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.
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References
Hughes GR (1983) Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 287:1088–1089
Shoenfeld Y (2003) Systemic antiphospholipid syndrome. Lupus 12:497–498
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
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
Li Z, Krilis SA (2003) Anti-beta(2)-glycoprotein I antibodies and the antiphospholipid syndrome. Autoimmun Rev 2:229–234
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
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
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
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
Balestrieri G, Tincani A, Spatola L et al (1995) Anti-beta2-glycoprotein I antibodies: A marker of antiphospholipid syndrome? Lupus 4:122–130
Arvieux J, Roussel B, Colomb MG (1994) Anticorps antiphospholipid et anti-beta2-gpI. Ann Biol Clin (Paris) 52:381–385
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
Levine JS, Branch DW, Rauch J (2002) Medical Progress: The aniphospholipid syndrome. N Engl J Med 346:752–763
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
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
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
Galli M (2004) Antiphospholipid antibodies and thrombosis: do test patterns identify the patients’ risk? Thromb Res 114:597–601
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
Verro P, Levine SR, Tietjen GE (1998) Cerebrovascular ischemic events with high positive anticardiolipin antibodies. Stroke 29:2245–2253
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
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
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
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
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
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
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
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
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
Hamilton RG (1987) Hamilton RG: Human IgG subclass measurements in the clinical laboratory. Clin Chem 33:1707–1725
Skvaril F (1986) IgG subclasses in viral infections. Monogr Allergy 19:134–143
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
Meroni PL, Riboldi P (2001) Pathogenic mechanisms mediating antiphospholipid syndrome. Curr Opin Rheumatol 13:377–382
Pierangeli SS, Gharavi AE, Harris EN (2000) Experimental thrombosis and antiphospholipid antibodies: new insights. J Autoimmun 15:241–247
Shoenfeld Y, Sherer Y, Blank M (1998) Antiphospholipid syndrome in pregnancy–animal models and clinical implications. Scand J Rheumatol Suppl 107:33–36
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
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
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
Marai I, Tincani A, Balestrieri G, Shoenfeld Y (2005) Anticardiolipin and anti-beta-glycoprotein-I antibodies. Autoimmunity 38:33–38
Oshiro BT, Silver RM, Scott JR, Yu H, Branch DW (1996) Antiphospholipid antibodies and fetal death. Obstet Gynecol 87:489–493
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Zwaal RF, Schroit AJ (1997) Pathophysiologic implications of membrane phospholipid assymmetry in blood cells. Blood 89:1121–1132
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
Voss A, Jacobsen S, Heegaard NH (2001) Association of beta2-glycoprotein-I IgG and IgM antibodies with thrombosis and thrombocytopenia. Lupus 10:533–538
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
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
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
D’Cruz DP (2005) Autoantibodies to 2-glycoprotein-I in systemic lupus erythematosus anBetaRenal manifestations of the antiphospholipid syndrome. Lupus 14:45–48
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
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
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
Tenedios F, Erkan D, Lockshin MD (2005) Cardiac involvement in the antiphospholipid syndrome. Lupus 14:691–696
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
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
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
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
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
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
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
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
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
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This work was partly supported by The Foundation Federico S.A. for research in Autoimmunity Diseases.
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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
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DOI: https://doi.org/10.1007/s12016-007-0001-3