Pathogenesis of antiphospholipid antibodies:

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The antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL). Tissue factor (TF), the major initiator of the coagulation system, is induced on monocytes by aPL in vitro, explaining, in part, the pathophysiology in this syndrome. Recently, it has been focused the nature of the aPL-induced signal transduction pathways leading to TF expression, and we reported that the mitogen-activated protein kinase (MAPK) pathway played an important role in aPL-induced TF expression on monocytes. In this study, we demonstrate that β_2 glycoprotein I (β_2GPI) interacts with plasma gelsolin that binds to integrin5β1 through fibronectin. The interaction between β_2GPI/monoclonal anti-β_2GPI antibody (β_2GPI dependent anticardiolipin antibodies; aCL/β_2GPI) complex and cell surface enhanced in the presence of plasma gelsolin. Western blotting studies using monocyte cell line (RAW264.7) demonstrated that p38 MAPK protein was phosphorylated by monoclonal aCL/β2GPI treatment, and the phosphorylation was attenuated in the presence of anti-integrinα5β1 antibody. Furthermore, focal adhesion kinase (FAK) that is downstream of fibronectin-integrin signaling pathway was phosphorylated by aPL treatment. These results demonstrated that the integrin-p38 MAPK signaling pathway plays an important role in aPL-induced TF expression on monocytes and suggest that the integrin may be a possible therapeutic target to modify a prothrombotic state in patients with APS