Pathogenesis of antiphospholipid antibodies : Impairment of fibrinolysis and monocyte activation via the p38 mitogen-activated protein kinase pathway
Abstract
Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis or pregnancy morbidity associated with antiphospholipid antibodies (aPL). Impaired fibrinolysis is a contributing factor for the development of thrombosis, and the effect of aPL in the fibrinolytic system has been investigated. Impaired release of tPA and enhanced release of PAI-1 after endothel activation is reported in patients with APS. Elevated Lipoprotein (a) levels have been found in APS, which results in inhibition of fibrinolytic activity. Phospholipid-bound β2-glycoprotein I (β2GPI) is a major autoantigen for aPLs. β2GPI exerts both anti-coagulant and pro-coagulant properties mainly by interacting with other phospholipid-binding proteins such as coagulation factors and protein C. Dramatic increase in the affinity of β2GPI to the cell surface is induced by binding of pathogenic anti-β2GPI antibodies, which may modify the physiological function of β2GPI and may affect the coagulation/fibrinolysis balance on the cell surface. Using chromogenic assays for measuring fibrinolytic activity, we demonstrated that addition of monoclonal anticardiolipin antibody (aCL) decreases the activity of extrinsic/intrinsic fibrinolysis. Significantly lower activity of intrinsic fibrinolysis was also demonstrated in the euglobulin fractions from APS patients. Endothelial cells and monocytes are activated by aPLs in vitro, resulting in production of tissue factor (TF), a major initiator of the coagulation system. Recently, aPLs are reported to induce thrombocytes to produce thromboxane. The importance of apoE receptor 2 on platelets for the binding of artificially-dimerized β2GPI was suggested. By investigating aPL-inducible genes in peripheral blood mononuclear cells, we found that mitogen-activated protein kinase (MAPK) pathway was up-regulated. Using monocyte cell line, phosphorylation of p38 MAPK, NF-κB translocation to the nuclear fraction, and up-regulated TF mRNA expression were demonstrated after treatment with monoclonal aCL. These phenomena were observed only in the presence of β2GPI. Moreover, a specific p38 MAPK inihibitor SB203580 decreased aCL/β2GPI-induced TF mRNA expression. Thus, aCL/β2GPI plays dual roles in the pathogenesis of APS, firstly by deranging fibrinolytic system and secondly by activating monocytes, endothelial cells and thrombocytes to produce tissue factor or thromboxane.
Journal
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- Immunobiology
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Immunobiology 210 (10), 775-780, 2005-12-13
Elsevier