Annexin A2 is involved in antiphospholipid antibody-mediated pathogenic effects in vitro and in vivo

• Published in: Blood Vol. 114; no. 14; pp. 3074 - 3083
• Main Authors: Romay-Penabad, Zurina, Montiel-Manzano, Maria Guadalupe, Shilagard, Tuya, Papalardo, Elizabeth, Vargas, Gracie, Deora, Arun B., Wang, Michael, Jacovina, Andrew T., Garcia-Latorre, Ethel, Reyes-Maldonado, Elba, Hajjar, Katherine A., Pierangeli, Silvia S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-10-2009; Americain Society of Hematology; American Society of Hematology
• Series: Thrombosis and Hemostasis
• Subjects: Animals; Annexin A2 - physiology; Antibodies, Antiphospholipid - immunology; Antibodies, Antiphospholipid - pharmacology; Antiphospholipid Syndrome - immunology; Antiphospholipid Syndrome - metabolism; Antiphospholipid Syndrome - pathology; Aorta - injuries; Aorta - metabolism; Aorta - pathology; Biological and medical sciences; Blotting, Western; Cardiovascular Diseases; Carotid Arteries - metabolism; Carotid Arteries - pathology; Cells, Cultured; E-Selectin - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Enzyme-Linked Immunosorbent Assay; General aspects; Humans; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; Immunopathology; In Vitro Techniques; Intercellular Adhesion Molecule-1 - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Thromboplastin - metabolism; Thrombosis and Hemostasis; Umbilical Veins - cytology; Umbilical Veins - metabolism; Vascular Cell Adhesion Molecule-1 - metabolism; Immunopathology; Antiphospholipid antibody syndrome; Rodentia; Autoimmune disease; Cardiovascular disease; Hemopathy; In vitro; Vascular disease; In vivo; Vertebrata; Platelet; Mammalia; Mouse; Animal; Pathogenic; Annexin
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-11-188698

Antiphospholipid (aPL) antibodies recognize receptor-bound β2 glycoprotein I (β2GPI) 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 β2GPI 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-β2GPI 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.