Anti-β2-glycoprotein I (β2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the β2GPI binding to phospholipids

Hiroyuki Takeya, Tatsuyuki Mori, Esteban C. Gabazza, Kenji Kuroda, Hiroshi Deguchi, Eiji Matsuura, Kenji Ichikawa, Takao Koike, Koji Suzuki

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126 Citations (Scopus)


β2-Glycoprotein I (βGPI), a plasma glycoprotein with phospholipid- binding property, is known to be the actual target antigen for autoimmune type anticardiolipin antibodies (aCLs). Certain groups of aCLs (anti-βGPI antibodies) exert lupus anticoagulant (LA) activity and perturb the function of vascular endothelial cells. This investigation aimed at highlighting some insights into the molecular basis by which aCLs exert their biological effects by using anti-β2GPI mAbs with well-characterized epitopes from mice and from patients with antiphospholipid syndrome. Antiβ2GPI mAbs directed against the third domain (Cof-20 and Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of β2GPI inhibited the thrombin generation induced by Russell's viper venom in diluted plasma and that induced by the prothrombinase complex reconstituted with purified clotting factors. This anticoagulant activity was abrogated in the presence of an excess amount of phospholipids, thus resembling the LA activity. In stark contrast, anti- β2GPI mAbs directed against the fifth domain and the carboxy-terminal region of the fourth domain showed no LA-Iike activity. These findings suggest that the LA activity of antiβ2GPI antibodies depends on their epitope specificity. Experiments carried out to clarify the mechanism of the LA activity showed that anti-β2GPI mAbs with LA-like activity, but not those without this effect, enhance the β2GPI binding to phospholipids. In addition, the F(ab')2 fragment, but not the Fab' fragment, of the anti- β2GPI mAbs was found to enhance the LA activity and the β2GPI binding to phospholipids, suggesting that anti-β2GPI antibodies induce formation of multiple complexes of β2GPI on the surface of phospholipids because of their bivalent property. This clustering of β2GPI molecules induced by anti- β2GPI antibodies, probably because of their multivalent property and epitope specificity, might hinder the lateral mobility and activation of clotting factors on the surface of phospholipids and thus exert LA activity. Clustering of β2GPI molecules may also explain the molecular mechanism by which anti-β2GPI antibodies alter the function of leukocytes and endothelial cells. The will-documented heterogeneous LA activity of aCLs (anti-β2GPI antibodies) may also be explained by their epitope specificity.

Original languageEnglish
Pages (from-to)2260-2268
Number of pages9
JournalJournal of Clinical Investigation
Issue number9
Publication statusPublished - May 1 1997
Externally publishedYes


  • antiphospholipid
  • apolipoprotein
  • autoantobodies
  • phospholipid
  • prothrombin

ASJC Scopus subject areas

  • Medicine(all)


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