Although the term juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases, they all share a common pathological hallmark: inflammation of the synovium. Highly activated T ...cells, monocytes, and neutrophils are attracted to the joint and secrete mediators that not only perpetuate inflammation, but also may attenuate immune regulation. In the oligoarticular and polyarticular forms of JIA, which are thought to be autoimmune conditions, dysregulated adaptive immunity is a likely factor in disease pathogenesis; the nature of the interactions between Teffector cells (Teffs) and Tregulatory cells (Tregs) is probably a key factor in controlling disease progression. Factors that affect the frequency and function of Tregs and/or the sensitivity of Teffs to mechanisms of immune suppression will therefore impact the disease course. In the systemic form of JIA, however, dysregulation of innate immune pathways appears more central to disease pathogenesis, resulting in augmented levels of interleukins IL1β, IL6, and IL18. In the end, a final common pathological pathway in JIA is the activation of monocytes and neutrophils which are the principal mediators of joint inflammation and damage. This is supported by the fact that the therapies that have targeted innate cytokine pathways have shown greater success in the treatment of JIA.
Objective To identify interleukin-17 (IL-17)aproducing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship ...to Treg cells at sites of inflammation, as well as to test the hypothesis that IL-17+ T cell numbers correlate with clinical phenotype in childhood arthritis. Methods Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL-17aproducing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)apositive Treg cells. Migration of IL-17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL-17 and IL-22. Results IL-17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL-17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL-17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL-17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL-17+ T cells had variable CCR4 expression. A proportion of IL-17+ synovial T cells produced IL-22 and interferon-I3. Conclusion This study is the first to define the frequency and characteristics of aTh17a cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL-17+ T cells and Treg cells may be critical to outcome.
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