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Figure 1 The pathogenetic cascade in RA. In the early phase of RA, CD4+ T cells are activated by APCs and differentiate into various subtypes producing different sets of cytokines (phase 1). Th1 and Th17 cells dominate and are thought to promote the infl ammatory and destructive processes by activating downstream effector cells including macrophages, osteoclasts, fi broblasts, chondrocytes and plasma cells (phase 2). Unpublished material of the author. Abbreviations: APC, antigen-presenting cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; RA, rheumatoid arthritis; TGF, transforming growth factor; TNF, tumor necrosis factor

All cell types involved in synovial infl ammation secrete cytokines, and many cytokines can be detected in the joints of patients with RA during active disease (Brennan and McInnes 2008). In particular, macrophage-derived cytokines, such as TNF, IL-1, IL-6, IL-10, IL15 and granulocyte-macrophage colony-stimulating factor (GMCSF), have been detected at high levels. Several cytokines are also spontaneously produced in synovial membrane cultures, and unlike physiological, brief cytokine response, cytokines are produced for extended periods. In addition to cytokines, several cytokine receptors are upregulated in the joints, resulting in chronic exposure of joint cells to multiple cytokines.