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. 1992 Sep;90(3):1105–1109. doi: 10.1172/JCI115927

Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H).

A E Gharavi 1, L R Sammaritano 1, J Wen 1, K B Elkon 1
PMCID: PMC329971  PMID: 1522219

Abstract

A subset of patients with systemic lupus erythematosus has autoantibodies to acidic phospholipids. Since lipids are poor immunogens, the mechanism responsible for the induction of these antibodies is unclear. Immunization of a normal rabbit and normal mice with purified human beta 2-glycoprotein I (apolipoprotein H) resulted in the production of high levels of two non-cross-reactive antibody populations, anti-apolipoprotein H, and antiphospholipid. The antiphospholipid antibodies had binding specificities indistinguishable from autoantibodies obtained from human and murine lupus. These findings suggest a novel mechanism for the induction of antiphospholipid autoantibodies.

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Selected References

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  1. Aho K., Rostedt I., Saris N. E. Reactivity of various anticardiolipin antibodies with intact mitochondria. Clin Exp Immunol. 1973 Aug;14(4):573–579. [PMC free article] [PubMed] [Google Scholar]
  2. Allison A. C., Denman A. M., Barnes R. D. Cooperating and controlling functions of thymus-derived lymphocytes in relation to autoimmunity. Lancet. 1971 Jul 17;2(7716):135–140. doi: 10.1016/s0140-6736(71)92306-3. [DOI] [PubMed] [Google Scholar]
  3. Alving C. R. Antibodies to liposomes, phospholipids and phosphate esters. Chem Phys Lipids. 1986 Jun-Jul;40(2-4):303–314. doi: 10.1016/0009-3084(86)90075-7. [DOI] [PubMed] [Google Scholar]
  4. Banerji B., Lyon J. A., Alving C. R. Membrane lipid composition modulates the binding specificity of a monoclonal antibody against liposomes. Biochim Biophys Acta. 1982 Jul 28;689(2):319–326. doi: 10.1016/0005-2736(82)90265-6. [DOI] [PubMed] [Google Scholar]
  5. Boey M. L., Colaco C. B., Gharavi A. E., Elkon K. B., Loizou S., Hughes G. R. Thrombosis in systemic lupus erythematosus: striking association with the presence of circulating lupus anticoagulant. Br Med J (Clin Res Ed) 1983 Oct 8;287(6398):1021–1023. doi: 10.1136/bmj.287.6398.1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Canoso R. T., Zon L. I., Groopman J. E. Anticardiolipin antibodies associated with HTLV-III infection. Br J Haematol. 1987 Apr;65(4):495–498. doi: 10.1111/j.1365-2141.1987.tb04157.x. [DOI] [PubMed] [Google Scholar]
  7. Galli M., Comfurius P., Maassen C., Hemker H. C., de Baets M. H., van Breda-Vriesman P. J., Barbui T., Zwaal R. F., Bevers E. M. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990 Jun 30;335(8705):1544–1547. doi: 10.1016/0140-6736(90)91374-j. [DOI] [PubMed] [Google Scholar]
  8. Gharavi A. E., Harris E. N., Asherson R. A., Hughes G. R. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis. 1987 Jan;46(1):1–6. doi: 10.1136/ard.46.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gharavi A. E., Mellors R. C., Elkon K. B. IgG anti-cardiolipin antibodies in murine lupus. Clin Exp Immunol. 1989 Nov;78(2):233–238. [PMC free article] [PubMed] [Google Scholar]
  10. Harris E. N., Gharavi A. E., Boey M. L., Patel B. M., Mackworth-Young C. G., Loizou S., Hughes G. R. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983 Nov 26;2(8361):1211–1214. doi: 10.1016/s0140-6736(83)91267-9. [DOI] [PubMed] [Google Scholar]
  11. Harris E. N., Gharavi A. E., Hughes G. R. Anti-phospholipid antibodies. Clin Rheum Dis. 1985 Dec;11(3):591–609. [PubMed] [Google Scholar]
  12. Harris E. N., Gharavi A. E., Loizou S., Derue G., Chan J. K., Patel B. M., Mackworth-Young C. G., Bunn C. C., Hughes G. R. Crossreactivity of antiphospholipid antibodies. J Clin Lab Immunol. 1985 Jan;16(1):1–6. [PubMed] [Google Scholar]
  13. Harvey A. M., Shulman L. E. Connective tissue disease and the chronic biologic false-positive test for syphilis (BFP reaction). Med Clin North Am. 1966 Sep;50(5):1271–1279. [PubMed] [Google Scholar]
  14. Hines J. J., Weissbach H., Brot N., Elkon K. Anti-P autoantibody production requires P1/P2 as immunogens but is not driven by exogenous self-antigen in MRL mice. J Immunol. 1991 May 15;146(10):3386–3395. [PubMed] [Google Scholar]
  15. Igarashi K., Umeda M., Tokita S., Nam K. S., Inoue K. Effective induction of anti-phospholipid and anticoagulant antibodies in normal mouse. Thromb Res. 1991 Jan 15;61(2):135–148. doi: 10.1016/0049-3848(91)90240-w. [DOI] [PubMed] [Google Scholar]
  16. Inoue K., Nojima S. Immunochemical studies of phospholipids. 3. Production of antibody to cardiolipin. Biochim Biophys Acta. 1967 Oct 2;144(2):409–414. [PubMed] [Google Scholar]
  17. Levy R. A., Gharavi A. E., Sammaritano L. R., Habina L., Qamar T., Lockshin M. D. Characteristics of IgG antiphospholipid antibodies in patients with systemic lupus erythematosus and syphilis. J Rheumatol. 1990 Aug;17(8):1036–1041. [PubMed] [Google Scholar]
  18. MOORE J. E., MOHR C. F. Biologically false positive serologic tests for syphilis; type, incidence, and cause. J Am Med Assoc. 1952 Oct 4;150(5):467–473. doi: 10.1001/jama.1952.03680050033010. [DOI] [PubMed] [Google Scholar]
  19. Madaio M. P., Hodder S., Schwartz R. S., Stollar B. D. Responsiveness of autoimmune and normal mice to nucleic acid antigens. J Immunol. 1984 Feb;132(2):872–876. [PubMed] [Google Scholar]
  20. Marcus D. M., Schwarting G. A. Immunochemical properties of glycolipids and phospholipids. Adv Immunol. 1976;23:203–240. [PubMed] [Google Scholar]
  21. McNeil H. P., Simpson R. J., Chesterman C. N., Krilis S. A. 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 U S A. 1990 Jun;87(11):4120–4124. doi: 10.1073/pnas.87.11.4120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Muckerheide A., Apple R. J., Pesce A. J., Michael J. G. Cationization of protein antigens. I. Alteration of immunogenic properties. J Immunol. 1987 Feb 1;138(3):833–837. [PubMed] [Google Scholar]
  23. Mueh J. R., Herbst K. D., Rapaport S. I. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med. 1980 Feb;92(2 Pt 1):156–159. doi: 10.7326/0003-4819-92-2-156. [DOI] [PubMed] [Google Scholar]
  24. Nimpf J., Bevers E. M., Bomans P. H., Till U., Wurm H., Kostner G. M., Zwaal R. F. Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I. Biochim Biophys Acta. 1986 Oct 29;884(1):142–149. doi: 10.1016/0304-4165(86)90237-0. [DOI] [PubMed] [Google Scholar]
  25. Pengo V., Thiagarajan P., Shapiro S. S., Heine M. J. Immunological specificity and mechanism of action of IgG lupus anticoagulants. Blood. 1987 Jul;70(1):69–76. [PubMed] [Google Scholar]
  26. Plotz P. H. Autoantibodies are anti-idiotype antibodies to antiviral antibodies. Lancet. 1983 Oct 8;2(8354):824–826. doi: 10.1016/s0140-6736(83)90740-7. [DOI] [PubMed] [Google Scholar]
  27. Polz E., Wurm H., Kostner G. M. Investigations on beta 2-glycoprotein-I in the rat: isolation from serum and demonstration in lipoprotein density fractions. Int J Biochem. 1980;11(3-4):265–270. doi: 10.1016/0020-711x(80)90229-3. [DOI] [PubMed] [Google Scholar]
  28. Rauch J., Janoff A. S. Phospholipid in the hexagonal II phase is immunogenic: evidence for immunorecognition of nonbilayer lipid phases in vivo. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4112–4114. doi: 10.1073/pnas.87.11.4112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rauch J., Tannenbaum H., Stollar B. D., Schwartz R. S. Monoclonal anti-cardiolipin antibodies bind to DNA. Eur J Immunol. 1984 Jun;14(6):529–534. doi: 10.1002/eji.1830140609. [DOI] [PubMed] [Google Scholar]
  30. Sammaritano L. R., Gharavi A. E., Lockshin M. D. Antiphospholipid antibody syndrome: immunologic and clinical aspects. Semin Arthritis Rheum. 1990 Oct;20(2):81–96. doi: 10.1016/0049-0172(90)90021-7. [DOI] [PubMed] [Google Scholar]
  31. Schleider M. A., Nachman R. L., Jaffe E. A., Coleman M. A clinical study of the lupus anticoagulant. Blood. 1976 Oct;48(4):499–509. [PubMed] [Google Scholar]
  32. Schousboe I. beta 2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway. Blood. 1985 Nov;66(5):1086–1091. [PubMed] [Google Scholar]
  33. Schuster B. G., Neidig M., Alving B. M., Alving C. R. Production of antibodies against phosphocholine, phosphatidylcholine, sphingomyelin, and lipid A by injection of liposomes containing lipid A. J Immunol. 1979 Mar;122(3):900–905. [PubMed] [Google Scholar]
  34. Sege K., Peterson P. A. Use of anti-idiotypic antibodies as cell-surface receptor probes. Proc Natl Acad Sci U S A. 1978 May;75(5):2443–2447. doi: 10.1073/pnas.75.5.2443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Stollar B. D. The antigenic potential and specificity of nucleic acids, nucleoproteins, and their modified derivatives. Arthritis Rheum. 1981 Aug;24(8):1010–1018. doi: 10.1002/art.1780240806. [DOI] [PubMed] [Google Scholar]
  36. WEIGLE W. O. THE INDUCTION OF AUTOIMMUNITY IN RABBITS FOLLOWING INJECTION OF HETEROLOGOUS OR ALTERED HOMOLOGOUS THYROGLOBULIN. J Exp Med. 1965 Feb 1;121:289–308. doi: 10.1084/jem.121.2.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. WITEBSKY E., ROSE N. R. Studies on organ specificity. IV. Production of rabbit thyroid antibodies in the rabbit. J Immunol. 1956 Jun;76(6):408–416. [PubMed] [Google Scholar]
  38. Wassermann N. H., Penn A. S., Freimuth P. I., Treptow N., Wentzel S., Cleveland W. L., Erlanger B. F. Anti-idiotypic route to anti-acetylcholine receptor antibodies and experimental myasthenia gravis. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4810–4814. doi: 10.1073/pnas.79.15.4810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Weigle W. O. The production of thyroiditis and antibody following injection of unaltered thyroglobulin without adjuvant into rabbits previously stimulated with altered thyroglobulin. J Exp Med. 1965 Dec 1;122(6):1049–1062. doi: 10.1084/jem.122.6.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wurm H. beta 2-Glycoprotein-I (apolipoprotein H) interactions with phospholipid vesicles. Int J Biochem. 1984;16(5):511–515. doi: 10.1016/0020-711x(84)90168-x. [DOI] [PubMed] [Google Scholar]

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