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More than just B-cell inhibition

DOI: 10.1186/ar3439

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Therapy for rheumatoid arthritis (RA) has advanced tremendously over the past 10 years. Biologic therapy employing recombinant antibodies and receptors has become the standard of care. Neutralization of cytokines (tumor necrosis factor-alpha and interleukin-6), inhibition of co-stimulatory pathways (CTLA4Ig), and B-cell depletion (anti-CD20) have all been shown to be effective therapies. However, each requires parenteral administration, is expensive, and may result in undesired side effects. Over the last several years, there have been intensified efforts to develop small-molecule inhibitors that can be taken orally and that may result in less expensive, safer, and more conveniently administered therapy. In this issue of Arthritis Research & Therapy, Chang and colleagues [1] present data demonstrating the effectiveness of a selective Bruton tyrosine kinase (Btk) inhibitor, PCI-32765, in two experimental models of RA.Btk was originally identified as defective in patients who had X-linked agammaglobulinemia and who exhibited a profound reduction of B cells. Btk is a non-receptor tyrosine kinase within the Tec family of kinases and contains six domains: pleckstrin homogy (PH), Btk homology, polyproline region, two Src homology (SH2 and SH3), and a tyrosine kinase. Though originally identified in B cells (identifying it as a potential B-cell target), it has been found more recently in myeloid cells, including monocytes, macrophages neutrophils, and mast cells [2]. Btk is activated by crosslinking immunoglobulins on the surface of B cells and by the ligation of Fc receptors and integrins on myeloid cells, mediated through Src kinases, including Lyn and Syk [3,4], the latter a promising therapeutic target in RA. Src kinase activation of plasma membrane-bound (through the PH domain) Btk results in tyrosine phosphorylation of tyrosine 551 (in the tyrosine kinase domain), which leads to autophosphorylation at tyrosine 223 (in the SH3 domain), resulting in full kinase activit

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