Differential Effects of Anti–β ₂ -Glycoprotein I Antibodies on Endothelial Cells and on the Manifestations of Experimental Antiphospholipid Syndrome

Abstract

Background-The antiphospholipid syndrome (APS) entails a prothrombotic state associated with the presence of anticardiolipin antibodies (aCL). aCL were shown to promote endothelial cell and platelet activation and to induce an APS-like syndrome in mice when administered intravenously. Recent data suggest that aCL target the plasma cofactor ␤ 2 -glycoprotein I (␤2GPI) rather than negatively charged phospholipids. However, it has not been determined whether different epitope-specific anti-␤2GPI antibodies obtained from one patient possess pathogenic properties. Methods and Results-Three ␤2GPI-binding IgM monoclonal antibodies (mAbs) (ILA-1, ILA-3, and ILA-4) were cloned from a patient with APS. The three antibodies were shown to bind ␤2GPI immobilized on irradiated plates, yet only ILA-1 bound ␤2GPI coated onto nonirradiated plates. Furthermore, when using the anti-␤2GPI enzyme-linked immunosorbent assay, ILA-1 was the only mAb inhibited by fluid phase ␤2GPI.

Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered β2-glycoprotein I

“…These findings are in accordance with the pathogenetic activity of both anti-␤ 2 GPI and human mAb 519 in murine passive transfer models of fetal loss in the APS (25,27) and with the reported association between the presence of anti-␤ 2 GPI antibodies and fetal loss (8)(9)(10)(11)(19)(20)(21)(22). In addition, defective placentation might be responsible for some of the early fetal losses reported to frequently occur in women with the APS (51).…”

“…Antibodies specific for ␤ 2 GPI have been identified and found to be associated with the clinical manifestations of the antiphospholipid syndrome (APS) (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The in vivo immunohistologic demonstration of ␤ 2 GPI on trophoblast surfaces (23,24) and the induction of fetal loss by anti-␤ 2 GPI antibodies in experimental animal models (25,26) suggested a role of anti-␤ 2 GPI antibodies in fetal loss. Moreover, even murine and human aPL monoclonal antibodies (mAb) specifically reacting with anionic PL in the absence of any plasma cofactor have been shown to produce fetal loss, growth retardation, placental deposition, and necrosis in experimental animal models (3,27,28).…”

Inflammatory response and the endothelium

“…These findings confirmed and extended the observation that anti-cardiolipin IgG fractions activated EC in the presence of h2GPI [2]. Following these studies, other groups have confirmed this finding by using both polyclonal and monoclonal aPL [5][6][7][8]. Interestingly, aPL-mediated activation with ADM upregulation and pro-inflammatory cytokine secretion was also found with human brain and skin primary EC cultures, suggesting that such an effect might be generalized to EC from different anatomical sites [9].…”

Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis

“…b2GP-I is the target auto-antigen in the anti-phospholipid syndrome. In experimental models, it has been demonstrated that immunization with b2GP-I and adoptive transfer of b2GP-I reactive lymphocytes enhances atherogenesis [98,99]. Autoantibodies to b2GP-I can be detected in a substantial proportion of patients with vasculitis.…”