Endothelium as a target for antiphospholipid antibodies.
Several, and not necessarily alternative, pathogenic mechanisms have been suggested to sustain the thrombophilic diathesis of the anti-phospholipid syndrome. Among them, interference of anti-phospholipid antibodies with cell acting in the coagulation cascade likely plays a major role. Anti-phospholipid antibodies have been shown to react with endothelial cells mainly by reacting with beta 2 glycoprotein I expressed on the cell membrane surface. Beta 2 glycoprotein I can adhere to endothelial cell surface through the Annexin II receptor and through negatively charged structures (heparin-like molecules) that are bound by the phospholipid-binding site of the molecule. The autoantibody binding involves a yet unknown receptor that activates a signalling pathway able to translocate NFkappaB from the cytoplasm to the nucleus and to activate genes for adhesion molecule, pro-inflammatory cytokine and Tissue Factor up-regulation. The ultimate effect is the induction of a pro-inflammatory and a pro-coagulant endothelial phenotype that has been reproduced both in vitro and in vivo experimental models. Additional effects of anti-phospholipid-mediated endothelial cell activation are the interference with the protein C/S system, with the Annexin V binding, the up-regulation of endothelin I synthesis and the induction of apoptosis. Altogether these effects cooperate in switching endothelium from an anti-coagulant to a pro-coagulant surface.
Riboldi
Piersandro
P
Allergy and Clinical Immunology Unit, IRCCS Istituto Auxologico Italiano, Department of Internal Medicine University of Milan, Milan, Italy.
Gerosa
Maria
M
Raschi
Elena
E
Testoni
Cinzia
C
Meroni
Pier Luigi
PL
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000737:chemistry / Q000276:immunology*; D017209:Apoptosis; D001665:Binding Sites; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D011992:Endosomes / Q000276:immunology; D019332:Endothelin-1 / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D015398:Signal Transduction; D013925:Thromboplastin / Q000096:biosynthesis; D015854:Up-Regulation; D053482:beta 2-Glycoprotein I
D017152:Antibodies, Antiphospholipid; D019332:Endothelin-1; D006023:Glycoproteins; D016328:NF-kappa B; D053482:beta 2-Glycoprotein I; D013925:Thromboplastin