What is the Origin of Antiphospholipid Antibodies?

  • Rohan Willis
  • Yehuda Shoenfeld
  • Silvia S. Pierangeli
  • Miri Blank


Antiphospholipid antibodies (aPLs) are associated with the recurrent pregnancy loss and thrombosis that characterizes the antiphospholipid antibody syndrome. Although the ontogeny of these pathogenic antibodies has not been fully elucidated, there is evidence that indicates the involvement of both genetic and environmental factors. The evidence for the influence of HLA- and non-HLA-associated genes on the development of aPL and on the expression of disease has been garnered from animal genetic studies and human family and population studies. Several in vitro and in vivo animal studies have demonstrated the important role played by several environmental factors, in particular infectious agents, in the production of pathogenic aPL. Infectious agents can potentially induce autoimmune responses by molecular mimicry, selectively activating or destroying unique lymphocyte subsets, directing cytokine/chemokine release, or exposing cryptic autoantigens during cell necrosis and/or apoptosis. This chapter reviews the most up-to-date scientific evidence relating to the contributions of genetic and environmental factors to the development of pathogenic aPL.


Factor Versus Leiden Factor Versus Leiden Mutation Human Leukocyte Antigen Association Factor Versus Leiden Factor Versus Leiden G1691A 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



S.P. and M.B. are funded by a grant from the US-Israeli Binnational Reseach Foundation # 2009099; S.P. and R.W. are funded by a grant from the National Institutes of Health (NIH) # 1R01AR056745.


  1. 1.
    Harris EN. Syndrome of the black swan. Br J Rheumatol. 1987;26:324–6.PubMedGoogle Scholar
  2. 2.
    Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42:1309–11.PubMedGoogle Scholar
  3. 3.
    Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.PubMedGoogle Scholar
  4. 4.
    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 U S A. 1990;87:4120–4.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet. 1990;335:1544–7.PubMedGoogle Scholar
  6. 6.
    Amengual O, Atsumi T, Koike T. Antiprothombin antibodies and the diagnosis of antiphospholipid syndrome. Clin Immunol. 2004;112:144–9.PubMedGoogle Scholar
  7. 7.
    Permpikul P, Rao LV, Rapaport SI. Functional and binding studies of the roles of prothrombin and beta 2-glycoprotein I in the expression of lupus anticoagulant activity. Blood. 1994;83:2878–92.PubMedGoogle Scholar
  8. 8.
    Rand JH, Wu XX, Quinn AS, et al. Hydroxychloroquine protects the annexin A5 anticoagulant shield from disruption by antiphospholipid antibodies: evidence for a novel effect for an old antimalarial drug. Blood. 2010;115:2292–9.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Gharavi EE, Chaimovich H, Cucurull E, et al. Induction of antiphospholipid antibodies by immunization with synthetic viral and bacterial peptides. Lupus. 1999;8:449–55.PubMedGoogle Scholar
  10. 10.
    Cesarman-Maus G, Rios-Luna NP, Deora AB, et al. Autoantibodies against the fibrinolytic receptor, annexin 2, in antiphospholipid syndrome. Blood. 2006;107:4375–82.PubMedCentralPubMedGoogle Scholar
  11. 11.
    Rand JH, Wu XX, Quinn AS, Taatjes DJ. Resistance to annexin A5 anticoagulant activity: a thrombogenic mechanism for the antiphospholipid syndrome. Lupus. 2008;17:922–30.PubMedGoogle Scholar
  12. 12.
    Sebastiani GD, Galeazzi M. Genetic aspects of the antiphospholipid syndrome: HLA associations, Chapter 6. In: Cervera R, Reverter JC, Khamashta M, editors. Antiphospholipid syndrome in systemic autoimmune diseases, Handbook of systemic autoimmune diseases, vol. 10. Oxford: Elsevier BC; 2009. p. 81–9.Google Scholar
  13. 13.
    Castro-Marrero J, Balada E, Vilardell-Tarres M, Ordi-Ros J. Genetic risk factors of thrombosis in the antiphospholipid syndrome. Br J Haematol. 2009;147:289–96.PubMedGoogle Scholar
  14. 14.
    Gharavi AE, Pierangeli SS, Harris EN. Origin of antiphospholipid antibodies. Rheum Dis Clin North Am. 2001;27:551–63.PubMedGoogle Scholar
  15. 15.
    Gharavi AE, Pierangeli SS, Harris EN. Viral origin of antiphospholipid antibodies: endothelial cell activation and thrombus enhancement by CMV peptide-induced APL antibodies. Immunobiology. 2003;207:37–42.PubMedGoogle Scholar
  16. 16.
    Hashimoto Y, Kawamura M, Ichikawa K, et al. Anticardiolipin antibodies in NZW × BXSB F1 mice. A model of antiphospholipid syndrome. J Immunol. 1992;149:1063–8.PubMedGoogle Scholar
  17. 17.
    Hang LM, Izui S, Dixon FJ. (NZW × BXSB)F1 hybrid. A model of acute lupus and coronary vascular disease with myocardial infarction. J Exp Med. 1981;154:216–21.PubMedGoogle Scholar
  18. 18.
    Oyaizu N, Yasumizu R, Miyama-Inaba M, et al. (NZW × BXSB)F1 mouse. A new animal model of idiopathic thrombocytopenic purpura. J Exp Med. 1988;167:2017–22.PubMedGoogle Scholar
  19. 19.
    Kita Y, Sumida T, Iwamoto I, Yoshida S, Koike T. V gene analysis of anti-cardiolipin antibodies from (NZW × BXSB) F1 mice. Immunology. 1994;82:494–501.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Ida A, Hirose S, Hamano Y, et al. Multigenic control of lupus-associated antiphospholipid syndrome in a model of (NZW × BXSB) F1 mice. Eur J Immunol. 1998;28:2694–703.PubMedGoogle Scholar
  21. 21.
    Izui S, Masuda K, Yoshida H. Acute SLE in F1 hybrids between SB/Le and NZW mice; prominently enhanced formation of gp70 immune complexes by a Y chromosome-associated factor from SB/Le mice. J Immunol. 1984;132:701–4.PubMedGoogle Scholar
  22. 22.
    Izui S, Higaki M, Morrow D, Merino R. The Y chromosome from autoimmune BXSB/MpJ mice induces a lupus-like syndrome in (NZW × C57BL/6)F1 male mice, but not in C57BL/6 male mice. Eur J Immunol. 1988;18:911–5.PubMedGoogle Scholar
  23. 23.
    Gharavi AE, Mellors RC, Elkon KB. IgG anti-cardiolipin antibodies in murine lupus. Clin Exp Immunol. 1989;78:233–8.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Kita Y, Sumida T, Ichikawa K, et al. V gene analysis of anticardiolipin antibodies from MRL-lpr/lpr mice. J Immunol. 1993;151:849–56.PubMedGoogle Scholar
  25. 25.
    Ahmed SA, Verthelyi D. Antibodies to cardiolipin in normal C57BL/6J mice: induction by estrogen but not dihydrotestosterone. J Autoimmun. 1993;6:265–79.PubMedGoogle Scholar
  26. 26.
    Verthelyi D, Ahmed SA. Characterization of estrogen-induced autoantibodies to cardiolipin in non-autoimmune mice. J Autoimmun. 1997;10:115–25.PubMedGoogle Scholar
  27. 27.
    Harvey AM, Shulman LE. Connective tissue disease and the chronic biologic false-positive test for syphilis (BFP reaction). Med Clin North Am. 1966;50:1271–9.PubMedGoogle Scholar
  28. 28.
    Exner T, Barber S, Kronenberg H, Rickard KA. Familial association of the lupus anticoagulant. Br J Haematol. 1980;45:89–96.PubMedGoogle Scholar
  29. 29.
    Jolidon RM, Knecht H, Humair L, de Torrente A. Different clinical presentations of a lupus anticoagulant in the same family. Klin Wochenschr. 1991;69:340–4.PubMedGoogle Scholar
  30. 30.
    Mackworth-Young C, Chan J, Harris N, et al. High incidence of anticardiolipin antibodies in relatives of patients with systemic lupus erythematosus. J Rheumatol. 1987;14:723–6.PubMedGoogle Scholar
  31. 31.
    Goldberg SN, Conti-Kelly AM, Greco TP. A family study of anticardiolipin antibodies and associated clinical conditions. Am J Med. 1995;99:473–9.PubMedGoogle Scholar
  32. 32.
    Goel N, Ortel TL, Bali D, et al. Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance. Arthritis Rheum. 1999;42:318–27.PubMedGoogle Scholar
  33. 33.
    Dagenais P, Urowitz MB, Gladman DD, Norman CS. A family study of the antiphospholipid syndrome associated with other autoimmune diseases. J Rheumatol. 1992;19:1393–6.PubMedGoogle Scholar
  34. 34.
    Rouget JP, Goudemand J, Montreuil G, Cosson A, Jaillard J. Lupus anticoagulant: a familial observation. Lancet. 1982;2:105.PubMedGoogle Scholar
  35. 35.
    Mackie IJ, Colaco CB, Machin SJ. Familial lupus anticoagulants. Br J Haematol. 1987;67:359–63.PubMedGoogle Scholar
  36. 36.
    May KP, West SG, Moulds J, Kotzin BL. Different manifestations of the antiphospholipid antibody syndrome in a family with systemic lupus erythematosus. Arthritis Rheum. 1993;36:528–33.PubMedGoogle Scholar
  37. 37.
    Arnett FC, Olsen ML, Anderson KL, Reveille JD. Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant. J Clin Invest. 1991;87:1490–5.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Asherson RA, Doherty DG, Vergani D, Khamashta MA, Hughes GR. Major histocompatibility complex associations with primary antiphospholipid syndrome. Arthritis Rheum. 1992;35:124–5.PubMedGoogle Scholar
  39. 39.
    Caliz R, Atsumi T, Kondeatis E, et al. HLA class II gene polymorphisms in antiphospholipid syndrome: haplotype analysis in 83 Caucasoid patients. Rheumatology (Oxford). 2001;40:31–6.Google Scholar
  40. 40.
    Bertolaccini ML, Atsumi T, Caliz AR, et al. Association of antiphosphatidylserine/prothrombin autoantibodies with HLA class II genes. Arthritis Rheum. 2000;43:683–8.PubMedGoogle Scholar
  41. 41.
    Vargas-Alarcon G, Granados J, Bekker C, Alcocer-Varela J, Alarcon-Segovia D. Association of HLA-DR5 (possibly DRB1*1201) with the primary antiphospholipid syndrome in Mexican patients. Arthritis Rheum. 1995;38:1340–1.PubMedGoogle Scholar
  42. 42.
    Galeazzi M, Sebastiani GD, Tincani A, et al. HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. Lupus. 2000;9:47–55.PubMedGoogle Scholar
  43. 43.
    Hashimoto H, Yamanaka K, Tokano Y, et al. HLA-DRB1 alleles and beta 2 glycoprotein I-dependent anticardiolipin antibodies in Japanese patients with systemic lupus erythematosus. Clin Exp Rheumatol. 1998;16:423–7.PubMedGoogle Scholar
  44. 44.
    Arnett FC, Thiagarajan P, Ahn C, Reveille JD. Associations of anti-beta2-glycoprotein I autoantibodies with HLA class II alleles in three ethnic groups. Arthritis Rheum. 1999;42:268–74.PubMedGoogle Scholar
  45. 45.
    Wilson WA, Perez MC, Michalski JP, Armatis PE. Cardiolipin antibodies and null alleles of C4 in black Americans with systemic lupus erythematosus. J Rheumatol. 1988;15:1768–72.PubMedGoogle Scholar
  46. 46.
    Wilson WA, Scopelitis E, Michalski JP, et al. Familial anticardiolipin antibodies and C4 deficiency genotypes that coexist with MHC DQB1 risk factors. J Rheumatol. 1995;22:227–35.PubMedGoogle Scholar
  47. 47.
    Petri M, Watson R, Winkelstein JA, McLean RH. Clinical expression of systemic lupus ­erythematosus in patients with C4A deficiency. Medicine (Baltimore). 1993;72:236–44.PubMedGoogle Scholar
  48. 48.
    Hirose N, Williams R, Alberts AR, et al. A role for the polymorphism at position 247 of the beta2-glycoprotein I gene in the generation of anti-beta2-glycoprotein I antibodies in the antiphospholipid syndrome. Arthritis Rheum. 1999;42:1655–61.PubMedGoogle Scholar
  49. 49.
    Atsumi T, Tsutsumi A, Amengual O, et al. Correlation between beta2-glycoprotein I valine/leucine247 polymorphism and anti-beta2-glycoprotein I antibodies in patients with primary antiphospholipid syndrome. Rheumatology (Oxford). 1999;38:721–3.Google Scholar
  50. 50.
    Prieto GA, Cabral AR, Zapata-Zuniga M, et al. Valine/valine genotype at position 247 of the beta2-glycoprotein I gene in Mexican patients with primary antiphospholipid syndrome: association with anti-beta2-glycoprotein I antibodies. Arthritis Rheum. 2003;48:471–4.PubMedGoogle Scholar
  51. 51.
    Reverter JC, Tàssies M. Genetic aspects of the antiphospholipid syndrome: associations with clinical manifestations. In: Cervera R, Reverter JC, Khamashta M, editors. Antiphospholipid syndrome in systemic autoimmune disease, vol. 10. Oxford: Elsevier BC; 2009. p. 91.Google Scholar
  52. 52.
    Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet. 1995;346:1133–4.PubMedGoogle Scholar
  53. 53.
    Franco RF, Elion J, Tavella MH, Santos SE, Zago MA. The prevalence of factor V Arg306–>Thr (factor V Cambridge) and factor V Arg306–>Gly mutations in different human populations. Thromb Haemost. 1999;81:312–3.PubMedGoogle Scholar
  54. 54.
    Schutt M, Kluter H, Hagedorn-Greiwe M, Fehm HL, Wiedemann GJ. Familial coexistence of primary antiphospholipid syndrome and factor VLeiden. Lupus. 1998;7:176–82.PubMedGoogle Scholar
  55. 55.
    Brenner B, Vulfsons SL, Lanir N, Nahir M. Coexistence of familial antiphospholipid ­syndrome and factor V Leiden: impact on thrombotic diathesis. Br J Haematol. 1996;94:166–7.PubMedGoogle Scholar
  56. 56.
    Chopra N, Koren S, Greer WL, et al. Factor V Leiden, prothrombin gene mutation, and thrombosis risk in patients with antiphospholipid antibodies. J Rheumatol. 2002;29:1683–8.PubMedGoogle Scholar
  57. 57.
    Bentolila S, Ripoll L, Drouet L, Crassard I, Tournier-Lasserve E, Piette JC. Lack of association between thrombosis in primary antiphospholipid syndrome and the recently described thrombophilic 3′-untranslated prothrombin gene polymorphism. Thromb Haemost. 1997;78:1415.PubMedGoogle Scholar
  58. 58.
    Bertolaccini ML, Atsumi T, Hunt BJ, Amengual O, Khamashta MA, Hughes GR. Prothrombin mutation is not associated with thrombosis in patients with antiphospholipid syndrome. Thromb Haemost. 1998;80:202–3.PubMedGoogle Scholar
  59. 59.
    Ruiz-Arguelles GJ, Garces-Eisele J, Ruiz-Delgado GJ, Alarcon-Segovia D. The G20210A polymorphism in the 3’-untranslated region of the prothrombin gene in Mexican mestizo patients with primary antiphospholipid syndrome. Clin Appl Thromb Hemost. 1999;5:158–60.PubMedGoogle Scholar
  60. 60.
    Sivera P, Bosio S, Bertero MT, Demaestri M, Mazza U, Camaschella C. G20210A homozygosity in antiphospholipid syndrome secondary to systemic lupus erythematosus. Haematologica. 2000;85:109–10.PubMedGoogle Scholar
  61. 61.
    de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood. 1999;93:1271–6.PubMedGoogle Scholar
  62. 62.
    Erkan D, Zhang HW, Shriky RC, Merrill JT. Dual antibody reactivity to beta2-glycoprotein I and protein S: increased association with thrombotic events in the antiphospholipid syndrome. Lupus. 2002;11:215–20.PubMedGoogle Scholar
  63. 63.
    Ames PR, Margaglione M, Tommasino C, Bossone A, Iannaccone L, Brancaccio V. Impact of plasma homocysteine and prothrombin G20210 A on primary antiphospholipid syndrome. Blood Coagul Fibrinolysis. 2001;12:699–704.PubMedGoogle Scholar
  64. 64.
    Lincz LF, Adams MJ, Scorgie FE, Thom J, Baker RI, Seldon M. Polymorphisms of the tissue factor pathway inhibitor gene are associated with venous thromboembolism in the antiphospholipid syndrome and carriers of factor V Leiden. Blood Coagul Fibrinolysis. 2007;18:559–64.PubMedGoogle Scholar
  65. 65.
    Jimenez S, Tassies D, Espinosa G, et al. Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus. Ann Rheum Dis. 2008;67:835–40.PubMedGoogle Scholar
  66. 66.
    Yasuda S, Tsutsumi A, Atsumi T, et al. Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with antiphospholipid antibodies. J Rheumatol. 2002;29:1192–7.PubMedGoogle Scholar
  67. 67.
    Diz-Kucukkaya R, Hancer VS, Inanc M, Nalcaci M, Pekcelen Y. Factor XIII Val34Leu polymorphism does not contribute to the prevention of thrombotic complications in patients with antiphospholipid syndrome. Lupus. 2004;13:32–5.PubMedGoogle Scholar
  68. 68.
    de Laat B, Derksen RH, Mackie IJ, et al. Annexin A5 polymorphism (-1C–>T) and the presence of anti-annexin A5 antibodies in the antiphospholipid syndrome. Ann Rheum Dis. 2006;65:1468–72.PubMedCentralPubMedGoogle Scholar
  69. 69.
    Diz-Kucukkaya R, Inanc M, Afshar-Kharghan V, Zhang QE, Lopez JA, Pekcelen Y. P-selectin glycoprotein ligand-1 VNTR polymorphisms and risk of thrombosis in the antiphospholipid syndrome. Ann Rheum Dis. 2007;66:1378–80.PubMedCentralPubMedGoogle Scholar
  70. 70.
    de la Red G, Tassies D, Espinosa G, et al. Factor XIII-A subunit Val34Leu polymorphism is associated with the risk of thrombosis in patients with antiphospholipid antibodies and high fibrinogen levels. Thromb Haemost. 2009;101:312–6.PubMedGoogle Scholar
  71. 71.
    Bugert P, Pabinger I, Stamer K, et al. The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154. Thromb Haemost. 2007;97:573–80.PubMedGoogle Scholar
  72. 72.
    Bertolaccini ML, Atsumi T, Lanchbury JS, et al. Plasma tumor necrosis factor alpha levels and the -238*A promoter polymorphism in patients with antiphospholipid syndrome. Thromb Haemost. 2001;85:198–203.PubMedGoogle Scholar
  73. 73.
    Pierangeli SS, Vega-Ostertag ME, Raschi E, et al. Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies. Ann Rheum Dis. 2007;66:1327–33.PubMedCentralPubMedGoogle Scholar
  74. 74.
    Gharavi AE, Sammaritano LR, Wen J, Elkon KB. Induction of antiphospholipid autoantibodies by immunization with beta 2 glycoprotein I (apolipoprotein H). J Clin Invest. 1992;90:1105–9.PubMedCentralPubMedGoogle Scholar
  75. 75.
    Uhtman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum. 2002;31:256–63.Google Scholar
  76. 76.
    Cervera R, Asherson RA, Acevedo ML, Gómez-Puerta JA, Espinosa G, De La Red G, Gil V, Ramos-Casals M, García-Carrasco M, Ingelmo M, Font J. Antiphospholipid syndrome associated with infections: clinical and microbiological characteristics of 100 patients. Ann Rheum Dis. 2004;63:1312–7.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Blank M, Asherson RA, Cervera R, Shoenfeld Y. Antiphospholipid syndrome infectious origin. J Clin Immunol. 2004;24:12–23.PubMedGoogle Scholar
  78. 78.
    Gharavi AE, Pierangeli SS, Colden-Stanfield M, Liu XW, Espinola RG, Harris EN. GDKV-induced antiphospholipid antibodies enhance thrombosis and activate endothelial cells in vivo and in vitro. J Immunol. 1999;163:2922–7.PubMedGoogle Scholar
  79. 79.
    Gharavi AE, Pierangeli SS, Gharavi EE, et al. Thrombogenic properties of antiphospholipid antibodies do not depend on their binding to beta2 glycoprotein 1 (beta2GP1) alone. Lupus. 1998;7:341–6.PubMedGoogle Scholar
  80. 80.
    Gharavi AE, Pierangeli SS, Espinola RG, et al. Antiphospholipid antibodies induced in mice by immunization with a cytomegalovirus-derived peptide cause thrombosis and activation of endothelial cells in vivo. Arthritis Rheum. 2002;46:545–52.PubMedGoogle Scholar
  81. 81.
    Gharavi AE, Vega-Ostertag M, Espinola RG, et al. Intrauterine fetal death in mice caused by cytomegalovirus-derived peptide induced aPL antibodies. Lupus. 2004;13:17–23.PubMedGoogle Scholar
  82. 82.
    Blank M, Krause I, Fridkin M, et al. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest. 2002; 109:797–804.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Pierangeli SS, Blank M, Liu X, et al. A peptide that shares similarity with bacterial antigens reverses thrombogenic properties of antiphospholipid antibodies in vivo. J Autoimmun. 2004;22:217–25.PubMedGoogle Scholar
  84. 84.
    Harris EN, Gharavi AE, Boey ML, et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983;2:1211–4.PubMedGoogle Scholar
  85. 85.
    Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum. 2002;31:256–63.PubMedGoogle Scholar
  86. 86.
    Asherson RA. Multiorgan failure and antiphospholipid antibodies: the catastrophic antiphospholipid (Asherson’s) syndrome. Immunobiology. 2005;210:727–33.PubMedGoogle Scholar
  87. 87.
    Sene D, Piette JC, Cacoub P. Antiphospholipid antibodies, antiphospholipid syndrome and viral infections. Rev Med Interne. 2009;30:135–41.PubMedGoogle Scholar
  88. 88.
    van de Berg PJ, Heutinck KM, Raabe R, et al. Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature. J Infect Dis. 2010;202:690–9.PubMedGoogle Scholar
  89. 89.
    Prandota J. Possible pathomechanism of autoimmune hepatitis. Am J Ther. 2003;10:51–7.PubMedGoogle Scholar
  90. 90.
    Nakagawa K, Harrison LC. The potential roles of endogenous retroviruses in autoimmunity. Immunol Rev. 1996;152:193–236.PubMedGoogle Scholar
  91. 91.
    Molina V, Shoenfeld Y. Infection, vaccines and other environmental triggers of autoimmunity. Autoimmunity. 2005;38:235–45.PubMedGoogle Scholar
  92. 92.
    Martinuc Porobic J, Avcin T, Bozic B, et al. Anti-phospholipid antibodies following vaccination with recombinant hepatitis B vaccine. Clin Exp Immunol. 2005;142:377–80.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Alusik S, Jandova R, Gebauerova M, Tesarek B, Fabian J. The anticardiolipin syndrome after breast reconstruction. Rozhl Chir. 1990;69:298–301.PubMedGoogle Scholar
  94. 94.
    Rothschild B. Acrylamine-induced autoimmune phenomena. Clin Rheumatol. 2010;29:999–1005.PubMedGoogle Scholar
  95. 95.
    Uetrecht J. Current trends in drug-induced autoimmunity. Autoimmun Rev. 2005;4:309–14.PubMedGoogle Scholar
  96. 96.
    El-Rayes BF, Edelstein M. Unusual case of antiphospholipid antibody syndrome presenting with extensive cutaneous infarcts in a patient on long-term procainamide therapy. Am J Hematol. 2003;72:154.PubMedGoogle Scholar
  97. 97.
    Sherer Y, Blank M, Shoenfeld Y. Antiphospholipid syndrome (APS): where does it come from? Best Pract Res Clin Rheumatol. 2007;21:1071–8.PubMedGoogle Scholar
  98. 98.
    Merrill JT, Shen C, Gugnani M, Lahita RG, Mongey AB. High prevalence of antiphospholipid antibodies in patients taking procainamide. J Rheumatol. 1997;24:1083–8.PubMedGoogle Scholar
  99. 99.
    Canoso RT, de Oliveira RM. Chlorpromazine-induced anticardiolipin antibodies and lupus anticoagulant: absence of thrombosis. Am J Hematol. 1988;27:272–5.PubMedGoogle Scholar
  100. 100.
    Lillicrap DP, Pinto M, Benford K, Ford PM, Ford S. Heterogeneity of laboratory test results for antiphospholipid antibodies in patients treated with chlorpromazine and other phenothiazines. Am J Clin Pathol. 1990;93:771–5.PubMedGoogle Scholar
  101. 101.
    Price BE, Rauch J, Shia MA, et al. Anti-phospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a beta 2-glycoprotein I-dependent manner. J Immunol. 1996;157:2201–8.PubMedGoogle Scholar
  102. 102.
    Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev. 2010;9:200–2.PubMedGoogle Scholar
  103. 103.
    Casciola-Rosen L, Rosen A, Petri M, Schlissel M. Surface blebs on apoptotic cells are sites of enhanced procoagulant activity: implications for coagulation events and antigenic spread in systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1996;93:1624–9.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Piroux V, Eschwege V, Freyssinet JM. Cell damage at the origin of antiphospholipid antibodies and their pathogenic potential in recurrent pregnancy loss. Infect Dis Obstet Gynecol. 1997;5:176–80.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 1995;184:39–51.PubMedGoogle Scholar
  106. 106.
    Verhoven B, Schlegel RA, Williamson P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J Exp Med. 1995;182:1597–601.PubMedGoogle Scholar
  107. 107.
    Koike T, Bohgaki M, Amengual O, Atsumi T. Antiphospholipid antibodies: lessons from the bench. J Autoimmun. 2007;28:129–33.PubMedGoogle Scholar
  108. 108.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 1992;148:2207–16.PubMedGoogle Scholar
  109. 109.
    Manfredi AA, Rovere P, Heltai S, et al. Apoptotic cell clearance in systemic lupus erythematosus. II. Role of beta2-glycoprotein I. Arthritis Rheum. 1998;41:215–23.PubMedGoogle Scholar
  110. 110.
    Mevorach D, Zhou JL, Song X, Elkon KB. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J Exp Med. 1998;188:387–92.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Levine JS, Subang R, Koh JS, Rauch J. Induction of anti-phospholipid autoantibodies by beta2-glycoprotein I bound to apoptotic thymocytes. J Autoimmun. 1998;11:413–24.PubMedGoogle Scholar
  112. 112.
    Rauch J, Subang R, D’Agnillo P, Koh JS, Levine JS. Apoptosis and the antiphospholipid syndrome. J Autoimmun. 2000;15:231–5.PubMedGoogle Scholar
  113. 113.
    Levine JS, Subang R, Nasr SH, et al. Immunization with an apoptotic cell-binding protein recapitulates the nephritis and sequential autoantibody emergence of systemic lupus erythematosus. J Immunol. 2006;177:6504–16.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Reed JH, Giannakopoulos B, Jackson MW, Krilis SA, Gordon TP. Ro 60 functions as a receptor for beta-glycoprotein I on apoptotic cells. Arthritis Rheum. 2009;60:860–9.PubMedGoogle Scholar
  115. 115.
    Kruse K, Janko C, Urbonaviciute V, et al. Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis. 2010;15:1098–113.PubMedGoogle Scholar
  116. 116.
    Papalardo E, Romay-Penabad Z, Christadoss P, Pierangeli S. Induction of pathogenic antiphospholipid antibodies in vivo are dependent on expression of MHC-II genes. Lupus. 2010;19:496 (abstract).Google Scholar
  117. 117.
    Van Os G, Herwald H, Derksen R, Meijers J, deGroot P. Induction of anti-B2GPI antibodies by Streptococcus pyogenes surface protein H. Lupus 2010;19:496 (Abstract A002).Google Scholar
  118. 118.
    Vista E, Crowe S, Dedeke A, et al. Influenza vaccination can induce new onset of anticardiolipins but no B2glycoprotein I antibodies among patients with systemic lupus erythematosus. Lupus 2010;19:496 (Abstract 003).Google Scholar
  119. 119.
    Wen YY, Thiagarajan P, Gibbs R, Arnett f. Genetic variants associated with antiphospholipid antibodies. Lupus 2010;19:496 (Abstract A004).Google Scholar
  120. 120.
    Kato M, Horita T, Atsumi T, et al. Association between CD36 single nucleotide polymorphism and antiphospholipid syndrome. Lupus 2010;19:499 (Abstract A012).Google Scholar
  121. 121.
    Omersel J, Cucnik S, Avbersek Luznik I, Kveder T, Rozman B, Bozic B. Oxidation of antibodies as a trigger for autoimmunity. Lupus 2010;19:496 (Abstract A005).Google Scholar
  122. 122.
    McIntyre J, Page Faulk W. Oxidation of monoclonal antibodies unmasks antiphospholipid autoantibodies. Lupus 2010;19:497 (A009).Google Scholar
  123. 123.
    Rauch J, Dieude M, Subang R, Levine JS. The dual role of innate immunity in the antiphospholipid syndrome. Lupus. 2010;19:347–53.PubMedCentralPubMedGoogle Scholar
  124. 124.
    Raschi E, Testoni C, Bosisio D, et al. Role of the MyD88 transduction signaling pathway in endothelial activation by antiphospholipid antibodies. Blood. 2003;101:3495–500.PubMedGoogle Scholar
  125. 125.
    Boggini V, D’aMelio F, Raschi E, et al. APS clinical manifestations are associated with SNPs of inflammatory genes. Lupus 2010;19:499 (Abstract A010).Google Scholar
  126. 126.
    Aguilar-Valenzuela R, Nickerson K, Romay-Penabad Z, et al. Involvement of TLR7 and TLR9 in the production of antiphospholipid antibodies (Abstract). Arthritis Rheum 2011;63:S281.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Rohan Willis
    • 1
  • Yehuda Shoenfeld
    • 2
  • Silvia S. Pierangeli
    • 1
  • Miri Blank
    • 2
  1. 1.Division of Rheumatology, Department of Internal MedicineUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel HashomerRamat-GanIsrael

Personalised recommendations