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During the past two decades intense research expanded our understanding of the mechanisms underlying the pathogenesis of autoimmune diseases. As a result, a new class of antirheumatic drugs, designed to target various signaling pathways abnormally activated in the immune system have been introduced into the clinic. The proliferation, differentiation and function of various cellular components of the immune system are mediated through a variety of extracellular and intracellular signals. This issue of Current Rheumatology Reviews focuses on the role signaling pathways play in the pathogenesis of rhematological diseases, and the clinical benefits specific signal transduction inhibitors provide. In their Chapter, Oshugi and Kishimoto outline the role of interleukin (IL)-6 and its signaling pathway in the pathogenesis of rheumatoid arthritis (RA) and the role of this pathway in the induction of Th 17 cells. In the second part of their review they focus on the emerging role of tocilizumab - an anti-IL-6 receptor monoclonal antibody in the treatment of RA. Yamaoka and Tanaka reviewed the role of Janus kinases (JAKs) in the signaling of inflammatory cytokines. They provide preclinical and clinical data on the effects of JAK inhibitors in animal models of autoimmune diseases and in patients with RA. They point out that activation of JAK3 is restricted to the hematopoietic cells. Therefore inhibition of JAK3 should not cause detrimental effects outside the hematologic/immune system. This makes JAK3 an attractive target in autoimmune disorders. Indeed, the JAK3 inhibitor Tasocitinib (CP690,550) was found to be safe and effective in phase II trials of patients with RA. Activation of the nuclear factor (NF)-κB is thought to play a key role in the pathogenesis of autoimmune disorders. Therefore, the role of NF-κB in systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS), and erosive arthritis was discussed in two separate chapters written by Kubota and Umezawa. Kubota outlines the role of NF-κB in establishing and maintaining self-tolerance and in its breakdown. He describes the role of B cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, in the pathogenesis of SLE, the role of NF-κB in the thrombogenesis in APS, and the benefits of NF-κB inhibition in SLE and APS. In a separate chapter, Kubota and Umezawa focus on the activation of NF-κB in pannus and synoviocytes obtained from patients with RA. They describe the development of NF-κB inhibitors and discuss their mechanism of action. They also describe the therapeutic modalities used to inhibit NF-κB, such as gene therapy, small molecules and specific inhibitors in animal models of erosive arthritis. In the last chapter, Rapoport et al. review the role of aberrations in the p21/Ras/MAP kinase pathway in the pathophysiology of autoimmune diseases such as autoimmune diabetes, SLE, chronic idiopathic urticaria and Celiac disease. They discuss whether monitoring the activity of the p21/Ras pathway might serve as a biomarker for disease activity, and whether this signaling pathway should be considered a therapeutic target in autoimmune diseases. Major breakthroughs in basic and translational research broadened our understanding of the pathbiology of autoimmune disorders. Drugs, broadly used to treat patients with these disorders, are being replaced by novel, targeted therapeutic modalities in recent years. As reviewed in this volume, targeted therapy has been successfully revolutionizing our therapeutic approach to autoimmune diseases. |
