Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression

Abstract

ObjectiveTo identify biomarkers in the first synovial fluid (SF) aspirate obtained from children with oligoarticular juvenile idiopathic arthritis (JIA), which could be used to identify children whose disease is likely to extend to a more severe phenotype.MethodsPatients with recent-onset oligoarticular JIA were identified and grouped according to those whose mild disease persisted (persistent disease) or those whose disease would extend from a mild to more severe phenotype (extended-to-be disease) at 1 year after diagnosis. Flow cytometry was used to delineate differences in the mononuclear cell populations between the first blood sample and first SF aspirate from the same patient and between outcome (persistent versus extended-to-be) groups. Proportions of lymphocytes in the joint were modeled on chemotaxis of lymphocytes to CCL5, using Transwell migration assays. Levels of CCL5 in the SF were quantified by enzyme-linked immunosorbent assay. RNA profiles of SF mononuclear cells were compared between groups using the Affymetrix GeneChip hybridization protocol and hierarchical clustering analyses.ResultsCompared with peripheral blood mononuclear cells, SF mononuclear cells displayed an expansion of CD8+ T cells, reduced proportion of B cells, and expansion of CD16− natural killer cells. The lower CD4:CD8 ratio in the SF was recapitulated in vitro by the observed migration of blood T cells in response to CCL5. Synovial CCL5 levels were higher in children whose disease extended to a more severe phenotype. The CD4:CD8 ratio in the SF was significantly lower in patients with extended-to-be oligoarticular JIA (0.57 compared with 0.90 in the persistent disease group, difference 0.33, 95% confidence interval 0.04–0.62; P = 0.009). Gene expression profiling revealed that 344 genes were >1.5-fold differentially expressed between outcome groups (P < 0.05), and these included genes associated with inflammation and macrophage differentiation, which showed increased levels in patients with extended disease at 1 year, and genes associated with immune regulation, which showed increased levels in patients with persistent disease at 1 year.ConclusionAnalyses of the proportions of synovial lymphocytes, levels of CCL5, and differential gene expression yielded potential biomarkers with which to predict the likelihood of extension of oligoarticular JIA to a more severe disease phenotype.

T cell protein tyrosine phosphatase deficiency results in spontaneous synovitis and subchondral bone resorption in mice

“…CD8ϩ T cells accumulate in synovial tissue of JIA patients (21) and in the synovial fluid of adult patients with RA (22), while CD4ϩ T cells have been considered the predominant T cell population in the latter. Although the role of CD8ϩ T cells in the synovium is largely unknown, a recent study by Hunter et al demonstrated that in JIA, CD8ϩ T cells are recruited to the synovium by the chemokine RANTES, and once there, they become important sources of RANTES secretion (23). We found significantly elevated levels of RANTES both in the serum and in the patellar washouts from TC-PTP Ϫ/Ϫ mice.…”

T cells out of control—impaired immune regulation in the inflamed joint

“…6,20 Furthermore, in patients with JIA high levels of synovial fluid CD8 + T cells are correlated with a more progressive course of disease than is observed in patients with lower levels of these cells. 21 Specific T cell skewing in inflamed joints Notably, in the peripheral blood of patients with RA, the level of demethylation of Ifnγ and Il-17a is the same Key points ■ The study of immune regulation at the site of inflammation is required to improve our understanding of autoimmune pathology ■ At the site of autoimmune inflammation, proinflammatory mediators interfere with T-cell regulation and may induce T-cell plasticity ■ Regulatory T (T REG ) cells are less functional, or might even become pathogenic, in an autoimmune inflammatory environment, which should be kept in mind when developing T REG -cell-based therapies ■ Resistance of effector T cells to suppression markedly contributes to the disturbed immune balance in the inflamed joints of patients with arthritis ■ In autoimmune inflammation, a perpetuating loop exists in which antigen presenting cells (APCs) instruct T-cell differentiation and function, and effector T cells promote and shape the infiltration and differentiation of APCs as in healthy controls. 15 Thus, skewed CD4 + T-cell commit ment occurs specifically at the site of inflammation, likely as a result of an inter action between CD4 + T cells and local APCs, which are found in increased numbers in inflamed joints.…”

“…55,56 In patients with JIA, unres ponsiveness to suppression was not only observed in CD4 + T cells, but also highly apparent in synovial fluid CD8 + T cells, 6 in line with their correlation to a more severe outcome of disease. 21 Furthermore, although this resistance to suppression is intrinsic to T cells and maintained in vitro even in the absence of synovial fluid APCs, 6 it seems that synovial fluid APCs are responsible for the initial induction of resistance to suppression in JIA (Wehrens et al unpublished observations).…”

Synovial membrane immunohistology in early untreated juvenile idiopathic arthritis: differences between clinical subgroups

“…Children were followed for 2 years after biopsies were taken. During this period children whose disease went on to involve more than four joints (after they had the disease for a total of six or more months) were re-classified as extended oligoarticular, ie, they were not extended at the time the biopsy was taken, this subgroup is referred to as ‘extended-to-be’24 from here on in. Clinical and demographic data are included in table 1.…”