Étude du rôle régulateur de la lamine B1 dans l’activation plaquettaire : base moléculaire de la thromboprotection chez les patients porteurs d'anticoagulant lupique et d'anti-lamine B1
Anti-phospholipid antibodies such as lupus anticoagulant antibodies (LAC) are associated with recurrent thrombotic events in systemic lupus erythematosus (SLE) patients. However, the risk of thrombosis in LAC positive patients is markedly reduced in the presence of high titers of autoantibodies to lamin B1 (anti-LB1). To date, the implication of lamin B1 (LB1) and anti-LB1 in thromboprotection remains unclear. Our objective was to examine the mechanism whereby LB1 and anti-LB1 induced thromboprotection. Functional platelet and endothelial cell activation assays were used to determine the effects of recombinant LB1 and affinity purified anti-LB1 on these two cell types. LB1, contrarily to anti-LB1, was found to possess an intrinsic anti-platelet activity. This protein reduced the activation and aggregation of platelets in vitro and in vivo. This activity was likely due to the direct binding of LB1 to platelets, followed by its rapid internalization within clathrin coated-pits. Coimmunoprecipitation revealed that LB1 interacted with the insulin receptor located within the platelet membrane. The binding of LB1 to this receptor induced its internalization and inhibited at least one of the phosphorylation cascade stimulated by the receptor, which in turn inhibited platelet functions. The addition of affinity-purified anti-LB1 in our model markedly increased the persistence of LB1 within platelets, a finding supported by the detection of LB1 only in platelets from anti-LB1 positive SLE patients. Our results suggest that LB1 regulates haemostasis in normal subjects. The presence of anti-LB1 in SLE patients prolongs the persistence of LB1 within platelets, thus possibly vi preventing further platelet activation. This mechanism likely explains the reduced risk of thrombotic events in LAC positive SLE patients with circulating anti-LB1 autoantibodies.
anti-lamine autoantibodies Systemic lupus erythematosus lupus anticoagulant lamin B1 platelets thrombosis