Innate immunity in the antiphospholipid syndrome: role of toll-like receptors in endothelial cell activation by antiphospholipid antibodies.
Antiphospholipid antibodies are mainly directed against beta 2 glycoprotein I (beta2GPI), a plasma phospholipid-binding protein expressed on endothelial cells of different anatomical localizations. Anti-beta2GPI antibodies recognize the molecule on endothelial monolayers in vitro, and, once bound, might activate the cells both in vitro and in vivo experimental models inducing a proinflammatory and a procoagulant phenotype. Cell activation is associated with nuclear factor-kappaB (NF-kappaB) translocation and with a signaling cascade comparable to that triggered by the toll-like receptors (TLRs)-4. The cell membrane receptor(s) for beta2GPI adhesion is still under investigation. It has been suggested that beta2GPI might adhere through electrostatic interaction between its cationic phospholipid binding site and anionic structures on the cell membrane; however, binding to annexin II-the endothelial cell receptor for tissue plasminogen activator-plays also a role. Because annexin II does not display any transmembrane protein, it has been suggested that it requires a yet unknown "adaptor" protein to signal the cells. Because of the molecular mimicry between beta2GPI and viral/bacterial structures-the natural ligands for TLRs-antibodies might cross-link the molecule associated to annexin II and TLR-4 eventually triggering the signaling.
Meroni
P L
PL
Allergy, Clinical Immunology and Rheumatology Unit, Department of Internal Medicine, University of Milan, IRCCS Istituto Auxologico Italiano, Via G. Spagnoletto, 3, Milan 20149, Italy. pierluigi.meroni@unimi.it
Raschi
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Testoni
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Parisio
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Borghi
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D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D004727:Endothelium / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D053482:beta 2-Glycoprotein I
D017152:Antibodies, Antiphospholipid; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D053482:beta 2-Glycoprotein I