title: Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo.
abstract: Antiphospholipid (aPL) antibodies recognize receptor-bound beta(2) glycoprotein I (beta(2)GPI) on target cells, and induce an intracellular signaling and a procoagulant/proinflammatory phenotype that leads to thrombosis. Evidence indicates that annexin A2 (A2), a receptor for tissue plasminogen activator and plasminogen, binds beta(2)GPI on target cells. However, whether A2 mediates pathogenic effects of aPL antibodies in vivo is unknown. In this work, we studied the effects of human aPL antibodies in A2-deficient (A2(-/-)) mice. A2(-/-) and A2(+/+) mice were injected with immunoglobulin G (IgG) isolated from either a patient with antiphospholipid syndrome (IgG-APS), a healthy control subject (IgG-normal human serum), a monoclonal anti-beta(2)GPI antibody (4C5), an anti-A2 monoclonal antibody, or monoclonal antibody of irrelevant specificity as control. We found that, after IgG-APS or 4C5 injections and vascular injury, mean thrombus size was significantly smaller and tissue factor activity was significantly less in A2(-/-) mice compared with A2(+/+) mice. The expression of vascular cell adhesion molecule-1 induced by IgG-APS or 4C5 in explanted A2(-/-) aorta was also significantly reduced compared with A2(+/+) mice. Interestingly, anti-A2 monoclonal antibody significantly decreased aPL-induced expression of intercellular cell adhesion molecule-1, E-selectin, and tissue factor activity on cultured endothelial cells. Together, these data indicate for the first time that A2 mediates the pathogenic effects of aPL antibodies in vivo and in vitro APS.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1165, USA.
authors.forename: Zurina
authors.initials: Z
authors.lastname: Romay-Penabad
authors.forename: Maria Guadalupe
authors.initials: MG
authors.lastname: Montiel-Manzano
authors.forename: Tuya
authors.initials: T
authors.lastname: Shilagard
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Papalardo
authors.forename: Gracie
authors.initials: G
authors.lastname: Vargas
authors.forename: Arun B
authors.initials: AB
authors.lastname: Deora
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Jacovina
authors.forename: Ethel
authors.initials: E
authors.lastname: Garcia-Latorre
authors.forename: Elba
authors.initials: E
authors.lastname: Reyes-Maldonado
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Pierangeli
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000502:physiology*; D017152:Antibodies, Antiphospholipid / Q000276:immunology / Q000494:pharmacology*; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D001011:Aorta / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002318:Cardiovascular Diseases; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D013925:Thromboplastin / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D017306:Annexin A2; D017152:Antibodies, Antiphospholipid; D019040:E-Selectin; D007074:Immunoglobulin G; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013925:Thromboplastin