Seminars in Arthritis and Rheumatism
Volume 26, Issue 5 , Pages 724-739 , April 1997

Antiphospholipid antibodies: Basic immunology and assays

    PhD
  • Duane R. Schultz (Professor of Medicine)

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Duane R. Schultz, Department of Medicine, Division of Allergy & Immunology (R-102), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101.

References 

  1. (chap 12) Stryer L. Introduction to biological membranes. In: Biochemistry. 3rd ed.. New York: WH Freeman & Company; 1988;p. 283–312
  2. Kataoka T, Nojima S. Immunochemical studies of phospholipids. VI. Haptenic activity of phosphatidylinositol and the role of lecithin as an auxiliary lipid. J Immunol. 1970;105:502–511
  3. Tamamura S, Hashimoto T, Hara I. The immunological relations between acid phospholipids and their antibodies. Jpn J Exp Med. 1971;41:31–38
  4. Harris EN, Gharavi AE, Tincani A, et al. Affinity purified anti-cardiolipin and anti-DNA antibodies. J Clin Lab Immunol. 1985;17:155–162
  5. Harris EN, Gharavi AE, Loizou S, et al. Cross reactivity of antiphospholipid antibodies. J Clin Lab Immunol. 1985;16:1–6
  6. Harris EN, Gharavi AE, Hughes GRV. Anti-phospholipid antibodies. Clin Rheum Dis. 1985;11:591–609
  7. Gharavi AE, Harris EN, Asherson RA, et al. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis. 1987;46:1–6
  8. Vlachoyiannopoulos PG, Beigbeder G, Dueymes M, et al. Antibodies to phosphatidylethanolamine in antiphospholipid syndrome and systemic lupus erythematosus: their correlation with anticardiolipin antibodies and β2-glycoprotein I plasma levels. Autoimmunity. 1993;16:245–249
  9. Cabral AR, Cabiedes J, Alarcon-Segovia D. Haemolytic anemia related to an IgM autoantibody to phosphatidylcholine that binds in vitro to stored and to bromelin-treated human erythrocytes. J Autoimmunol. 1990;3:773–787
  10. Triplett DA. New diagnostic strategies for lupus anticoagulants and antiphospholipid antibodies. Haemostasis. 1994;24:155–164
  11. Wassermann A, Neisser A, Bruck C. Eine serodiagnostische reaktion bei syphilis. Dtsch Med Wochenschr. 1906;32:745–746
  12. Pangborn MC. A simplified preparation of cardiolipin, with a note on purification of lecithin for serologic use. J Biol Chem. 1945;161:71–82
  13. Kahn RL, McDermott EB. Universal serologic reaction with lipid antigen. III. In syphilis. Am J Clin Pathol. 1949;19:401–407
  14. Fiumara NJ. Biologic false positive reaction for syphilis. N Engl J Med. 1963;268:402–405
  15. McNeil HP, Chesterman CN, Krills SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol. 1991;49:193–259
  16. Moore JE, Mohr CF. Biologically false positive serologic tests for syphilis. JAMA. 1952;150:467–473
  17. Moore JE, Lutz WB. The natural history of systemic lupus erythematosus: an approach to its study through chronic biologic false positive reactors. J Chronic Dis. 1955;1:297–316
  18. Haserick JR, Long R. Systemic lupus erythematosus preceded by false positive test for syphilis: presentation of five cases. Ann Intern Med. 1951;37:559–565
  19. Harvey AM, Shulman LE. Connective tissue disease and the chronic biologic false positive test for syphilis. Med Clin North Am. 1966;50:1271–1279
  20. McNeil HP, Simpson RJ, Chesterman CN, et al. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H). In: Proc Natl Acad Sci USA. 87:1990;p. 4120–4124
  21. Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990;335:1544–1547
  22. Matsuura E, Igarashi Y, Fujimoto M, et al. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet. 1990;336:177–178
  23. Matsuura E, Igarashi Y, Fujimoto M, et al. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol. 1992;148:3885–3891
  24. Hunt JE, McNeil HP, Morgan GJ, et al. A phospholipid β2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection. Lupus. 1992;1:75–81
  25. In: Asherson RA, Cervera R, Piette J-C, Shoenfeld Y editor. The Antiphospholipid Syndrome. Boca Raton, FL: CRC Press; 1996;p. 3–12In: Asherson RA, Cervera R, Piette J-C, Shoenfeld Y editor. The Antiphospholipid Syndrome. Boca Raton, FL: CRC Press; 1996;p. 29–48(Chapt 3)
  26. Hughes GRV, Khamashta MA. The antiphospholipid syndrome. J R Coll Phys Lond. 1994;28:301–304
  27. Gharavi AE, Aron AL. Experimental models for antiphospholipid studies. Haemostasis. 1994;24:204–207
  28. Norden DK, Ostrov BE, Shafritz AB, et al. Vasculitis associated with antiphospholipid syndrome. Semin Arthritis Rheum. 1995;24:273–281
  29. Cervera R, Asherson RA, Lie JT. Clincopathologic correlations of the antiphospholipid syndrome. Semin Arthritis Rheum. 1995;24:262–272
  30. Aron AL, Gharavi AE, Shoenfeld Y. Mechanisms of action of antiphospholipid antibodies in the antiphospholipid syndrome. Int Arch Allergy Immunol. 1995;106:8–12
  31. Belmont HM, Abramson SB, Lie JT. Pathology and pathogenesis of vascular injury in systemic lupus erythematosus: interactions of inflammatory cells and activated endothelium. Arthritis Rheum. 1996;39:9–22
  32. Schultze HE, Heide K, Haupt H. Über ein bisher unbekanntes niedermoleculares β2-globulin des Human Serums. Naturwissenschaften. 1961;48:719
  33. Steinkasserer A, Estaller C, Weiss EH, et al. Complete nucleotide and deduced amino acid sequence of human β2-glycoprotein I. Biochem J. 1991;277:387–391
  34. Gries A, Nimpf J, Wurm H, et al. Characterization of isoelectric subspecies of asialo-β2-glycoprotein I. Biochem J. 1989;260:531–554
  35. Lozier J, Takahashi N, Putnam FW. Complete amino acid sequence of human plasma β2-glycoprotein I. In: Proc Natl Acad Sci USA. 81:1984;p. 3640–3644
  36. Reid KBM, Day AJ. Structure-function relationships of the complement components. Immunol Today. 1989;10:177–180
  37. Schousboe I. Binding of β2-glycoprotein I to platelets: effect of adenylate cyclase activity. Thromb Res. 1980;19:225–237
  38. Schousboe I. Purification, characterization and identification of an agglutinin in human serum. Biochim Biophys Acta. 1979;579:396–408
  39. Wurm H. β2-glycoprotein I (apolipoprotein H) interactions with phospholipid vesicles. Int J Biochem. 1984;16:511–515
  40. Krøll J, Larsen JK, Loft H, et al. DNA-binding proteins in Yoshida ascites tumor fluid. Biochem Biophys Acta. 1976;434:490–501
  41. Polz E, Wurm H, Kostner GM. Investigations on β2-glycoprotein I in the rat: isolation from serum and demonstration in lipoprotein density fractions. Int J Biochem. 1980;11:265–270
  42. Polz E, Kostner GM. The binding of β2-glycoprotein I to human serum lipoproteins: distribution among density fractions. FEBS Lett. 1979;102:183–186
  43. Schousboe I. β2-glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway. Blood. 1985;66:1086–1091
  44. Nimpf J, Bevers EM, Bomans PHH, et al. Prothrombinase activity of human platelets is inhibited by β2-glycoprotein I. Biochim Biophys Acta. 1986;884:142–149
  45. Nimpf J, Wurm H, Kostner GM. β2-glycoprotein I (apo-H) inhibits the release reaction of human. platelets during ADP-induced aggregation. Atherosclerosis. 1987;63:109–114
  46. Gharavi AE, Sammaritano LR, Wen J, et al. Induction of antiphospholipid autoantibodies by immunization with β2-glycoprotein I (apolipoprotem H). J Clin Invest. 1992;90:1105–1109
  47. Kouts S, Wang M-X, Adelstein S, et al. Immunization of a rabbit with β2-glycoprotein I induces charge-dependent crossreactive antibodies that bind anionic phospholipids and have similar reactivity as autoimmune anti-phospholipid antibodies. J Immunol. 1995;155:958–966
  48. Pierangeli SS, Harris EN. Induction of phospholipid-binding antibodies in mice and rabbits by immunization with human β2-glycoprotein I or anti-cardiolipin antibodies alone. Clin Exp Immunol. 1993;93:269–272
  49. Martinuzzo ME, Forastiero RR, Carreras LO. Anti-β2-glycoprotein I antibodies: detection and association with thrombosis. Br J Haematol. 1995;89:397–402
  50. Steinkasserer A, Barlow PN, Willis AC, et al. Activity, disulphide mapping and structural modelling of the fifth domain of human β2-glycoprotein I. FEBS Lett. 1992;313:193–197
  51. Hunt JE, Simpson RJ, Krills SA. Identification of a region of β2-glycoprotein I critical for lipid binding and anti-cardiolipin antibody cofactor activity. In: Proc Natl Acad Sci USA. 90:1993;p. 2141–2145
  52. 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;152:653–659
  53. Wang MX, Kandiah DA, Ichikawa K, et al. Epitope specificity of monoclonal anti-β2-glycoprotein I antibodies derived from patients with the anti-phospholipid syndrome. J Immunol. 1995;155:1629–1636
  54. Arvieux J, Roussel B, Jacob MC, et al. Measurement of anti-phospholipid antibodies by ELISA using β2-glycoprotein I as an antigen. J Immunol Methods. 1991;143:223–229
  55. Viard J-P, Amoura Z, Bach J-F. Association of anti-β2-glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Am J Med. 1992;93:181–186
  56. Keeling DM, Wilson AJ, Mackie IJ, et al. Some antiphospholipid antibodies bind to beta 2-glycoprotein I in the absence of phospholipid. Br J Haematol. 1992;82:571–574
  57. Matsuura E, Igarashi Y, Yasuda T, et al. Anticardiolipin antibodies recognize β2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med. 1994;179:457–462
  58. Onyiriuka EC, Hersh IS, Herti W. Surface modification of polystyrene by γ-irradiation. Appl Spectrosc. 1990;44:808–814
  59. Roubey RAS, Eisenberg RA, Harper MF, et al. Anticardiolipin autoantibodies recognize β2-glycoprotein I in the absence of phospholipid. J Immunol. 1995;154:954–960
  60. Wagenknecht DR, McIntyre JA. Changes in β2-glycoprotein I antigenicity induced by phospholipid binding. Thromb Haemostasis. 1993;69:361–365
  61. Gao B, Esnouf MP. Multiple interactive residues of recognition: elucidation of discontinuous epitopes with linear peptides. J Immunol. 1996;157:183–188
  62. Monestier M, Kandiah DA, Kouts S, et al. Monoclonal antibodies from NZW X BXSB F1 mice to β2-glycoprotein I and cardiolipin: species specificity and charge-dependent binding. J Immunol. 1996;156:2631–2641
  63. Hang LM, Izui S, Dixon FJ. (NZW X BXSB) Fl hybrid: a model of acute lupus and coronary disease with myocardial infarction. J Exp Med. 1996;154:216–221
  64. Hashimoto Y, Kawamura M, Ichikawa K, et al. Anticardiolipin antibodies in NZW X BXSB Fl mice: a model of anti-phospholipid syndrome. J Immunol. 1992;149:1063–1068
  65. Feinstein DI, Rapaport SI. Acquired inhibitors of blood coagulation. Prog Hemostas Thromb. 1972;1:75–95
  66. Conley CL, Hartmann RC. A hemorrhagic disorder caused by circulating anticoagulant in patients with disseminated lupus erythematosus. J Lab Clin Invest. 1952;13:621–622
  67. Laurell AB, Nilsson IM. Hypergammaglobulinemia, circulating anticoagulant, and biological false positive Wassermann reaction: a study of two cases. J Lab Clin Med. 1957;49:694–707
  68. Exner T, Triplett D. Lupus anticoagulants: characteristics, methods of laboratory detection and some clinical associations. In: Harris EN, Exner T, Hughes GRV, Asherson RA editor. Phospholipid binding antibodies. Boca Ratan, FL: CRC; 1991;p. 141–158
  69. Thiagarajan P, Shapiro SS, DeMarco L. Monoclonal immunoglobulin Mλ coagulation inhibitor with phospholipid specificity: mechanism of a lupus anticoagulant. J Clin Invest. 1980;66:397–405
  70. Galli M, Beguin S, Lindhout T, et al. Inhibition of phospholipid and platelet-dependent prothrombinase activity in the plasma of patients with lupus anticoagulants. Br J Haematol. 1989;72:549–555
  71. Yin ET, Gaston LW. Purification and kinetic studies of a circulating anticoagulant in a suspected case of lupus erythematosus. Thromb Haemorrh. 1985;14:88–115
  72. Pengo V, Thiagarajan P, Shapiro SS, et al. Immunological specificity and mechanism of action of IgG lupus anticoagulants. Blood. 1996;70:69–76
  73. Roubey RAS, Pratt CW, Buyon JP, et al. Lupus anticoagulant activity of autoimmune antiphospholipid antibodies is dependent upon β2-glycoprotein I. J Clin Invest. 1992;90:1100–1104
  74. Exner T, Sahman N, Trudinger B. Separation of anticardiolipin antibodies from lupus anticoagulant on a phospholipid-coated polystyrene column. Biochem Biophys Res Commun. 1988;155:1001–1007
  75. McNeil HP, Chesterman CN, Krilis SA. Anticardiolipin antibodies and lupus anticoagulants comprise antibody subgroups with different phospholipid binding characteristics. Br J Haematol. 1989;73:506–513
  76. Oosting JD, Derksen RHWM, Entjies HTI, et al. Lupus anticoagulant activity is frequently dependent on the presence of β2-glycoprotein I. Thromb Haemost. 1992;67:499–502
  77. Galli M, Comfurius P, Barbui T, et al. Anticoagulant activity of β2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies. Thromb Haemost. 1992;68:297–300
  78. Ozawa N, Makino T, Matsubayashi H, et al. β2-glycoprotein I-dependent and independent binding of anticardiolipin antibodies in patients with recurrent spontaneous abortions. J Clin Lab Anal. 1994;8:255–259
  79. Frick PG. Acquired circulating anticoagulants in systemic collagen disease autoimmune thromboplastin deficiency. Blood. 1955;10:691–706
  80. Loeliger A. Prothrombin as co-factor in the circulating anticoagulant in systemic lupus erythematosus?. Thromb Diath Haemorrh. 1959;3:237–256
  81. Bajaj SP, Rapaport SI, Fierer DS, et al. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombineia-lupus anticoagulant syndrome. Blood. 1983;61:684–692
  82. Bajaj SP, Rapaport SI, Barclay S, et al. Acquired hypoprothrombinernia due to nonneutralizing antibodies to prothrombin: mechanism and management. Blood. 1985;65:1538–1543
  83. Edson JR, Vogt JM, Hasegawa DK. Abnormal prothrombin crossed-immunoelectrophoresis in patients with lupus inhibitors. Blood. 1984;64:807–816
  84. Fleck RA, Rapaport SI, Rao LV. Antiprothrombin antibodies and the lupus anticoagulant. Blood. 1988;72:512–519
  85. Bevers EM, Galli M, Barbui T, et al. Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost. 1991;66:629–632
  86. Chap 2 Ichinose A, Davie EW. The blood coagulation factors: their cDNAs, genes, and expression. In: Colman RW, Hirsh J, Marder VJ, Salzman EW editor. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia: Lippincott; 1994;p. 19–54
  87. Chap 13 Broze GJ, Miletich JP. Biochemistry and physiology of protein C, protein S, and thrombomodulin. In: Colman RW, Hirsh J, Marder VJ, et al. editor. Hemostasis and thrombosis: basic principles and clinical practice. ed 3. Philadelphia: Lippincott; 1994;p. 259–276
  88. Oosting JD, Derksen RHWM, Bobbink IWG, et al. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for theirpathogenic mechanism?. Blood. 1993;81:2618–2625
  89. [abstract] Comp PC, DeBault LE, Esmon NL, et al. Human thrombomodulin is inhibited by IgG from two patients with nonspecific anticoagulants. Blood. 1983;62:299a
  90. Freyssinet JM, Cazenave JP. Lupus-like anticoagulants, modulation of the protein C pathway and thrombosis. Thromb Haemost. 1987;58:679–681
  91. Cariou R, Tobelum G, Bellucci S, et al. Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells: inhibition of thrombomodulin-dependent protein C activation. Thromb Haemost. 1988;60:54–58
  92. Marcimak K, Romond E. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood. 1989;74:2426–2432
  93. Malia RG, Kitchen S, Greaves M, et al. Inhibition of activated protein C and its cofactor protein S by antiphospholipid antibodies. Br J Haematol. 1990;76:101–107
  94. de Groot PG, Oosting JD, Derksen RHWM. Antiphospholipid antibodies: specificity and pathophysiology. Baillieres Clin Haematol. 1993;6:691–709
  95. Schorer AE, Duane PG, Woods VL, et al. Some antiphospholipid antibodies inhibit phospholipase A2 activity. J Lab Clin Med. 1992;120:67–77
  96. Reges H, Dearing L, Shoenfeld Y, et al. Antiphospholipid antibodies: a critique of their heterogeneity and hegemony. Semin Thromb Hemost. 1994;20:89–100
  97. Mackworth-Young CG. Antiphospholipid antibodies and disease. Br J Rheumatol. 1995;34:1009–1030
  98. Gharavi AE, Harris EN, Lockshin MD, et al. IgG subclass and light chain distribution of anticardiolipin and anti-DNA antibodies in systemic lupus erythematosus. Ann Rheum Dis. 1988;47:286–290
  99. Tsutsumi A, Koike T, Ichikawa K, et al. IgG subclass distribution of anticardiolipin antibody in patients with systemic lupus erythematosus. J Rheumatol. 1988;15:1764–1767
  100. Tiikkainen U, Wangel A, Appleton SL, et al. Subclasses of IgG anticardiolipin antibodies in patients with systemic lupus erythematosus. Scand J Immunol. 1991;34:265–271
  101. Vermylen J, Arnout J. Is the antiphospholipid syndrome caused by antibodies directed against physiologically relevant phospholipid-protein complexex?. J Lab Clin Med. 1992;120:10–12
  102. Janoff AS, Rauch J. The structural specificity of antiphospholipid antibodies in autoimmune disease. Chem Phys Lipids. 1986;40:315–332
  103. Nelson RA, Mayer MM. Immobilization of Treponema pallidum in vitro by antibody produced in syphilis infection. J Exp Med. 1949;89:369–393
  104. Lee SL, Sanders M. A disorder of blood coagulation in systemic lupus erythematosus. J Clin Invest. 1955;34:1814–1822
  105. Lechner K. Acquired inhibitors in nonhemophilic patients. Haemostasis. 1974;3:65–93
  106. Lee SL, Miotti AB. Disorders of hemostatic function in patients with systemic lupus erythematosus. Semin Arthritis Rheum. 1975;4:241–252
  107. Schleider MA, Nachman RL, Jaffe EA, et al. A clinical study of the lupus anticoagulant. Blood. 1976;48:499–509
  108. Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983;2:1211–1214
  109. Colaco CB, Male DK. Antiphospholipid antibodies in syphilis and a thrombotic subset of SLE: distinct profiles of epitope specificity. Clin Exp Immunol. 1985;59:449–456
  110. Koike T, Sueishi M, Funaki H, et al. Antiphospholipid antibodies and biological false positive serological test for syphilis in patients with systemic lupus erythematosus. Clin Exp Immunol. 1984;56:193–199
  111. Harris EN, Gharavi AE, Wasley GD, et al. Use of an enzyme-linked immunosorbent assay and of inhibition studies to distinguish between antibodies to cardiolipin from patients with syphilis or autoimmune disorders. J Infect Dis. 1988;157:23–31
  112. Asherson RA, Khamashta MA, Ordi-Ros J, et al. The primary antiphospholipid syndrome: major clinical and serological features. Medicine. 1989;68:366–374
  113. Strandberg Pedersen N, Orum O, Mouritsen S. Enzyme linked immunosorbent assay for detection of antibodies to the veneral disease research laboratory (VDRL) antigen in syphilis. J Clin Microbiol. 1987;25:1711–1716
  114. Harris EN. Serological detection of antiphospholipid antibodies. Stroke. 1992;23:I
  115. Loizou S, McCrea JD, Rudge AC. Measurement of anti-cardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol. 1985;62:738–745
  116. Stewart MW, Etches WS, Russel AS, et al. Detection of antiphospholipid antibodies by flow cytometry: rapid detection of antibody isotype and phospholipid specificity. Thromb Haemost. 1993;70:603–607
  117. Eschwege V, Laude I, Toti F, et al. Detection of bilayer phospholipid-binding antibodies using flow cytometry. Clin Exp Immunol. 1996;103:171–175
  118. Bick RL, Baker WE. Anticardioiipin antibodies and thrombosis. Hematol Oncol Clin North Am. 1992;6:1287–1299
  119. Jouhikainen T, Julkunen H, Vaarala O, et al. Antiphospholipid antibodies and thrombosis in systemic lupus erythematosus: Comparison of three lupus anticoagulant assays and anticardiolipin ELISA in 188 patients. Blood Coagul Fibrinolysis. 1992;3:407–414
  120. Lockshin MD. Antiphospholipid antibody syndrome. JAMA. 1992;268:1451–1453
  121. Triplett DA. Coagulation assays for the lupus anticoagulant: review and critique of current methodology. Stroke. 1992;23(Suppl 1):I
  122. Rauch J, Tannenbaum M, Janoff AS. Distinguishing plasma lupus anticoagulants from anti-factor antibodies using hexagonal (II) phase phospholipids. Thromb Haemost. 1989;62:892–896

PII: S0049-0172(97)80041-8

Seminars in Arthritis and Rheumatism
Volume 26, Issue 5 , Pages 724-739 , April 1997