The Prevalence of a Non-phospholipid-binding Form of β2-Glycoprotein I in Human Plasma

Daniëlle A. Horbach; Erica van Oort; Mariëlle J. Tempelman; Ronald H. W. M. Derksen; Philip G. de Groot

doi:10.1055/s-0037-1615360

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1998; 80(05): 791-797
DOI: 10.1055/s-0037-1615360

Review Article

Schattauer GmbH

The Prevalence of a Non-phospholipid-binding Form of β₂-Glycoprotein I in Human Plasma

Consequences for the Development of Anti-β₂-glycoprotein I Antibodies

Daniëlle A. Horbach

¹From the Departments of Haematology, The Netherlands

²From the Departments of Rheumatology and Clinical Immunology, University Hospital Utrecht, The Netherlands

³From the Departments of Institute of Biomembranes, University Utrecht, The Netherlands

,

Erica van Oort

¹From the Departments of Haematology, The Netherlands

²From the Departments of Rheumatology and Clinical Immunology, University Hospital Utrecht, The Netherlands

,

Mariëlle J. Tempelman

¹From the Departments of Haematology, The Netherlands

,

Ronald H. W. M. Derksen

²From the Departments of Rheumatology and Clinical Immunology, University Hospital Utrecht, The Netherlands

,

Philip G. de Groot

¹From the Departments of Haematology, The Netherlands

³From the Departments of Institute of Biomembranes, University Utrecht, The Netherlands

› Author Affiliations

Abstract

Summary

The presence of antiphospholipid antibodies (aPL) is strongly correlated with venous and arterial thrombosis, fetal loss and thrombocytopenia. This relation is called the antiphospholipid syndrome (APS). It is well recognized that thrombosis related aPL are not directed against phospholipids alone, but to phospholipid bound plasma proteins like β₂-glycoprotein I (β₂GPI). aPL that need β₂GPI for the binding to negatively charged phospholipids are called anti-β₂GPI-antibodies. Recently, a mutation in the gene encoding β₂GPI has been described, which results in an amino acid substitution Trp316 into Ser316. This Ser316-β₂GPI did not bind to negatively charged phospholipids. Because only phospholipid bound β₂GPI is recognized by human anti-β₂GPI-antibodies, it might be argued that individuals carrying the Trp316Ser mutation are protected against the development of anti-β₂GPI-antibodies.

To investigate this hypothesis, the prevalence of the Trp316Ser mutation was measured in 170 systemic lupus erythematosus (SLE) patients and in 18 patients with the primary antiphospholipid syndrome (PAPS) and the mutation was correlated with the presence of anti-β₂ GPI-antibodies. In the total patient group 1 homozygous patient and 21 heterozygous patients were found. The allele frequency of the mutation in SLE patients with anti-β₂GPI-antibodies (0.063) was comparable to that found in SLE patients without anti-β_2-GPI-antibodies (0.062). These results indicate that the heterozygous presence of Trp316Ser mutation does not prevent an individual from developing anti-β₂GPI-antibodies. We showed that this can be explained by the concentration of Trp316-β₂GPI in heterozygous patients, which is far above the minimal β₂GPI level necessary for optimal phospholipid binding. In our single patient homozygous for the Trp316Ser mutation no binding of β₂GPI to the phospholipid surface was detected and no anti-β₂GPI-antibodies were present in the plasma of this patient.

In conclusion, heterozygous Trp316Ser β₂GPI persons are not protected against the development of anti-β₂GPI-antibodies. To confirm that homozygotes do not develop anti-β₂GPI-antibodies a very large population is needed, due to the relatively low prevalence of the mutation.

Full Text

References

References
1 Lozier J, Takahashi N, Putnam FW. Complete amino acid sequence of human plasma β₂-glycoprotein. Proc Natl Acad Sci USA 1984; 81: 3640-4.
2 Steinkasserer A, Barlow PN, Willis AC, Kertesz Z, Campbell ID, Sim RB, Norman DG. Activity, disulphide mapping and structural modelling of the fifth domain of human β₂-glycoprotein I. FEBS Lett 1992; 313: 193-7.
3 Kato H, Enjyoji K. Amino acid sequence and location of the disulfide bonds in bovine β₂-glycoprotein I: the presence of five sushi domains. Biochemistry 1991; 30: 11687-94.
4 Schousboe I. β₂-glycoproteine I: A plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway. Blood 1985; 66: 1086-91.
5 Nimpf J, Bevers EM, Bomans PHH, Till U, Wurm H, Kostner GM, Zwaal RFA. Prothrombinase activity of human platelets is inhibited by β₂-glycoprotein-I. Biochim Biophys Acta Gen Subj 1986; 884: 142-9.
6 Matsuda J, Gohchi K, Kawasugi K, Gotoh M, Saitoh N, Tsukamoto M. Inhibitory activity of anti-β₂-glycoprotein I antibody on factor Va degradation by activated-protein C and its cofactor protein S. Am J Hematol 1995; 49: 89-91.
7 Shi W, Chong BH, Hogg PJ, Chesterman CN. Anticardiolipin antibodies block the inhibition by β₂-glycoprotein I of the factor Xa generating activity of platelets. Thromb Haemost 1993; 70: 342-5.
8 Keeling DM, Wilson AJG, Mackie IJ, Isenberg DA, Machin SJ. Role of β₂-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro. J Clin Pathol 1993; 46: 908-11.
9 Schousboe I, Rasmussen MS. Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by β₂-glycoprotein I and anti-β₂-glycoprotein I. Thromb Haemost 1995; 73: 798-804.
10 Mori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K. β₂-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface. Thromb Haemost 1996; 75: 49-55.
11 Schousboe I. Binding of β₂-glycoprotein I to platelets: effect of adenylate cyclase activity. Thromb Res 1980; 19: 225-37.
12 Nimpf J, Wurm H, Kostner GM. Interaction of β₂-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation. Thromb Haemost 1985; 54: 397-401.
13 Forastiero RR, Martinuzzo M, Carreras LO, Maclouf J. Anti-β₂-glycoprotein I antibodies and platelet activation in patients with antiphospholipid antibodies: association with increased excretion of platelet-derived thromboxane urinary metabolites. Thromb Haemost 1998; 79: 42-5.
14 Dahlback B, Nilsson IM, Frohm B. Inhibition of platelet prothrombinase activity by a lupus anticoagulant. Blood 1983; 62: 218-25.
15 Wurm H, Polz E, Holasek A, Kostner GM. Studies on the possible function of β₂-glycoprotein I: influence in the triglyceride metabolism in the rat. Metabolism 1982; 31: 484-6.
16 Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T. Involvement of β₂-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages Involvement of β₂-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol 1997; 107: 569-73.
17 Chonn A, Semple SC, Cullis PR. β₂-Glycoprotein I is a major protein associated with very rapidly cleared liposomes in vivo, suggesting a significant role in the immune clearance of “non-self” particles. J Biol Chem 1995; 270: 25845-9.
18 Balasubramanian K, Chandra J, Schroit AJ. Immune clearance of phosphatidylserine-expressing cells by phagocytes. The role of β₂-glycoprotein I in macrophage recognition. J Biol Chem 1997; 272: 31113-7.
19 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 factor. Lancet 1990; 335: 1544-7.
20 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid binding inhibitor of coagulation: β₂-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4.
21 Oosting JD, Derksen RHWM, Entjes HTI, Bouma BN, De Groot PG. Lupus anticoagulant activity is frequently dependent on the presence of β₂-glycoprotein I. Thromb Haemost 1992; 67: 499-502.
22 Roubey RAS, Pratt CW, Buyon JP, Winfield JB. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon β₂-glycoprotein I. J Clin Invest 1992; 90: 1100-4.
23 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112: 682-98.
24 Harris EN, Asherson RA, Hughes GR. Antiphospholipid antibodies-auto-antibodies with a difference. Annu Rev Med 1988; 39: 261-71.
25 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.
26 De Groot PG, Oosting JD, Derksen RHWM. Antiphospholipid antibodies: specificity and pathophysiology. Baillieres Clin Haematol 1993; 6: 691-709.
27 Roubey RAS. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibo-dies. Blood 1994; 84: 2854-67.
28 McNally T, Purdy G, Mackie IJ, Machin SJ, Isenberg DA. The use of an anti-β₂-glycoprotein-I assay for discrimination between anticardiolipin antibodies associated with infection and increased risk of thrombosis. Br J Haematol 1995; 91: 471-3.
29 Weiss L, You JF, Giral P, Alhenc-Gelas M, Senger D, Kazatchkine MD. Anti-cardiolipin antibodies are associated with anti-endothelial cell antibodies but not with anti-β₂-glycoprotein I antibodies in HIV infection. Clin Immunol Immunopathol 1995; 77: 69-74.
30 Forastiero RR, Martinuzzo ME, Kordich LC, Carreras LO. Reactivity to β₂-glycoprotein I clearly differentiates anticardiolipin antibodies from anti-phospholipid syndrome and syphilis. Thromb Haemost 1996; 75: 717-20.
31 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.
32 Hagihara Y, Goto Y, Kato H, Yoshimura T. Role of the N- and C-terminal domains of bovine β₂-glycoprotein I in its interaction with cardiolipin. J Biochem 1995; 118: 129-36.
33 Hunt J, Krilis S. The fifth domain of β₂-glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies. J Immunol 1994; 152: 653-9.
34 Sheng YH, Sali A, Herzog H, Lahnstein J, Krilis SA. Site-directed mutagenesis of recombinant human β₂-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity. J Immunol 1996; 157: 3744-51.
35 Kertesz Z, Yu B, Steinkasserer A, Haupt H, Benham A, Sim RB. Characterization of binding of human β₂-glycoprotein I to cardiolipin. Biochem J 1995; 310: 315-21.
36 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.
37 Hagihara Y, Goto Y, Kato H, Yoshimura T. Structure and function of β₂-glycoprotein I: with special reference to the interaction with phospholipid. Lupus 1995; 4 (Suppl. 01) S3-5.
38 Sanghera DK, Kristensen T, Hamman RF, Kamboh MI. Molecular basis of the apolipoprotein H (β₂-glycoprotein I) protein polymorphism. Hum Genet 1997; 100: 57-62.
39 Sanghera DK, Wagenknecht DR, McIntyre JA, Kamboh MI. Identification of structural mutations in the fifth domain of apolipoprotein H (β₂-glyco-protein I) which affect phospholipid binding. Hum Mol Genet 1997; 6: 311-6.
40 Kamboh MI, Wagenknecht DR, McIntyre JA. Heterogeneity of the apolipoprotein H*3 allele and its role in affecting the binding of apolipoprotein H (β₂-glycoprotein I) to anionic phospholipids. Hum Genet 1995; 95: 385-8.
41 Wagenknecht DR, McIntyre JA. Changes in β₂-glycoprotein I antigenicity induced by phospholipid binding. Thromb Haemost 1993; 69: 361-5.
42 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.
43 Matsuura E, Igarashi Y, Yasuda T, Triplett DA, Koike T. Anticardiolipin antibodies recognize β₂-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457-62.
44 Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7.
45 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.
46 de Kruif J, Terstappen L, Boel E, Logtenberg T. Rapid selection of cell subpopulation-specific human monoclonal antibodies from a synthetic phage antibody library. Proc Natl Acad Sci USA 1995; 92: 3938-42.
47 Marks JD, Hoogenboom HR, Bonnert TP, McCafferty J, Griffiths AD, Winter G. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J Mol Biol 1991; 222: 581-97.
48 Brunner J, Skrabal P, Hauser H. Single bilayer vesicles prepared without sonication. Physio-chemical properties. Biochim Biophys Acta 1976; 455: 322-31.
49 Van Wijnen M, Stam JG, Van’t Veer C, Meijers JCM, Reitsma PH, Bertina RM, Bouma BN. The interaction of protein S with the phospholipid surface is essential for the activated protein C-independent activity of protein S. Thromb Haemost 1996; 76: 397-403.
50 Rouser G, Fkeischer S, Yamamoto A. Two dimensional thin layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids 1970; 5: 494-6.
51 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA. 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.
52 Willems GM, Janssen MP, Pelsers MAL, Comfurius P, Galli M, Zwaal RFA, Bevers EM. Role of divalency in the high-affinity binding of anti-cardiolipin antibody-β₂-glycoprotein I complexes to lipid membranes. Biochemistry 1996; 35: 13833-42.