phosphorylate this receptor after IL-18 stimulation. Conclusion The mechanism of the impaired NK cell function in systemic-onset JIA involves a defect in IL-18R, phosphorylation. This observation has major implications for the understanding and, ultimately, the treatment of systemic-onset JIA. [source] The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1, form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 3 2009Michael Frosch Objective Fever of unknown origin is a diagnostic challenge in children, especially for differentiation of systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) and infectious diseases. We undertook this study to analyze the relevance of myeloid-related proteins (MRPs) 8 and 14, endogenous activators of Toll-like receptor 4, in diagnosis and pathogenesis of systemic-onset JIA. Methods Serum concentrations of MRP-8/MRP-14 were analyzed in 60 patients with systemic-onset JIA, 85 patients with systemic infections, 40 patients with acute lymphoblastic leukemia, 5 patients with acute myeloblastic leukemia, 18 patients with neonatal-onset multisystem inflammatory disease (NOMID), and 50 healthy controls. In addition, we investigated the link between interleukin-1, (IL-1,) and MRP-8/MRP-14 in systemic-onset JIA. Results Serum MRP-8/MRP-14 concentrations were significantly (P < 0.001) elevated in patients with active systemic-onset JIA (mean ± 95% confidence interval 14,920 ± 4,030 ng/ml) compared with those in healthy controls (340 ± 70 ng/ml), patients with systemic infections (2,640 ± 720 ng/ml), patients with acute lymphoblastic leukemia (650 ± 280 ng/ml), patients with acute myeloblastic leukemia (840 ± 940 ng/ml), and patients with NOMID (2,830 ± 580 ng/ml). In contrast to C-reactive protein levels, MRP-8/MRP-14 concentrations distinguished systemic-onset JIA from infections, with a specificity of 95%. MRP-14 in serum of patients with systemic-onset JIA was a strong inducer of IL-1, expression in phagocytes. Conclusion The analysis of MRP-8/MRP-14 in serum is an excellent tool for the diagnosis of systemic-onset JIA, allowing early differentiation between patients with systemic-onset JIA and those with other inflammatory diseases. MRP-8/MRP-14 and IL-1, represent a novel positive feedback mechanism activating phagocytes via 2 major signaling pathways of innate immunity during the pathogenesis of systemic-onset JIA. [source] S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown originARTHRITIS & RHEUMATISM, Issue 12 2008Helmut Wittkowski Objective Fever of unknown origin (FUO) in children presents a diagnostic challenge. The differential diagnosis includes systemic-onset juvenile idiopathic arthritis (JIA), an autoinflammatory syndrome associated with activation of phagocytic cells that, at presentation, is difficult to differentiate from severe systemic infections. The aim of this study was to investigate whether serum concentrations of the phagocytic proinflammatory protein S100A12 may help in deciding whether to treat patients with FUO with antibiotics or immunosuppressive agents. Methods Serum samples were obtained from 45 healthy control subjects and from 240 patients (60 with systemic-onset JIA, 17 with familial Mediterranean fever [FMF], 18 with neonatal-onset multisystem inflammatory disease [NOMID], 17 with Muckle-Wells syndrome [MWS], 40 with acute lymphoblastic leukemia [ALL], 5 with acute myeloblastic leukemia [AML], and 83 with systemic infections). All samples were collected at the time of presentation, before the initiation of any treatment, and concentrations of S100A12 were determined by enzyme-linked immunosorbent assay. Results The mean ± 95% confidence interval serum levels of S100A12 were as follows: in patients with JIA, 7,190 ± 2,690 ng/ml; in patients with FMF, 6,720 ± 4,960 ng/ml; in patients with NOMID, 720 ± 450 ng/ml; in patients with MWS, 150 ± 60 ng/ml; in patients with infections, 470 ± 160 ng/ml; in patients with ALL, 130 ± 80 ng/ml; in patients with AML, 45 ± 60 ng/ml; in healthy control subjects, 50 ± 10 ng/ml. The sensitivity and specificity of S100A12 to distinguish between systemic-onset JIA and infections were 66% and 94%, respectively. Conclusion S100A12, a marker of granulocyte activation, is highly overexpressed in patients with systemic-onset JIA or FMF, which may point to as-yet unknown common inflammatory mechanisms in these diseases. The measurement of S100A12 serum levels may provide a valuable diagnostic tool in the evaluation of FUO. [source] Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic-onset juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 4 2007Rebecca Lamb Objective To investigate SLC26A2, the gene that causes diastrophic dysplasia, in juvenile idiopathic arthritis (JIA). Methods Nine polymorphisms across the SLC26A2 gene locus were investigated using MassArray genotyping in 826 UK Caucasian JIA cases and 617 ethnically matched healthy controls. Results Significant associations between multiple single-nucleotide polymorphisms (SNPs) across SLC26A2 and systemic-onset JIA were found. In each case, homozygosity for the minor allele conferred the increased risk of disease susceptibility: rs1541915 (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4,3.7, P = 0.0003), rs245056 (OR 2.8, 95% CI 1.7,4.6, P = 0.00002), rs245055 (OR 2.5, 95% CI 1.2,5.0, P = 0.004), rs245051 (OR 2.3, 95% CI 1.4,3.7, P = 0.0005), rs245076 (OR 2.7, 95% CI 1.3,5.4, P = 0.0015), and rs8073 (OR 2.3, 95% CI 0.9,5.6, P = 0.04). Conclusion These findings show the value of using monogenic disease loci as candidates for investigation in JIA. We identified a subgroup-specific association between SNPs within the SLC26A2 gene and systemic-onset JIA. Our findings also highlight systemic-onset JIA as being a distinctly different disease from that in the other JIA subgroups. [source] Functional and prognostic relevance of the ,173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 5 2003Fabrizio De Benedetti Objective To address the functional and prognostic relevance of the ,173 single-nucleotide G-to-C polymorphism of the macrophage migration inhibitory factor (MIF) gene in patients with systemic-onset juvenile idiopathic arthritis (systemic-onset JIA) by evaluating its association with serum and synovial fluid levels of MIF, with glucocorticoid requirement, and with the outcome of the disease. Methods A total of 136 patients with systemic-onset JIA were studied, including 98 patients from the British Paediatric Rheumatology Study Group's National Repository for JIA and 38 patients who were followed up at the IRCCS Policlinico San Matteo (Pavia, Italy) and the IRCCS G. Gaslini (Genoa, Italy). The MIF-173 polymorphism was genotyped using SnaPshot ddNTP primer extension and capillary electrophoresis. MIF levels were measured by enzyme-linked immunosorbent assay. The evaluation of the association of the MIF-173 polymorphism with outcome was performed only in Italian patients who were followed up for >5 years, by analyzing retrospectively 1) the number of joints with active arthritis and the number of joints with limited range of motion; 2) the score, at the last visit, on the Italian version of the Childhood Health Assessment Questionnaire (C-HAQ); and 3) data concerning the treatment regimens during the disease course. Results Systemic-onset JIA patients carrying a MIF-173*C allele had serum and synovial fluid levels of MIF significantly higher than those in patients with the GG genotype. The duration of glucocorticoid treatment on a daily regimen was significantly longer in patients carrying a MIF-173*C allele than in MIF-173 GG homozygous patients. Moreover, the duration of clinical response to intraarticular injection of triamcinolone hexacetonide was significantly shorter in patients carrying a MIF-173*C allele. At the last visit, the numbers of joints with active arthritis, the C-HAQ scores, and the numbers of joints with limited range of motion were significantly higher in patients carrying the MIF-173*C allele. Conclusion Our study shows the functional relevance of the MIF-173 polymorphism and suggests that the MIF-173*C allele is a predictor of poor outcome in systemic-onset JIA. [source] | ||||||||||