Comparable evidence was observed also during the treatment of RA patients with adalimumab, a fully humanized monoclonal IgG1 antibody against TNF- (65), supporting again the important role of this cytokine in the pathogenesis of such diseases

Comparable evidence was observed also during the treatment of RA patients with adalimumab, a fully humanized monoclonal IgG1 antibody against TNF- (65), supporting again the important role of this cytokine in the pathogenesis of such diseases. described that human non-classic Th1 cells development is usually promoted by the transcription factors Eomes (43), which induces and reinforces IFN- production, maintains the Th1 phenotype stability by inhibiting and preventing the re-expression of ROR-T and IL-17A and promotes GM-CSF secretion (43). Finally, it was shown that Eomes induces, stimulating healthy-derived SFbs with culture supernatants from activated classic and non-classic Th1, but not from Th17, lymphocytes. Indeed, also in these experimental conditions SFbs upregulated CD106 expression and underwent morphological changes (50). It has been exhibited that TNF- is the main cytokine involved in this process and that IFN- exerts a synergic effect (51, 54). The concept that cytokines produced by T cells play an important role around the activation of SFbs has been confirmed also by the paper of Lavocat et al. (55). It demonstrates with experiments that IL-17A and TNF- alone are able to induce the expression of IL-6 and IL-8 (55) by both endothelial cells and synoviocytes (even if AR-A 014418 with different kinetics on each cell type), and that a synergistic effect can be achieved from AR-A 014418 the use of both cytokines (55). Comparable results were obtained also by stimulating endothelial cells and synoviocytes in the presence of culture supernatants from activated T cell clones or recombinant cytokines. Indeed, the main increase in IL-6 and IL-8 production was observed when cells were cultured in presence of supernatants from Th17/Th1 T cell clones that contained both IL-17A and TNF- (55). The early expression of IL-8 in inflamed joints, directly produced also by AR-A 014418 Th17 cells itself (9), might explain the massive neutrophil recruitment in the acute phase (56). On the other hand, IL-6 production might be important to sustain the pro-inflammatory process since it is usually involved in the differentiation and expansion of Th17 cell (57), in VEGF production [thus mediating angiogenesis (58)], as well as in antibody production (59) and in osteoclast activation (55). The IL-17 signature, which is usually common of JIA, is usually important also for bone and CCL2 cartilage erosion. In fact, it has been exhibited that IL-17A acts on SFbs increasing the expression of different types of matrix metalloproteinases, MMP-1, MMP-3 (60). Finally, it is important to note that IL-17A production is not strictly associated to Th17 cells, since it is usually produced also by additional cells of the immune system enriched in SF of JIA patients, such as CD3+CD8+ and CD3+CD4-CD8- T cells (17, 61, 62) and innate lymphoid cells (62). Collectively, these data suggest that mechanisms actively contributing to joint inflammation in the synovia of JIA patients depend on the final balance and cross-talk between tissue resident cells and immune cells from both the adaptive and innate immune systems. Effects of Biological Drugs in the Treatment of JIA: and Observations Cytokines produced by immune cells (in particular T cells and monocytes) and by tissue resident cells in the synovia contribute to the development of JIA and are responsible for most of the clinical manifestations of the disease. In this view, pro-inflammatory cytokines represent a key therapeutic target for biological treatment. The drugs mainly used and effective in JIA inhibit the activity of TNF-, IL-1, or IL-6. TNF- has pleiotropic effects in the inflamed environment of affected joints, acting on different cell populations (51): TNF- mediates monocyte, macrophage and SFb activation, and it is also responsible for inflammation induction, cartilage degradation, bone erosion and tissue damage (51). Moreover, as previously stated, TNF- acts on SFbs inducing the upregulation of CD106, thus favoring leukocytes retention within the synovia and increasing joint inflammatory status (51). TNF- is also involved in the neovascularization process, leading to synovial membrane growth, and in the process of osteoclast-containing ‘pannus’ formation (51). Additionally, TNF- interferes with T helper cells phenotype plasticity, mediating the shifting of Th17 lymphocytes toward non-classic Th1 cells (20, 51). Nowadays, JIA patients are treated with non-steroidal antiinflammatory.