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• W2045607534 abstract "Antiphospholipid (APL) antibodies are associated with thrombosis and pregnancy loss and other clinical manifestations in patients with antiphospholipid syndrome (APS). APL antibodies are heterogeneous in function and specificity and recognize various protein antigens on the surface of target cells (i.e. platelets, endothelial cells, throphoblasts, monocytes). Among those, β2-glycoprotein I (β2GPI) seems to be the most relevant. APL/anti-β2GPI antibody binding to endothelial cell-bound β2GPI mediates various cell dysfunctions that are potentially important in determining different APS clinical manifestations. APL antibodies also have been shown to affect platelet activation. Recently, some of the intracellular pathways activated by APL antibodies in platelets, monocytes and endothelial cells have been examined. Studies have conclusively shown that APL antibodies induce phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) in platelets, monocytes and endothelial cells, and activate the transcriptional factor nuclear factor-kappa B (NF-κB) in monocytes and endothelial cells [1-5]. Although there is convincing evidence that APL antibodies can stimulate endothelial cells, monocytes and platelets, relatively little is known about the cell surface receptors that are engaged or crosslinked to induce intracellular signaling. In endothelial cells, there is indirect evidence that annexin A2, a receptor for tissue plasminogen activator (t-PA) and plasminogen, and toll-like receptor 4 (TLR-4), a receptor for bacterial lipopolysaccharide (LPS), may be binding β2-GPI and triggering intracellular signaling. Studies have recently shown that annexin A2 mediates endothelial cell activation by APL/anti-β2GPI antibodies after binding to β2GPI [6, 7]. Because annexin A2 does not span the cell membrane, this interaction may require an ‘adaptor’ protein able to transduce intracellular signaling. Raschi et al. [8] have previously shown that MyD88 signalling cascade – associated to TLR-4- is triggered by APL/anti-β2GPI antibodies on the endothelial cell surface membrane. Zhang et al. [9] recently were able to identify a protein of 83 kDa that appeared to be TLR-4 among those that bound immobilized β2GPI by affinity-purification in Affi-Gel HZ columns followed by elution, sodium docecylsulfate polyacyrlamide gel electrophoresis (SDS-PAGE) and liquid chromatography with mass spectrometry (LC-MS) analysis. In recent studies, our group showed that APL/anti-β2GPI antibodies do not exert pathogenic effects in vivo in LPS non-responsive mice, indicating that TLR-4 may be a receptor for APL/anti-β2GPI antibodies in vivo [10]. It is also possible that other molecules might act as receptors for β2GPI in various cell types. In previous studies, Lutters et al. [11] showed that APL/anti-β2GPI complexes can bind to platelets leading to phosphorylation of p38MAPK, thromboxane production and cell activation, and that this effect could be mimicked by a recombinant form of dimeric β2GPI. The authors showed that a splice variant of the apolipoprotein E receptor 2′ (apoER2′) that is present in platelets is involved in the binding of dimeric β2GPI to human platelets. Interestingly apoER2′, a member of the low density lipoprotein (LDL) family is expressed in endothelial cells, brain, placenta and testis and shares homology with other members of the LDL receptor family. In addition to functioning as a scavenger receptor for lipoproteins, apoER2′ it has been shown to induce intracellular signaling and activation of p38MAPK [12, 13]. In this issue of the Journal, Pennings and collaborators [14] elegantly show that dimeric β2GPI interacts with four other LDL-R family members: LDL-R related protein (LRP), megalin, the LDL-R. and the very low density lipoprotein receptor (VLDL-R). Utilizing deletion mutants, the interaction was found to be dependent on a binding site within domain V of β2GPI, which does not appear to overlap with the phospholipid-binding site within domain V. These receptors – found ubiquitously in many cells – are anchored to the membrane via an intracellular tail and are capable of harboring endocytosis and intracellular signaling. Based on the information provided in this study, it is possible to hypothesize that members of the LDL receptor family may bind β2GPI/anti-β2GPI complexes and trigger intracellular signaling in various target cell types responsible for the multiple clinical manifestations associated with APS. The studies by Pennings et al. [14] are relevant not only because they help to delineate the molecular mechanisms triggered by APL antibodies. Understanding the nature of the receptor(s) and the interaction with β2GPI and APL/anti-β2GPI antibodies on target cells may help to devise new targeted modalities, that is, specific antibodies and/or antagonists that block the binding of the receptor to the ligand, for treatment and prevention of the clinical manifestations observed in patients with APS. The authors state that they have no conflict of interest." @default.
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• W2045607534 date "2006-08-01" @default.
• W2045607534 modified "2023-10-16" @default.
• W2045607534 title "In search for a receptor for antiphospholipid antibodies on target cells" @default.
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• W2045607534 doi "https://doi.org/10.1111/j.1538-7836.2006.02080.x" @default.
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