Beta-2-glycoprotein I Dependent Lupus Anticoagulants Form Stable Bivalent Antibody Beta-2-Glycoprotein I Complexes on Phospholipid Surfaces

J. Arnout; C. Wittevrongel; M. Vanrusselt; M. Hoylaerts; J. Vermylen

doi:10.1055/s-0037-1614224

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1998; 79(01): 79-86
DOI: 10.1055/s-0037-1614224

Review Article

Schattauer GmbH

Beta-2-glycoprotein I Dependent Lupus Anticoagulants Form Stable Bivalent Antibody Beta-2-Glycoprotein I Complexes on Phospholipid Surfaces

J. Arnout

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

,

C. Wittevrongel

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

,

M. Vanrusselt

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

,

M. Hoylaerts

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

,

J. Vermylen

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

› Institutsangaben

Abstract

Summary

The precise mechanism by which Beta-2-glycoprotein I (β₂GPI-) dependent lupus anticoagulants lengthen phospholipid-dependent clotting reactions is still poorly understood. In order to study this, murine monoclonal antibodies (moabs) against human β₂GPI were raised. Eight of the 21 anti-β₂GPI moabs, obtained from 2 fusions, fulfilled the criteria for lupus anticoagulant (LA) activity as tested with a variety of sensitive screening assays and confirmatory tests. Seven moabs did not influence any clotting test. The LA positive moabs were found to compete for similar or closely spaced epitopes on immobilized β₂GPI. Two moabs with potent LA activity (moabs 22 F 6 and 22 B 3) and 1 moab without LA activity (moab 16 B 3) were selected to study the interaction between antibody, β₂GPI and phospholipid. Interactions were investigated by real-time biospecific interaction analysis (BIA) based on plasmon surface resonance technology on a BIA-core instrument using a sensor chip coated with phospholipid. When 22 F 6, the moab with the most pronounced LA activity, was allowed to interact with the phospholipid surface at concentrations between 0 and 400 nmol/l, no appreciable binding could be detected. Likewise, no binding could be measured when β₂GPI at concentrations between 0 and 400 nmol/l was passed over the phospholipid coated sensor chip. Combinations of β₂GPI and 22 F 6 resulted in significant binding. Similar results were obtained with 22 B 3, another moab with LA activity. A LA negative Moab, 16 B 3, did not cause binding of antibody-β₂GPI complexes. Fab’ fragments, derived from moab 22 F 6, inhibited the binding of β₂GPI-22 F 6 and β₂GPI-22 B 3 in a concentration dependent way, indicating that only bivalent β₂GPI-antibody complexes bind with high affinity to phospholipids. Fab’ fragments, derived from moab 22 F 6, also inhibited the LA effect of moabs 22 F 6 and 22 B 3 in diluted plasma. In summary, these experiments indicate that the β₂GPI-dependent LA effect depends on the formation of bivalent β₂GPI-antibody complexes on phospholipid surfaces.

Volltext

Referenzen

References
1 McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol 1991; 49: 193-280.
2 Vermylen J, Blockmans D, Spitz B, Arnout J, Grillet B. Thrombosis as an immune phenomenon. Baillière’s Clinical Immunology and Allergy 1987; 1: 619-41.
3 Love PE, Santoro SA. Antiphospholipid antibodies: Anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682-98.
4 Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486-9.
5 Exner T, Triplett DA, Taberner D, Machin SJ. Guidelines for testing and revised criteria for lupus anticoagulants. Thromb Haemost 1991; 65: 320-2.
6 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 1185-90.
7 Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GRV. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; ii: 1211-4.
8 Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN. Measurement of anticardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-45.
9 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta-2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4.
10 Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van BredaVriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-7.
11 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-8.
12 Vermylen J, Arnout J. Is the antiphospholipid syndrome caused by antibodies directed against physiologically relevant phospholipid-protein complexes?. J Lab Clin Med 1992; 120: 10-2.
13 Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA. A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus 1992; 1: 75-81.
14 Wagenknecht DR, McIntyre JA. Changes in beta 2-glycoprotein I antigenicity induced by phospholipid binding. Thromb Haemost 1993; 69: 361-5.
15 Ichikawa K, Khamashta MA, Koike T, Matsuura E, Hughes GR. β₂-Glycoprotein I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome. Arthritis Rheum 1994; 37: 1453-61.
16 Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a cryptic epitope expressed when β2-glycoprotein I is bound to a suitable surface. Thromb Haemost 1995; 73: 29-34.
17 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of anti-phospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991; 143: 223-9.
18 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β2-Glycoprotein I structure altered by interaction with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-62.
19 Viard JP, Amoura Z, Bach JF. Association of anti-beta 2-glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med 1992; 93: 181-6.
20 Martinuzzo ME, Forastiero RR, Carreras LO. Anti beta 2 glycoprotein I antibodies: detection and association with thrombosis. Br J Haematol 1995; 89: 397-402.
21 Roubey RAS, Eisenberg RA, Harper MF, Winfield JB. Anticardiolipin autoantibodies recognize β2-glycoprotein I in the absence of phospholipid. Importance of Ag density and bivalent binding. J Immunol 1995; 154: 954-60.
22 Oosting JD, Derksen RH, Entjes HT, Bouma BN, de Groot PG. Lupus anticoagulant activity is frequently dependent on the presence of beta 2-Glycoprotein I. Thromb Haemost 1992; 67: 499-502.
23 Roubey RA, Pratt CW, Buyon JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon beta 2-glycoprotein I. J Clin Invest 1992; 90: 1100-4.
24 Galli M, Comfurius P, Barbui T, Zwaal RF, Bevers EM. Anticoagulant activity of beta 2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies. Thromb Haemost 1992; 68: 297-300.
25 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-32.
26 Wurm H. B-2-glycoprotein I (apolipoprotein H) interactions with phospholipid vesicles. Int J Biochem 1984; 16: 511-5.
27 Arnout J, Spitz B, Wittevrongel C, Vanrusselt M, Van Assche A, Vermylen J. High-dose intravenous immunoglobulin treatment of a pregnant patient with an antiphospholipid antibody syndrome: immunological changes associated with a succesful outcome. Thromb Haemost 1994; 71: 741-7.
28 Galfré G, Milstein C. Preparation of monoclonal antibodies: strategies and procedures. Methods Enzymol 1981; 73: 3-46.
29 Fazekas de St, Groth S, Scheidegger D. Production of monoclonal antibodies: strategy and tactics. J Immunol Methods 1980; 35: 1-21.
30 Anderson PM, Potter M. Induction of plasma cell tumors in Balb/c mice with 2,6,10,14 etramethyl-pentadecane (pristane). Nature 1969; 222: 994-5.
31 Ey PL, Prowse SJ, Jenkin CR. Isolation of pure IgG1, IgG2a and IgG2b immunoglobulins from mouse serum using protein A-sepharose. Immunochemistry 1978; 15: 429-36.
32 Arnout J, Vanrusselt M, Huybrechts E, Vermylen J. Optimisation of the dilute prothrombin time for the detection of the lupus anticoagulant by use of a recombinant tissue thromboplastin. Br J Haematol 1994; 87: 94-9.
33 Rauch J, Tannenbaum M, Janoff AS. Distinguishing plasma lupus anticoagulants from anti-factor antibodies using hexagonal (II) phase phospholipids. Thromb Haemost 1989; 62: 892-6.
34 Jönsson U, Malmqvist M. Real time biospecific interaction analysis: the integration of surface plasmon resonance detection, general biospecific interface chemistry and microfluidities into one analytical system. Adv Biosensors 1992; 2: 291-336.
35 Nakane PA, Kawaoi A. Peroxidase labeled antibody. A new method for conjugation. J Histochem Cytochem 1974; 22: 1084-91.
36 Karlsson R, Michaelsson A, Mattsson L. Kinetic analysis of monoclonal antibody-antigen interactions with a new biosensor based analytical system. J Immunol Methods 1991; 145: 229-40.
37 BIAtechnology note 106. Uppsala, Sweden: Pharmacia Biosensor AB; 1995
38 Kertesz Z, Yu B, Steinkasserer A, Haupt H, Benham A, Sim R. Characterization of binding of human B2-glycoprotein I to cardiolipin. Biochem J 1995; 310: 315-21.
39 Willems GM, Janssen MP, Pelsers MMAL, Comfurius P, Galli M, Zwaal RFA, Bevers EM. Role of divalency in the high-affinity binding of anticardiolipin antibody-β₂-glycoprotein I complexes to lipid membranes. Biochemistry 1996; 35: 13833-42.
40 Takeya H, Mori T, Gabazza EC, Kuroda K, Deguchi H, Matsuura E, Ichikawa K, Koike T, Suzuki K. Anti-β₂-Glycoprotein I (β₂GP I ) monoclonal antibodies with lupus anticoagulant-like activity enhance the β₂GP I binding to phospholipids. J Clin Invest 1997; 99: 2260-8.
41 Romans DG, Tilley CA, Dorrington KJ. Monogamous bivalency of IgG antibodies. I. Deficiency of branched ABHI-active oligosaccharide chains on red cells of infants causes the weak antiglobulin reactions in hemolytic disease of the newborn due to ABO incompatibility. J Immunol 1980; 124: 2807.
42 Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemost 1996; 75: 536-41.
43 Arvieux J, Roussel B, Pouzol P, Colomb MG. Platelet activating properties of murine monoclonal antibodies to beta 2-glycoprotein I. Thromb Haemost 1993; 70: 336-41.
44 Arvieux J, Jacob MC, Roussel B, Bensa JC, Colomb MG. Neutrophil activation by anti-β₂ glycoprotein I monoclonal antibodies via Fcg receptor II. J Leukoc Biol 1995; 57: 387-94.
45 Horbach DA, van Oort E, Donders RCJM, Derksen RHWM, de Groot PG. Lupus anticoagulant is the strongest risk factor for both venous and arterial thrombosis in patients with systemic lupus erythematosus. Comparison between different assays for the detection of antiphospholipid antibodies. Thromb Haemost 1996; 76: 916-24.
46 Simantov R, LaSala JM, Lo SK, Gharavi AE, Sammaritano LR, Salmon JE. Activation of cultured vascular endothelial cells by antiphospholipid antibodies. J Clin Invest 1995; 96: 2211-9.