Juvenile idiopathic arthritis

Prakken, Berent J.; Albani, Salvatore; Martini, Alberto

doi:10.1016/s0140-6736(11)60244-4

Cited by 723 publications

(595 citation statements)

References 126 publications

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“…In full-blown clinical disease, the immune response may expand to include multiple autoantigens presented by dendritic cells to autoreactive CD4 + T cells that subsequently activate Sfib and innate immune cells, all producing multiple proinflammatory cytokines (12). It has been shown that autoreactive effector CD4 + T cells can be suppressed by CD4 + CD25 high FOXP3 + T cells, theoretically providing a mechanism to terminate such pathogenic activation.…”

Section: Discussionmentioning

confidence: 99%

“…Current International League of Associations for Rheumatology classification differentiates subtypes of JIA on the basis of clinical manifestations (oligoarthritis, persistent and extended; rheumatoid factor-positive and -negative polyarthritis; systemic, psoriatic, enthesitis-related, and other undifferentiated arthritis) (11). Although the precise etiology is still unknown, JIA is an autoimmune disease, and T cells are thought to be key players in this process (12). Interestingly, although the Vg9Jg1.2 gene rearrangement is less commonly expressed among synovial fluid (SF) than peripheral blood (PB) gd T cells, IPP was recently found to induce expansion of SF Vg9 + T in virtually all forms of JIA (13,14).…”

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confidence: 99%

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Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Bendersky

Marcu-Malina

Berkun

et al. 2012

The Journal of Immunology

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The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9+Vδ2+ (Vγ9+) T cells, in JIA. We found that as opposed to CD4+ T cells, equally high percentages (∼35%) of Vγ9+ T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2+ T cells, similarly amplified cytokine secretion by SF and PB Vγ9+ T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vγ9+ T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9+ T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4+CD25+FOXP3+ cells (regulatory T cells). Furthermore, coculture with the Vγ9+ T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9+ T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Bendersky

Marcu-Malina

Berkun

et al. 2012

The Journal of Immunology

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“…Tumour necrosis factor‐alpha (TNF‐ α ) is believed to be a key inflammatory mediator in inflammatory joint diseases such as juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) 1, 2, 3. Drugs that efficiently bind and neutralise soluble TNF‐ α have been used to treat these conditions for nearly two decades.…”

Section: Introductionmentioning

confidence: 99%

Circulating complexes between tumour necrosis factor‐alpha and etanercept predict long‐term efficacy of etanercept in juvenile idiopathic arthritis

et al. 2016

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AimThe relationship between tumour necrosis factor‐alpha (TNF‐α) and drug survival had not been studied in juvenile idiopathic arthritis (JIA), and there were no laboratory tests to predict the long‐term efficacy of biological drugs for JIA. We studied whether serum levels of TNF‐α, free or bound to etanercept, could predict long‐term efficacy of etanercept in children with JIA.MethodsWe included 41 biologic‐naïve patients with JIA who started treatment with etanercept at Skåne University Hospital between 1999 and 2010. Serum taken at the start of treatment and at the six‐week follow‐up were analysed for TNF‐α and the long‐term efficacy of etanercept was assessed using the drug survival time.ResultsLevels of TNF‐α increased significantly at the six‐week follow‐up, and this was almost exclusively comprised of TNF‐α in complex with etanercept. The increase in TNF‐α showed a dose‐dependent correlation to long‐term drug survival (p < 0.01).ConclusionIncreasing levels of circulating TNF‐α at treatment initiation predicted long‐term efficacy of etanercept in children with JIA, which may have been due to different pathophysiological mechanisms of inflammation. Our result may provide a helpful clinical tool, as high levels of circulating TNF‐α/etanercept complexes could be used as a marker for the long‐term efficacy of etanercept.

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“…Tregs prevent the development of various inflammatory diseases by suppressing autoaggressive T and B cell responses (Sakaguchi et al 2009). Intensive research has focused on Tregs in RA and other chronic rheumatic diseases (Prakken et al 2001;Wehrens et al 2013). Some studies have shown reduced numbers and/or suppressive function of Tregs in peripheral blood of RA patients compared to healthy controls (Ehrenstein et al 2004;Valencia et al 2006;Jiao et al 2007;Sempere-Ortells et al 2009;Lina et al 2011;Nie et al 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Barberá

Lorenzo

Kooten

et al. 2016

Cell Stress and Chaperones

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

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Juvenile idiopathic arthritis

Cited by 723 publications

References 126 publications

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Cellular Interactions of Synovial Fluid γδ T Cells in Juvenile Idiopathic Arthritis

Circulating complexes between tumour necrosis factor‐alpha and etanercept predict long‐term efficacy of etanercept in juvenile idiopathic arthritis

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

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