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Anti-Beta2-Glycoprotein I (Beta2gpi) Monoclonal Antibodies with Lupus Anticoagulant-Like Activity Enhance the Beta2gpi Binding to Phospholipids

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Anti-Beta2-Glycoprotein I (Beta2gpi) Monoclonal Antibodies with Lupus Anticoagulant-Like Activity Enhance the Beta2gpi Binding to Phospholipids Anti-beta2-glycoprotein I (beta2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta2GPI binding to phospholipids. H Takeya, … , T Koike, K Suzuki J Clin Invest. 1997;99(9):2260-2268. https://doi.org/10.1172/JCI119401. Research Article beta2-Glycoprotein I (beta2GPI), 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-beta2GPI 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-beta2GPI mAbs with well-characterized epitopes from mice and from patients with antiphospholipid syndrome. Anti-beta2GPI mAbs directed against the third domain (Cof-20 and Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of beta2GPI 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-beta2GPI mAbs directed against the fifth domain and the carboxy-terminal region of the fourth domain showed no LA-like activity. These findings suggest that the LA activity of anti-beta2GPI antibodies depends on their epitope specificity. Experiments carried out to clarify the mechanism of the LA activity showed that anti-beta2GPI mAbs with LA-like activity, but not those without this effect, enhance the beta2GPI binding to phospholipids. In addition, the F(ab')2 fragment, but not the Fab' fragment, of the anti-beta2GPI mAbs was found […] Find the latest version: https://jci.me/119401/pdf Anti–␤2-Glycoprotein I (␤2GPI) Monoclonal Antibodies with Lupus Anticoagulant-like Activity Enhance the ␤2GPI Binding to Phospholipids Hiroyuki Takeya,* Tatsuyuki Mori,* Esteban C. Gabazza,* Kenji Kuroda,* Hiroshi Deguchi,* Eiji Matsuura,‡ Kenji Ichikawa,§ Takao Koike,§ and Koji Suzuki* *Department of Molecular Pathobiology, Mie University School of Medicine, Tsu-City, Mie 514, Japan; and ‡Department of Biochemistry I, and §Department of Medicine II, Hokkaido University School of Medicine, Sapporo 060, Japan Abstract endothelial cells. The well-documented heterogeneous LA activity of aCLs (anti-␤2GPI antibodies) may also be ex- ␤2-Glycoprotein I (␤2GPI), a plasma glycoprotein with plained by their epitope specificity. (J. Clin. Invest. 1997. 99: phospholipid-binding property, is known to be the actual 2260–2268.) Key words: antiphospholipid • apolipoprotein • target antigen for autoimmune type anticardiolipin anti- autoantibodies • prothrombin • phospholipid bodies (aCLs). Certain groups of aCLs (anti-␤2GPI anti- bodies) exert lupus anticoagulant (LA) activity and perturb Introduction the function of vascular endothelial cells. This investigation aimed at highlighting some insights into the molecular basis ␤2-Glycoprotein I (␤2GPI)1 is a plasma glycoprotein with an by which aCLs exert their biological effects by using anti- apparent molecular mass of 50 kD (326 amino acids) (1–3). ␤2GPI mAbs with well-characterized epitopes from mice ␤2GPI is composed of five short-consensus-repeat domains, and from patients with antiphospholipid syndrome. Anti- the so-called sushi domains, often found in the structure of ␤2GPI mAbs directed against the third domain (Cof-20 and complement factors and selectins (4). ␤2GPI strongly binds to Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of anionic phospholipids; the fifth sushi domain (domain V) be- ␤2GPI inhibited the thrombin generation induced by Rus- ing the major phospholipid-binding region (5–9). The high sell’s viper venom in diluted plasma and that induced by the structural homology among the human, bovine, rat, and mouse prothrombinase complex reconstituted with purified clot- ␤2GPI molecules suggests that ␤2GPI might play an important ting factors. This anticoagulant activity was abrogated in physiological role in vivo (10). ␤2GPI exhibits anticoagulant the presence of an excess amount of phospholipids, thus properties in vitro, such as the inhibition of the intrinsic blood resembling the LA activity. In stark contrast, anti-␤2GPI coagulation pathway (11, 12), and the prothrombinase activity mAbs directed against the fifth domain and the carboxy- of activated platelets (13). Recently, ␤2GPI became the sub- terminal region of the fourth domain showed no LA-like ject of increasing interest since it was demonstrated that it is activity. These findings suggest that the LA activity of anti- the actual target antigen of autoimmune-type anticardiolipin ␤2GPI antibodies depends on their epitope specificity. Ex- antibodies (aCLs) (14–17, see references 18 and 19 for recent periments carried out to clarify the mechanism of the LA review). We and others have also recently demonstrated that activity showed that anti-␤2GPI mAbs with LA-like activ- aCLs bind to ␤2GPI even in the absence of cardiolipin (20, 21). ity, but not those without this effect, enhance the ␤2GPI The presence of antiphospholipid antibodies is defined by binding to phospholipids. In addition, the F(abЈ)2 fragment, the detection of aCL by immunoabsorbent assays or by the de- but not the FabЈ fragment, of the anti-␤2GPI mAbs was tection of lupus anticoagulant (LA) activity (22–24). Bevers et found to enhance the LA activity and the ␤2GPI binding to al. (25) reported that the expression of LA activity depends on phospholipids, suggesting that anti-␤2GPI antibodies in- the potential of LA antibodies to bind to phospholipid-bound duce formation of multiple complexes of ␤2GPI on the sur- prothrombin. However, originally, the term LA was defined as face of phospholipids because of their bivalent property. antiphospholipid antibodies that prolong the clotting time of This clustering of ␤2GPI molecules induced by anti-␤2GPI phospholipid-dependent coagulation tests. Based on this defi- antibodies, probably because of their multivalent property nition, LA antibodies may recognize a heterogeneous group of and epitope specificity, might hinder the lateral mobility antigens. In fact, certain groups of aCLs also possess LA activ- and activation of clotting factors on the surface of phospho- ity (26). According to the classification by Galli et al. (26), lipids and thus exert LA activity. Clustering of ␤2GPI mole- aCLs of type A prolong the phospholipid-dependent clotting cules may also explain the molecular mechanism by which time, while those of type B lack this anticoagulant activity. anti-␤2GPI antibodies alter the function of leukocytes and Nevertheless, both types require ␤2GPI for detection in aCL tests.2 The molecular basis of the different properties of types A and B aCLs (aCLs with or without LA activity, respectively) is unknown. Address correspondence to Koji Suzuki, Ph.D., Department of Mo- lecular Pathobiology, Mie University School of Medicine, Edobashi 2-174, Tsu-city, Mie 514, Japan. Phone: 81-592-31-5036; FAX: 81-592- 31-5209; E-mail: [email protected] 1. Abbreviations used in this paper: aCL, anticardiolipin antibody; Received for publication 28 June 1996 and accepted in revised APTT, activated partial thromboplastin time; ␤2GPI, ␤2-glycopro- form 27 January 1997. tein I; LA, lupus anticoagulant; RVV, Russell’s viper venom. 2. References 25 and 26 use the term LA in a limited fashion to desig- J. Clin. Invest. nate antibodies with anticoagulant activity that recognize prothrom- © The American Society for Clinical Investigation, Inc. bin; type A and type B aCL refer to antibodies to ␤2GPI with and 0021-9738/97/05/2260/09 $2.00 without anticoagulant activity, respectively. In this report, however, Volume 99, Number 9, May 1997, 2260–2268 we consider type A aCL to be LA. 2260 Takeya et al. The presence of antiphospholipid antibodies has been X activator coupled to 2-fluoro-1-methylpyridinium toluene-4-sul- linked to a major risk of developing thromboembolic compli- fonate-activated Cellulofine (Seikagaku Kogyo Co., Tokyo, Japan) cations in various autoimmune disorders (27, 28). Numerous (45). Factor V was purified from freshly frozen platelet-free plasma studies have been carried out regarding the effect of antiphos- (46, 47), using affinity column chromatography with anti–Factor V mu- pholipid antibodies on coagulation factors and inhibitors present rine mAb-coupled Sepharose gel, and was activated with thrombin, as described (46). ␤2GPI was purified from normal human sera by se- in the fluid phase, and on cellular regulators of hemostasis. quential cardiolipin-affinity, ion exchange and protein A–Sepharose However, the paradox of the in vitro anticoagulant activity of column chromatographies, as described (41). All purified proteins antiphospholipid antibodies and their relation with increased were homogeneous with Ͼ 95% of purity, as judged by SDS-poly- thrombotic complication in vivo remain unsolved (29). Epide- acrylamide gel electrophoresis followed by silver staining and were miological studies described a significant relationship be- stored in small aliquots at Ϫ80ЊC until use. The synthetic chromoge- tween the presence of aCL (anti-␤2GPI antibodies) and the nic peptide substrate of thrombin, S-2238 (D-Phe-pipecolyl-Arg- history of thrombosis (30–33). Induction of antiphospholipid pNA), was purchased from Chromogenix AB (Mölndal,
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