Update on the pathogenesis and treatment of the antiphospholipid syndrome

Abstract

http://links.lww.com/COR/A26.

Anti-beta-2 glycoprotein I epitope specificity: from experimental models to diagnostic tools

“…The composition of the complex appears to be different depending on the cell type, since it consists of Annexin A2, TLR4, calreticulin, and nucleolin in endothelial cells, while NF-kB translocation in monocytes is engaged through a clathrin-dependent endocytic pathway, a mechanism that requires CD14 (TLR4 co-receptor) and Annexin A2. 10 The phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been recently identified as an additional signalling cascade engaged by aPL that recruits the mammalian target of rapamycin (mTOR), a kinase modulating cellular growth, proliferation and apoptosis. 10 Some of these candidate receptors for b2GPI have been investigated in animal models and a critical role has been confirmed for TLRs, Annexin A2 and LRP8.…”

“…10 The phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been recently identified as an additional signalling cascade engaged by aPL that recruits the mammalian target of rapamycin (mTOR), a kinase modulating cellular growth, proliferation and apoptosis. 10 Some of these candidate receptors for b2GPI have been investigated in animal models and a critical role has been confirmed for TLRs, Annexin A2 and LRP8. However, animals deficient in each of these molecules are protected from the thrombogenic effect of aPL only in part, suggesting that none of the receptors is essential and that all are semi-redundant.…”

“…9 Role of b2GPI in the pathophysiology of APS Antibodies directed against b2GPI have been shown to be pathogenic in APS animal models since they are able to trigger clotting or to increase the size of a preformed thrombus and to increase resorptions in the fetal-loss model. 2,3,10 The most widely accepted hypothesis suggests that the antibodies may activate the cells involved in the coagulation cascade (endothelial cells, monocytes, platelets) by recognizing the target molecule present on their cell membrane.…”

“…2 As for the binding to anionic phospholipids, the affinity for these receptors can be increased after b2GPI dimerization or its complexing with the antibodies; both events ultimately would stabilize the binding and allow intracellular signalling. 10 Upon engagement of b2GPI receptors on target cells, antib2GPI antibody binding results in the activation of intracellular mediators such as nuclear factor kappa B (NF-kB) and p38 mitogen-activated protein kinase (p38MAPK). Recently, a multiprotein complex including TLR4 and Annexin A2 was suggested to be involved in anti-b2GPI antibodymediated signalling both in monocytes and in endothelial cells.…”

Therapy for antiphospholipid miscarriages: Throwing the baby out with the bathwater?

“…Accordingly, heparin and low‐dose aspirin (LDASA) were used alone or in combination with the aim to prevent ischemic lesions at the placental levels. On the other hand, the previous use of high doses of corticosteroids resulted dangerous rather than protective in spite of the idea that an inflammatory autoimmune mechanism was behind miscarriages …”