Skip to main content

Advertisement

Log in

Novel Insights Into Associations of Antibodies Against Cardiolipin and beta2-glycoprotein I with Clinical Features of Antiphospholipid Syndrome

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Antiphospholipid syndrome (APS) is a clinical autoimmune disorder characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with the persistence of lupus anticoagulant or anticardiolipin (aCL) antibodies. Accumulating evidence indicates that phospholipid binding protein, beta2-glycoprotein I (β2GPI) represents the major target antigen for antiphospholipid (aPL) antibodies and plays a role in the pathogenesis of APS. It is widely accepted that aPL antibodies detected by conventional solid phase assays in patients with APS are mainly directed against a complex of aCL and anti-β2GPI, although antibodies against β2GPI protein can now also be detected by specific ELISA using purified proteins in solid phase. Despite the fact that these antibodies are not listed in the new diagnostic criteria, a high specificity of anti-β2GPI assay for the clinical features of APS was established. During the last decade, numerous studies have investigated the clinical link between aCL and/or anti-β2GPI antibodies and diverse features of APS. This manuscript reviews the current studies published recently in this field and discusses the relationship between the existence of aCL and anti-β2GPI antibodies and the main and unusual manifestations of APS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Hughes GR (1983) Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 287:1088–1089

    Article  CAS  Google Scholar 

  2. Shoenfeld Y (2003) Systemic antiphospholipid syndrome. Lupus 12:497–498

    Article  PubMed  CAS  Google Scholar 

  3. Arvieux J, Roussel B, Jacob MC, Colomb MG (1991) Measurement of antiphospholipid antibodies by ELISA using ß2-glycoprotein I as an antigen. J Immunol Methods 143:223–229

    Article  PubMed  CAS  Google Scholar 

  4. Wilson WA, Gharavi AE, Koike T et al (1999) International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 42:1309–1311

    Article  PubMed  CAS  Google Scholar 

  5. Li Z, Krilis SA (2003) Anti-beta(2)-glycoprotein I antibodies and the antiphospholipid syndrome. Autoimmun Rev 2:229–234

    Article  PubMed  CAS  Google Scholar 

  6. Blank M, Faden D, Tincani A et al (1994) Immunization with anticardiolipin cofactor (beta 2 GP-I) induces experimental antiphospholipid syndrome in naive mice. J Autoimmun 7:441–455

    Article  PubMed  CAS  Google Scholar 

  7. Blank M, Krause I, Fridkin M et al (2002) Bacterial induction of autoantibodies to beta 2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest 109:797–804

    Article  PubMed  CAS  Google Scholar 

  8. Alarcon-Segovia D, Mestanza M, Cabiedes J, Cabral AR (1997) The antiphospholipid/cofactor syndromes. 2. A Variant in patients with systemic lupus erythematosus with antibodies to beta(2)-glycoprotein I but no antibodies detectable in standard antiphospholipid assays. J Rheumatol 24:1545–1551

    PubMed  CAS  Google Scholar 

  9. Sanfilippo SS, Khamashta MA, Atsumi T et al (1998) Antibodies to ß2-glycoprotein I: A potential marker for clinical features of antiphospholipid antibody syndrome in patients with systemic lupus erythematosus. J Rheumatol 25:2131–2134

    PubMed  CAS  Google Scholar 

  10. Balestrieri G, Tincani A, Spatola L et al (1995) Anti-beta2-glycoprotein I antibodies: A marker of antiphospholipid syndrome? Lupus 4:122–130

    PubMed  CAS  Google Scholar 

  11. Arvieux J, Roussel B, Colomb MG (1994) Anticorps antiphospholipid et anti-beta2-gpI. Ann Biol Clin (Paris) 52:381–385

    CAS  Google Scholar 

  12. Tincani A, Balestrieri G, Spatola L, Cinquini M, Meroni PL, Roubey RA (1998) Anticardiolipin and anti-beta 2glycoprotein I immunoassays in the diagnosis of antiphospholipid syndrome. Clin Exp Rheumatol 16:396–402

    PubMed  CAS  Google Scholar 

  13. Levine JS, Branch DW, Rauch J (2002) Medical Progress: The aniphospholipid syndrome. N Engl J Med 346:752–763

    Article  PubMed  CAS  Google Scholar 

  14. Galli M, Luciani D, Bertolini G, Barbui T (2003) Anti-beta2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 102:2717–2723

    Article  PubMed  CAS  Google Scholar 

  15. Galli M, Luciani D, Bertolini G, Barbui T (2003) Lupus anticoagulants are stronger risk factors of thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: A systematic review of the literature. Blood 101:1827–1832

    Article  PubMed  CAS  Google Scholar 

  16. Locht H, Wiik A (2006) IgG og IgM isotypes of anti-cardiolipin and anti Beta2-glycoprotein-I antibodies reflect different forms of recent thrombo-embolic events. Clin Rheumatol 25:246–250

    Article  PubMed  Google Scholar 

  17. Galli M (2004) Antiphospholipid antibodies and thrombosis: do test patterns identify the patients’ risk? Thromb Res 114:597–601

    Article  PubMed  CAS  Google Scholar 

  18. Tuhrim S, Rand JH, Wu XX, Weinberger J, Horowitz DR, Goldman ME et al (1999) Elevated anticardiolipin antibody titre is a stroke risk factor in a multiethnic population independent of Iso type of degree of positivity. Stroke 30:1561–1565

    PubMed  CAS  Google Scholar 

  19. Verro P, Levine SR, Tietjen GE (1998) Cerebrovascular ischemic events with high positive anticardiolipin antibodies. Stroke 29:2245–2253

    PubMed  CAS  Google Scholar 

  20. Szczepanski M, Cieslak E, Gardas A, Bauer A, Majkowski J (1998) Prevalence of high IgM anticardiolipins in patients with ischemic stroke. Eur J Neurol 5:287–290

    Article  PubMed  Google Scholar 

  21. Ahmed E, Stegmayr B, Trifunovic J, Weinehall L, Hallmans G, Lefvert AK (2000) Anticardiolipin antibodies are not an independent risk factor for stroke: An incident case-referent study nested within the MONICA and Vasterbotten cohort project. Stroke 31:1289–1293

    PubMed  CAS  Google Scholar 

  22. Samarkos M, Davies KA, Gordon C, Loizou S (2006) Clinical significance of IgA anticardiolipin and anti-beta(2)-GP1 antibodies in patients with systemic lupus erythematosus and primary antiphospholipid syndrome. Clin Rheumatol 25:199–204

    Article  PubMed  CAS  Google Scholar 

  23. Lopez LR, Santos ME, Espinoza LR, La Rosa FG (1992) Clinical significance of immunogloublin A versus immunoglobulins G and M anti-cardiolipin antibodies in patients with systemic lupus erythematosus: Correlations with thrombosis, thrombocytopenia, and recurrent abortion. Am J Clin Pathol 98:449–454

    PubMed  CAS  Google Scholar 

  24. Cucurull E, Espinoza LR, Mendez E et al (1999) Anticardiolipin and anti-beta2glycoprotein-I antibodies in patients with systemic lupus erythematosus: comparison between Colombians and Spaniards. Lupus 8:134–141

    Article  PubMed  CAS  Google Scholar 

  25. Tsutsumi A, Matsuura E, Ichikawa K, Fujisaku A, Mukai M, Koike T (1998) IgA class anti-beta2-glycoprotein I in patients with systemic lupus erythematosus. J Rheumatol 25:74–78

    PubMed  CAS  Google Scholar 

  26. Lee SS, Cho ML, Joo YS et al (2001) Isotypes of anti-ß2-glycoprotein I antibodies: association with thrombosis in patients with systemic lupus erythematosus. J Rheumatol 28:520–524

    PubMed  CAS  Google Scholar 

  27. Tsutsumi A, Koike T, Ichikawa K et al (1988) IgG subclass distribution of anticardiolipin antibody in patients with systemic lupus erythematosus. J Rheumatol 15:1764–1767

    PubMed  CAS  Google Scholar 

  28. Sammaritano LR, Ng S, Sobel R et al (1997) Anticardiolipin IgG subclasses: association of IgG2 with arterial and/or venous thrombosis. Arthritis Rheum 40:1998–2006

    Article  PubMed  CAS  Google Scholar 

  29. Hamilton RG (1987) Hamilton RG: Human IgG subclass measurements in the clinical laboratory. Clin Chem 33:1707–1725

    PubMed  CAS  Google Scholar 

  30. Skvaril F (1986) IgG subclasses in viral infections. Monogr Allergy 19:134–143

    PubMed  CAS  Google Scholar 

  31. Samarkos M, Davies KA, Gordon C, Walport MJ, Loizou S (2001) IgG subclass distribution of antibodies against beta (2)-GP1 and cardiolipin in patients with systemic lupus erythematosus and primary antiphospholipid syndrome, and their clinical associations. Rheumatology (Oxford) 40:1026–1032

    Article  CAS  Google Scholar 

  32. Meroni PL, Riboldi P (2001) Pathogenic mechanisms mediating antiphospholipid syndrome. Curr Opin Rheumatol 13:377–382

    Article  PubMed  CAS  Google Scholar 

  33. Pierangeli SS, Gharavi AE, Harris EN (2000) Experimental thrombosis and antiphospholipid antibodies: new insights. J Autoimmun 15:241–247

    Article  PubMed  CAS  Google Scholar 

  34. Shoenfeld Y, Sherer Y, Blank M (1998) Antiphospholipid syndrome in pregnancy–animal models and clinical implications. Scand J Rheumatol Suppl 107:33–36

    PubMed  CAS  Google Scholar 

  35. Blank M, Cohen J, Toder V, Shoenfeld Y (1991) Induction of anti-phospholipid syndrome by passive transfer of anti-cardiolipin antibodies. Proc Natl Acad Sci USA 15:3069–3073

    Article  Google Scholar 

  36. Meroni PL, di Simone N, Testoni C, D’Asta M, Acaia B, Caruso A (2004) Antiphospholipid antibodies as cause of pregnancy loss. Lupus 13:649–652

    Article  PubMed  CAS  Google Scholar 

  37. Faden D, Tincani A, Tanzi P, Spatola L, Lojacono A, Tarantini M, Balestrieri G (1997) Anti-beta 2 glycoprotein I antibodies in a general obstetric population: Preliminary results on the prevalance and correlation with pregnancy outcome. Anti-beta 2 glycoprotein I antibodies are associated with some obstetrical complications, mainly preeclampsia-eclampsia. Eur J Obstet Gynecol Reprod Biol 73:37–42

    Article  PubMed  CAS  Google Scholar 

  38. Marai I, Tincani A, Balestrieri G, Shoenfeld Y (2005) Anticardiolipin and anti-beta-glycoprotein-I antibodies. Autoimmunity 38:33–38

    Article  PubMed  CAS  Google Scholar 

  39. Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW (1996) Antiphospholipid antibodies and fetal death. Obstet Gynecol 87:489–493

    Article  PubMed  CAS  Google Scholar 

  40. Gris JC, Perneger TV, Quere I et al (2003) Antiphospholipid/antiprotein antibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for a first early pregnancy loss: a matched case-control study. Blood 102:3504–3513

    Article  PubMed  CAS  Google Scholar 

  41. Gris JC, Quere I, Sanmarco M et al (2000) Antiphospholipid and antiprotein syndromes in nonthrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss: The Nîmes Obstetricians and Haematologists Study—NOHA. Thromb Haemost 84:228–236

    PubMed  CAS  Google Scholar 

  42. Cortes-Hernandez J, Ordi-Ros J, Paredes F, Casellas M, Castillo F, Vilardell-Tarres M (2002) Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus. A prospective study of 103 pregnancies. Rheumatology (Oxford) 41:643–650

    Article  CAS  Google Scholar 

  43. Forastiero RR, Martinuzzo ME, Cerrato GS, Kordich LC, Carreras LO (1997) Relationship of anti-beta-2-glycoprotein-I and anti prothrombin antibodies to thrombosis and pregnancy loss in patients with antiphospholipid antibodies. Thromb Haemost 78:1008–1014

    PubMed  CAS  Google Scholar 

  44. Lynch A, Byers T, Emlen W, Rynes D, Shetterly SM, Hamman RF (1999) Association of antibodies to beta 2-glycoprotein I with pregnancy loss pregnancy-induced hypertension: a prospective study in low-risk pregnancy. Obstet Gynecol 93:193–198

    Article  PubMed  CAS  Google Scholar 

  45. Ailus K, Tulppala M, Palosuo T, Ylikorkala O, Vaarala O (1996) Antibodies to beta-2-glycoprotein and prothrobin in habitual abortion. Fertil Steril 66:937–941

    PubMed  CAS  Google Scholar 

  46. Bizzaro N, Tonutti E, Villalta D, Tampoia M, Tozzoli R (2005) Prevalence and clinical correlation of anti-phospholipid-binding protein antibodies in anticardiolipin-negative patients with systemic lupus erythematosus and women with unexplained recurrent miscarriages. Arch Pathol Lab Med 129:61–68

    PubMed  Google Scholar 

  47. Zammiti W, Mtiraoui N, Kallel C, Mercier E, Almawi WY, Mahjoub T (2006) A case-control study on the association of idiopathic recurrent pregnancy loss with autoantibodies against beta2-glycoprotein I and annexin V. Reproduction 131:817–822

    Article  PubMed  CAS  Google Scholar 

  48. Selva-O’Callaghan A, Ordi-Ros J, Monegal-Ferran F, Martinez N, Cortes-Hernandez F, Vilardell-Tarres M (1998) IgA anticardiolipin antibodies- Relation with other antiphospholipid antibodies and clinical significance. Thromb Haemost 79:282–285

    PubMed  CAS  Google Scholar 

  49. Yamada H, Tsutsumi A, Ichikawa K, Kato EH, Koike T, Fujimoto S (1999) IgA-class anti-beta2-glycoprotein I in women with unexplained recurrent spontaneous abortion. Arthritis Rheum 42:2727–2728

    Article  PubMed  CAS  Google Scholar 

  50. Lee RM, Branch DW, Silver RM (2001) Immunoglobulin A anti-beta2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death. Am J Obstet Gynecol 185:748–753

    Article  PubMed  CAS  Google Scholar 

  51. Lee RM, Emlen W, Scott JR, Branch DW, Silver RM (1999) Anti-beta2-glycoprotein-I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome. Am J Obstet Gynecol 181:642–648

    Article  PubMed  CAS  Google Scholar 

  52. Carmo-Pereira S, Bertolaccini ML, Escudero-Contreras A, Khamashta MA, Hughes GR (2003) Values of IgA anticardiolipin and anti-ß2-Glycoprotein I antibody testing in pateints with pregnancy morbidity. Ann Rheum Dis 62:540–543

    Article  PubMed  CAS  Google Scholar 

  53. Krause I, Blank M, Fraser A, Lorber M, Stojanovich L, Rovensky J et al (2005) The association of thrombocytopenia with systemic manifestations in the antiphospholipid syndrome. Immunobiology 210:749–754

    Article  PubMed  CAS  Google Scholar 

  54. Harris EN, Gharavi AE, Hegde U, Derue G, Morgan SH, Englert H et al (1985) Anticardiolipin antibodies in autoimmune thrombocytopenic purpura. Br J Haematol 59:231–234

    PubMed  CAS  Google Scholar 

  55. Galli M, Finazzi G, Barbui T (1996) Thrombocytopenia in the antiphospholipid syndrome: pathophysiology, clinical revelance and treatment. Ann Med Interne (Paris) 147(Suppl 1):24–27

    Google Scholar 

  56. Bidot CJ, Jy W, Horstman LL, Ahn ER, Jimenez JJ, Yaniz M et al (2005) Antiphospholipid antibodies in immune thrombocytopenic purpura tend to emerge in exacerbation and decline in remission. Br J Haematol 128:366–372

    Article  PubMed  CAS  Google Scholar 

  57. Biasiolo A, Pengo V (1993) Antiphospholipid antibodies are not present in the membrane of gel-filtered platelets of patients with IgG anticardiolipin antibodies, lupus anticoagulant and thrombosis. Blood Coagul Fibrinolysis 4:425–428

    Article  PubMed  CAS  Google Scholar 

  58. Godeau B, Piette JC, Fromont P, Intrator L, Schaeffer A, Bierling P (1997) Specific antiplatelet glycoprotein autoantibodies are associated with the thrombocytopenia of primary antiphospholipid syndrome. Br J Haematol 98:873–879

    Article  PubMed  CAS  Google Scholar 

  59. Zwaal RF, Schroit AJ (1997) Pathophysiologic implications of membrane phospholipid assymmetry in blood cells. Blood 89:1121–1132

    PubMed  CAS  Google Scholar 

  60. Tsutsumi A, Matsuura E, Ichikawa K, Fujisaku A, Mukai M, Kobayashi S et al (1996) Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus. Arthritis Rheum 39:1466–1474

    Article  PubMed  CAS  Google Scholar 

  61. Voss A, Jacobsen S, Heegaard NH (2001) Association of beta2-glycoprotein-I IgG and IgM antibodies with thrombosis and thrombocytopenia. Lupus 10:533–538

    Article  PubMed  CAS  Google Scholar 

  62. Teixido M, Font J, Reverter JC, Cervera R, Tassies D, Ingelmo M et al (1997) A useful marker for the antiphospholipid syndrome. Br J Rheumatol 36:113–116

    Article  PubMed  CAS  Google Scholar 

  63. Day HM, Thiagarajan P, Ahn C, Reveille JD, Tinker KF, Arnett FC (1998) Autoantibodies to ß2-glycoprotein I in systemic lupus erythematosus and primary antiphospholipid antibody syndrome: Clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol 25:667–674

    PubMed  CAS  Google Scholar 

  64. George J, Gilburd B, Langevitz P, Levy Y, Nezlin R, Harats D et al (1999) Beta-2 glycoprotein-I containing immune-complexes in lupus patients: association with thrombocytopenia and lipoprotein (a) levels. Lupus 8:116–120

    Article  PubMed  CAS  Google Scholar 

  65. D’Cruz DP (2005) Autoantibodies to 2-glycoprotein-I in systemic lupus erythematosus anBetaRenal manifestations of the antiphospholipid syndrome. Lupus 14:45–48

    Article  PubMed  CAS  Google Scholar 

  66. Tektonidou MG, Sotsiou F, Nakopoulou L, Vlachoyiannopoulos PG, Moutsopoulos HM (2004) Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum 50:2569–2579

    Article  PubMed  Google Scholar 

  67. Loizou S, Samarkos M, Norsworthy PJ, Cazabon JK, Walport MJ, Davies KA (2000) Significance of anticardiolipin and anti-beta(2)-glycoprotein I antibodies in lupus nephritis. Rheumatology (Oxford) 39:962–968

    Article  CAS  Google Scholar 

  68. Vaidya S, Daller J, Gugliuzza K (2002) Role of anti-beta 2 glycoprotein 1 antibodies in ESRD patients with antiphospholipid antibody syndrome. Clin Transplant 16:362–367

    Article  PubMed  CAS  Google Scholar 

  69. Tenedios F, Erkan D, Lockshin MD (2005) Cardiac involvement in the antiphospholipid syndrome. Lupus 14:691–696

    Article  PubMed  CAS  Google Scholar 

  70. Ziporen L, Goldberg I, Arad M, Hojnik M, Ordi-Ros J, Afek A et al (1996) Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic findings in deformed heart valves. Lupus 5:196–205

    PubMed  CAS  Google Scholar 

  71. Afek A, Shoenfeld Y, Manor R, Goldberg I, Ziporen L, George J et al (1999) Increased endothelial cell expression of alpha3 beta1 integrin in cardiac valvulopathy in the primary (Hughes) and secondary antiphospholipid syndrome. Lupus 8:502–507

    Article  PubMed  CAS  Google Scholar 

  72. Blank M, Krause I, Magrini L, Spina G, Kalil J, Jacobsen S et al (2006) Overlapping humoral autoimmunity links rheumatic fever and the antiphospholipid syndrome. Rheumatology (Oxford) 45:833–841

    Article  CAS  Google Scholar 

  73. Chapman J, Rand JH, Brey RL, Levine SR, Blatt I, Khamashta MA et al (2003) Non-stroke neurological syndromes associated with antiphospholipid antibodies: evaluation of clinical and experimental study. Lupus 12:514–517

    Article  PubMed  CAS  Google Scholar 

  74. Miesbach W, Gilzinger A, Gokpinar B, Claus D, Scharrer I (2006) Prevalence of antiphospholipid antibodies in patients with neurolgical symptoms. Clin Neurol Neurosurg 108:135–142

    Article  PubMed  Google Scholar 

  75. Shrivastava A, Dwivedi S, Aggarwal A, Misra R (2001) Anti-cardiolipin and anti-beta2 glycoprotein I antibodies in Indian patients with systemic lupus erythematosus: association with the presence of seizures. Lupus 10:45–50

    Article  PubMed  CAS  Google Scholar 

  76. Weder-Cisneros ND, Tellez-Zenteno JF, Cardiel MH, Guibert-Toledano M, Cabiedes J, Velasquez-Paz AL et al (2004) Prevalence and factors associated with headache in patients with systemic lupus erythematosus. Cephalalgia 24:1031–1044

    Article  PubMed  CAS  Google Scholar 

  77. Frances C, Niang S, Laffitte E, Pelletier F, Costedoat N, Piette JC (2005) Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum 52:1785–1793

    Article  PubMed  Google Scholar 

  78. Naldi L, Locati F, Marchesi L, Cortelazzo S, Finazzi G, Galli M et al (1993) Cutaneous manifestations associated with antiphospholipid antibodies in patients with suspected primary antiphospholipid syndrome: a case-control study. Ann Rheum Dis 52:219–222

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This work was partly supported by The Foundation Federico S.A. for research in Autoimmunity Diseases.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Y. Shoenfeld.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shovman, O., Gilburd, B., Barzilai, O. et al. Novel Insights Into Associations of Antibodies Against Cardiolipin and beta2-glycoprotein I with Clinical Features of Antiphospholipid Syndrome. Clinic Rev Allerg Immunol 32, 145–152 (2007). https://doi.org/10.1007/s12016-007-0001-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-007-0001-3

Keywords

Navigation