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Among the heterogeneous antiphospholipid antibodies, many studies suggest that those directed to beta2-glycoprotein I (beta2GPI) are the major pathogenic antibodies in antiphospholipid syndrome (APS). They have been shown to activate the coagulation pathway via several mechanisms, activate platelets via thrombin formation, and suppress fibrinolysis. Additionally, we propose another possible mechanism that involves certain chemokines and results in platelet activation. This hypothesis is based on the observations that anti-beta2GPI antibodies stimulated monocytes to secrete inflammatory cytokines such as IL-1beta and TNF-alpha, which in turn stimulated vascular endothelial cells to express chemokines such as CX3CL1 and CCL5. CX3CL1 increased the ability of normal platelets to adhere to collagen at a high shear rate, while CCL5 induced platelet aggregation. Expression of tissue factor, IL-1beta, and TNF-alpha by monocytes stimulated with anti-beta2GPI antibodies, as well as CX3CL1 and CCL5 by vascular endothelial cells stimulated with IL-1beta or TNF-alpha were all suppressed by the NF-kappaB-specific inhibitor DHMEQ. These results suggest that the NF-kappaB pathway may be a potential therapeutic target relating to both the coagulation pathway and platelet activity.

Heparins represent an efficient treatment of acute thrombosis and obstetric complications in antiphospholipid syndrome (APS). Enhanced microvesiculation of cell membranes, as detected by reduced membrane adhesion, can contribute to hypercoagulability in APS. Healthy donor IgG antibodies significantly increased beta2-glycoprotein I (beta2-GPI)-induced membrane adhesion, indicating that IgG antibodies might supplement the role of beta2-GPI in the regulation of membrane microvesiculation in healthy individuals. Anti-beta2-GPI IgG antibodies significantly reduced beta2-GPI-induced membrane adhesion, suggesting a direct role of anti-beta2-GPI antibodies in enhancing membrane microvesiculation in APS. Therapeutic concentration of nadroparin completely restored beta2-GPI-induced membrane adhesion in the presence of anti-beta2-GPI IgG antibodies. A novel anticoagulant mechanism of nadroparin in APS is suggested that supplements its direct effect on the coagulation cascade. Restoration of adhesion between negatively charged membranes in the presence of nadroparin might decrease shedding of microvesicles into the surrounding solution and could thus contribute to the efficacy of heparin treatment in APS.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission in which antibodies are directed against voltage-gated calcium channels (VGCCs). We studied the action of LEMS immunoglobulin G (IgG) on cloned human VGCCs stably transfected into human embryonic kidney cells (HEK293). All LEMS IgGs tested bound to the surface of the P/Q-type VGCC cell line and caused a significant reduction in whole-cell calcium currents in these cells. By contrast, only 2 out of 6 IgGs bound extracellularly to the N-type VGCC cell line, and none of the LEMS IgGs tested was able to reduce whole-cell calcium currents in these cells. We used this apparent specificity of LEMS IgG for the P/Q-type VGCC to investigate the action of these IgGs on model systems where a number of different VGCC populations exist in equilibrium. LEMS IgG caused a significant downregulation in the omega-agatoxin IVA-sensitive P/Q-type VGCCs of cultured rat cerebellar neurons, but this was accompanied by a concomitant rise in the "resistant" R-type VGCCs. By using the passive transfer model of LEMS, similar results were observed at the mouse neuromuscular junction, where a significant reduction in P/Q-type VGCCs was paralleled by an increase in L- and R-type VGCCs. These results demonstrate an unexpected plasticity in the expression of VGCCs in mammalian neurons and may represent a mechanism by which the pathogenic effects of LEMS IgG are reduced.