β2-glycoprotein I-dependent Anticardiolipin Antibodies Preferentially Bind the Amino Terminal Domain of β2-glycoprotein I

Patricia A. McNeeley; Jeffrey S. Dlott; Richard A. Furie; Richard M. Jack; Thomas L. Ortel; Douglas A. Triplett; Edward J. Victoria; Matthew D. Linnik

doi:10.1055/s-0037-1616091

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 86(02): 590-595
DOI: 10.1055/s-0037-1616091

Review Article

Schattauer GmbH

β₂-glycoprotein I-dependent Anticardiolipin Antibodies Preferentially Bind the Amino Terminal Domain of β₂-glycoprotein I

Authors

Patricia A. McNeeley

¹La Jolla Pharmaceutical Company, San Diego, CA
Jeffrey S. Dlott

²Midwest Hemostasis and Thrombosis Laboratories, Medical Education Department, Ball Memorial Hospital, Muncie, IN
Richard A. Furie

³Division of Rheumatology and Allergy-Clinical Immunology, North Shore University Hospital-NYU School of Medicine, Manhasset, NY
Richard M. Jack

⁴Triad Therapeutics, San Diego, CA
Thomas L. Ortel^*

⁵Department of Medicine, Duke University Medical Center, Durham, NC, USA
Douglas A. Triplett

²Midwest Hemostasis and Thrombosis Laboratories, Medical Education Department, Ball Memorial Hospital, Muncie, IN
Edward J. Victoria

¹La Jolla Pharmaceutical Company, San Diego, CA
Matthew D. Linnik^*

¹La Jolla Pharmaceutical Company, San Diego, CA

Abstract

Summary

Many of the autoantibodies in antiphospholipid syndrome (APS) are directed against β₂-glycoprotein I (β₂-GPI). Recent studies from our laboratories have indicated that the immunodominant binding epitope(s) for high titer, affinity purified antibodies from 11 APS patients are localized to the amino terminal domain (domain 1) of β₂-GPI. The present study employed surface plasmon resonance to localize the immunodominant domain in serum samples from a large cohort of patients with GPL values ranging from 21 to 230 units (n = 106 patients). Eighty-eight percent of patients showed ≥ threefold selectivity for β₂-GPI containing domain 1 relative to the domain deletion mutant that lacked domain 1. The domain 1 binding activity in patient serum was abolished by removing the IgG fraction from the serum and the binding activity could be fully reconstituted with the IgG fraction. Thus, analysis of serum samples from a large cohort of APS patients indicates that the immunodominant binding epitope(s) for anti- ₂ antibodies are localized to the amino terminal domain of β₂-GPI.

Keywords

Anticardiolipin antibodies - antiphospholipid syndrome - β₂-glyco-protein I

Full Text

References

References
1 Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 1983; 287: 1088-9.
2 Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-4.
3 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.
4 Galli M, Comfurius P, Maassen C, Hemker HC, de Baets MH, van-BredaVriesman PJ, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a serum protein cofactor. Lancet 1990; 335: 1544-7.
5 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177-8.
6 Kato H, Enjyoji K. Amino acid sequence and location of the disulfide bonds in bovine beta 2 glycoprotein I: the presence of five sushi domains. Biochemistry 1991; 30: 11687-94.
7 Hunt J, Krilis SA. The fifth domain of beta 2-glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies. J Immunol 1994; 152: 653-9.
8 Del Papa N, Sheng YH, Raschi E, Kandiah DA, Tincani A, Khamashta MA, Atsumi T, Hughes GRV, Ichikawa K, Koike T, Balestrieri G, Krilis SA, Meroni PL. Human beta 2-glycoprotein I binds to endothelial cells through a cluster of lysine residues that are critical for anionic phospholipid binding and offers epitopes for anti-beta 2-glycoprotein I antibodies. J Immunol 1998; 160: 5572-8.
9 Igarashi M, Matsuura E, Igarashi Y, Nagae H, Ichikawa K, Triplett DA, Koike T. Human β₂-glycoprotein I as an anticardiolipin cofactor determined using deleted mutants expressed by a baculovirus system. Blood 1996; 87: 3262-70.
10 Koike T, Matsuura E. Anti-beta 2-glycoprotein I antibody: specificity and clinical significance. Lupus 1996; 5: 378-80.
11 Koike T, Ichikawa K, Kasahara H, Atsumi T, Matsuura E. Epitopes on β_2-GPI recognized by anticardiolipin antibodies. Lupus 1998; 7: S14-7.
12 Hunt JE, Simpson RJ, Krilis SA. Identification of a region of β₂-glyco-protein I critical for lipid binding and anti-cardiolipin antibody cofactor activity. Proc Natl Acad Sci USA 1993; 90: 2141-5.
13 Yang CD, Chen SL, Shen Qi M, Xu F. Detection of anti-recombinant β_2-glycoprotein 1 fifth-domain antibodies in sera from patients with systemic lupus erythematosus. Rheumatol Int 1998; 18: 5-10.
14 Wang MX, Kandiah DA, Ichikawa K, Khamashta M, Hughes G, Koike Roubey SA. Epitope specificity of monoclonal anti-beta 2-glycoprotein I antibodies derived from patients with the antiphospholipid syndrome. J Immunol 1995; 155: 1629-36.
15 Iverson GM, Victoria EJ, Marquis DM. Anti- β₂ glycoprotein I (β₂-GPI) autoantibodies recognize an epitope on the first domain of β₂-GPI. Proc Natl Acad Sci USA 1998; 95: 15542-6.
16 Iverson GM, Jones DS, Marquis D, Linnik MD, Victoria EJ. A chemically defined, toleragen-based approach for targeting anti-β₂-glycoprotein I antibodies. Lupus 1998; 7: S166-9.
17 Harris EN. Antiphospholipid antibodies. Annotation. Brit J Haematol 1990; 74: 1-9.
18 Sem DS, McNeeley PA, Linnik MD. Antibody affinities and relative titers in polyclonal populations: surface plasmon resonance analysis of anti-DNA antibodies. Arch Biochem Biophys 1999; 372: 62-8.
19 Stenberg E, Persson B, Roos H, Urbaniczky C. Quantitative determination of surface concentration of protein with surface plasmon resonance by using radiolabeled proteins. J Colloid Inter Sci 1991; 143: 513.
20 George J, Gilburd B, Hojnik M, Levy Y, Langevitz P, Matsuura E, Koike T, Shoenfeld Y. Target recognition of beta2-glycoprotein I (beta2GPI)-dependent anticardiolipin antibodies: evidence for involvement of the fourth domain of beta2GPI in antibody binding. J Immunol 1998; 160: 3917-23.
21 Bouma B, deGroot PG, vanden Elsen JMH, Ravelli RBG, Schouten A, Simmelink MJA, Derksen RHWM, Kroon J, Gros P. Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids based on its crystal structure. EMBO J 1999; 18: 5166-74.
22 Arvieux J, Roussel B, Pouzol P, Colomb MG. Platelet activating properties of murine monoclonal antibodies to beta 2-glycoprotein I. Thromb Haemos. 1993; 70: 336-41.
23 Shi W, Chong BH, Hogg PJ, Chesterman CN. Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets. Thromb Haemost 1993; 70: 342-5.
24 Vazquez-Mellado J, Llorente L, Richaud-Patin Y, Alarcon-Segovia D. Exposure of anionic phospholipids upon platelet activation permits binding of beta 2 glycoprotein I and through it that of IgG antiphospholipid antibodies. Studies in platelets from patients with antiphospholipid syndrome and normal subjects. J Autoimmun 1994; 7: 335-48.
25 Pierangeli SS, Colden-Stanfield M, Liu X, Barker JH, Anderson GL, Harris EN. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo . Circulation 1999; 15: 1997-2002.
26 Galli M, Duca F, Ruggeri L, Finazzi G, Begri B, Moia M. Congenital resistance to activated protein C in patients with lupus anticoagulants: evaluation of two functional assays. Thromb Haemost 1998; 80: 246-9.
27 Merrill JT, Zhang HW, Shen C, Butman BT, Jeffries EP, Lahita RG, Myone BL. Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its serum inhibitor, C4b-binding protein. Thromb Haemost 1999; 81: 748-57.
28 Rand JH, Wu XX, Andree HA, Ross JB, Rusinova E, Gascon-Lema MG, Calandri C, Harpel PC. Antiphospholipid antibodies accelerate serum coagulation by inhibiting annexin-V binding to phospholipids: a “lupus procoagulant” phenomenon. Blood 1998; 92: 1652-60.
29 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.
30 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.
31 Regnault V, De Maistre E, Wahl D, Lecompte T. Monovalent binding of autoantibodies to B2-glycoprotein I, detected using surface plasmon resonance at low antigen density. Brit J Haemoto. 2000; 109: 187-94.
32 Sem DS, Baker BL, Victoria EJ, Jones DS, Marquis D, Yu L, Parks J, Coutts SM. Structural characterization and optimization of antibody-selected phage library mimotopes of an antigen associated with autoimmune recurrent thrombosis. Biochemistry 1998; 37: 16069-81.
33 Blank M, Shoenfeld Y, Cabilly S, Heldman Y, Fridkin M, KatchalskiKatzir E. Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Natl Acad Sci USA 1999; 96: 5164-8.
34 Jones DS, Coutts SM, Gamino CA, Iverson GM, Linnik MD, Randow ME, Ton-Nu HT, Victoria EJ. Multivalent thioether-peptide conjugates: B cell tolerance of an anti-peptide immune response. Bioconjug Chem 1999; 10: 480-8.