Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin

The synovium is the primary site of pathology in rheumatoid arthritis (RA). The rheumatoid synovium contains large numbers of CD4+ T cells. Patients with severe disease frequently express DR4 molecules that share an epitope in the third hypervariable region of the β-chain [1], suggesting a pathogenic role for T cells. However, the presence of only low levels of T cell related cytokines in the synovium and synovial fluid of established RA patients [2,3] led many to question the role of T cells in persistent disease. Nevertheless, this synovial cytokine profile is consistent with the highly differentiated CD45RObrightRBdull phenotype of synovial T cells [4]. A widely accepted model has emerged in which the persistence of inflammation in established RA is driven by interactions between T cells, macrophages and fibroblasts in an abnormal microenvironment [5,6]. The synovial T cell population is maintained through active inhibition of apoptosis, mediated at least in part by fibroblast and macrophage derived type 1 IFNs, and active retention facilitated by fibroblast derived transforming growth factor-β [7-9]. Contact dependent interactions between T cells and macrophages stimulate the production of proinflammatory cytokines, including tumour necrosis factor (TNF)-α, in an antigen independent manner [10-12].This model of persistence in established disease requires the presence of hyperplastic synovial tissue, which is unlikely to be present at the onset of RA. Consequently, the processes manifest at initiation that lead to persistence are likely to be distinct. Difficulties in accessing patients with very early disease and in sampling those joints involved at clinical onset have proved to be obstacles to addressing these issues. The role of T cells and antigen in the initiation of RA, the mechanisms that drive early fibroblast expansion, and the interplay between T cells and the stromal environment therefore remain obscure.In order to study mechanisms of very early synovi