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DOI: 10.1055/s-0037-1601329
The Significance of Antibodies against Domain I of Beta-2 Glycoprotein I in Antiphospholipid Syndrome
Publication History
Publication Date:
18 July 2017 (online)
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Abstract
The antiphospholipid syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Progress is being made in understanding the pathogenesis of the syndrome, but difficulties persist in the identification of patients at risk for thrombosis and/or pregnancy morbidity. Beta-2 glycoprotein I (β2GPI), a plasma protein consisting of five sushi domains, is thought to be the main antigenic target of aPLs. Antibodies recognizing domain I of β2GPI are predominantly present in patients with an elevated risk of thrombosis, whereas antidomain IV/V antibodies are found in nonthrombotic autoimmune diseases. Indeed, domain I antibodies proved to be pathogenic in multiple studies. Retrospective studies have provided evidence for an added clinical value of antidomain I antibodies in the risk stratification of patients with APS. Still, wide ranges of odds ratio exist between studies, probably due to differences in the study and control population, and detection methods used. Despite the proven pathogenicity of antidomain I antibodies and their correlations with clinical manifestations of APS, heterogeneity of the current studies has prohibited their acceptance in the official diagnostic criteria. Well-designed large longitudinal prospective studies with available and new, preferentially functional, assays for the risk stratification of patients with APS are required.
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References
- 1 Ortel TL. Antiphospholipid syndrome: laboratory testing and diagnostic strategies. Am J Hematol 2012; 87 (Suppl. 01) S75-S81
- 2 Devreese KM, Pierangeli SS, Tripodi A, Atsumi T, Ortel TL. ; Subcommittee on Lupus Anticoagulant/Phospholipid/Dependent Antibodies. Testing for antiphospholipid antibodies with solid phase assays: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12 (05) 792-795
- 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 (02) 295-306
- 4 Devreese KM. Antiphospholipid antibodies: evaluation of the thrombotic risk. Thromb Res 2012; 130 (Suppl. 01) S37-S40
- 5 Devreese K, Hoylaerts MF. Laboratory diagnosis of the antiphospholipid syndrome: a plethora of obstacles to overcome. Eur J Haematol 2009; 83 (01) 1-16
- 6 Pengo V, Ruffatti A, Legnani C. , et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8 (02) 237-242
- 7 Kelchtermans H, Pelkmans L, de Laat B, Devreese KM. IgG/IgM antiphospholipid antibodies present in the classification criteria for the antiphospholipid syndrome: a critical review of their association with thrombosis. J Thromb Haemost 2016; 14 (08) 1530-1548
- 8 Kasahara H, Matsuura E, Kaihara K. , et al. Antigenic structures recognized by anti-beta2-glycoprotein I auto-antibodies. Int Immunol 2005; 17 (12) 1533-1542
- 9 Wang MX, Kandiah DA, Ichikawa K. , et al. Epitope specificity of monoclonal anti-beta 2-glycoprotein I antibodies derived from patients with the antiphospholipid syndrome. J Immunol 1995; 155 (03) 1629-1636
- 10 Guerin J, Sim R, Yu BB, Ferluga J, Feighery C, Jackson J. Heterogeneous recognition of beta 2-glycoprotein I by antibodies from antiphospholipid syndrome patients. Thromb Haemost 2000; 84 (03) 374-380
- 11 George J, Gilburd B, Hojnik M. , et al. Target recognition of beta2-glycoprotein I (beta2GPI)-dependent anticardiolipin antibodies: evidence for involvement of the fourth domain of beta2GPI in antibody binding. J Immunol 1998; 160 (08) 3917-3923
- 12 Iverson GM, Victoria EJ, Cockerill KA, Linnik MD. Advances in understanding what we measure when detecting anticardiolipin autoantibodies. Clin Chim Acta 2004; 343 (1-2): 37-44
- 13 Chighizola CB, Gerosa M, Meroni PL. New tests to detect antiphospholipid antibodies: anti-domain I beta-2-glycoprotein-I antibodies. Curr Rheumatol Rep 2014; 16 (02) 402
- 14 Iverson GM, Victoria EJ, Marquis DM. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Proc Natl Acad Sci U S A 1998; 95 (26) 15542-15546
- 15 Iverson GM, Reddel S, Victoria EJ. , et al. Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies. J Immunol 2002; 169 (12) 7097-7103
- 16 de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood 2005; 105 (04) 1540-1545
- 17 McNeeley PA, Dlott JS, Furie RA. , et al. Beta2-glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of beta2-glycoprotein I. Thromb Haemost 2001; 86 (02) 590-595
- 18 Reddel SW, Wang YX, Sheng YH, Krilis SA. Epitope studies with anti-beta 2-glycoprotein I antibodies from autoantibody and immunized sources. J Autoimmun 2000; 15 (02) 91-96
- 19 Ioannou Y, Pericleous C, Giles I, Latchman DS, Isenberg DA, Rahman A. Binding of antiphospholipid antibodies to discontinuous epitopes on domain I of human beta(2)-glycoprotein I: mutation studies including residues R39 to R43. Arthritis Rheum 2007; 56 (01) 280-290
- 20 Agar C, van Os GM, Mörgelin M. , et al. Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome. Blood 2010; 116 (08) 1336-1343
- 21 Hammel M, Kriechbaum M, Gries A, Kostner GM, Laggner P, Prassl R. Solution structure of human and bovine beta(2)-glycoprotein I revealed by small-angle X-ray scattering. J Mol Biol 2002; 321 (01) 85-97
- 22 de Laat B, van Berkel M, Urbanus RT. , et al. Immune responses against domain I of b(2)-glycoprotein I are driven by conformational changes: domain I of b(2)-glycoprotein I harbors a cryptic immunogenic epitope. Arthritis Rheum 2011; 63 (12) 3960-3968
- 23 de Laat B, Derksen RH, van Lummel M, Pennings MT, de Groot PG. Pathogenic anti-beta2-glycoprotein I antibodies recognize domain I of beta2-glycoprotein I only after a conformational change. Blood 2006; 107 (05) 1916-1924
- 24 Ioannou Y. The Michael Mason Prize: pathogenic antiphospholipid antibodies, stressed out antigens and the deployment of decoys. Rheumatology (Oxford) 2012; 51 (01) 32-36
- 25 de Laat B, Wu XX, van Lummel M, Derksen RH, de Groot PG, Rand JH. Correlation between antiphospholipid antibodies that recognize domain I of beta2-glycoprotein I and a reduction in the anticoagulant activity of annexin A5. Blood 2007; 109 (04) 1490-1494
- 26 de Laat B, Mertens K, de Groot PG. Mechanisms of disease: antiphospholipid antibodies-from clinical association to pathologic mechanism. Nat Clin Pract Rheumatol 2008; 4 (04) 192-199
- 27 Wahezi DM, Ilowite NT, Wu XX. , et al; Atherosclerosis Prevention in Pediatric Lupus Erythematosus Investigators. Annexin A5 anticoagulant activity in children with systemic lupus erythematosus and the association with antibodies to domain I of b2-glycoprotein I. Lupus 2013; 22 (07) 702-711
- 28 de Laat B, Pengo V, Pabinger I. , et al. The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study. J Thromb Haemost 2009; 7 (11) 1767-1773
- 29 Hunt BJ, Wu XX, de Laat B, Arslan AA, Stuart-Smith S, Rand JH. Resistance to annexin A5 anticoagulant activity in women with histories for obstetric antiphospholipid syndrome. Am J Obstet Gynecol 2011; 205 (05) 485.e17-485.e23
- 30 Hulstein JJ, Lenting PJ, de Laat B, Derksen RH, Fijnheer R, de Groot PG. beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. Blood 2007; 110 (05) 1483-1491
- 31 Ninivaggi M, Kelchtermans H, Lindhout T, de Laat B. Conformation of beta2glycoprotein I and its effect on coagulation. Thromb Res 2012; 130 (Suppl. 01) S33-S36
- 32 Subang R, Levine JS, Janoff AS. , et al. Phospholipid-bound beta 2-glycoprotein I induces the production of anti-phospholipid antibodies. J Autoimmun 2000; 15 (01) 21-32
- 33 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 (05) 413-424
- 34 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 (05) 2922-2927
- 35 Pierangeli SS, Liu X, Espinola R. , et al. Functional analyses of patient-derived IgG monoclonal anticardiolipin antibodies using in vivo thrombosis and in vivo microcirculation models. Thromb Haemost 2000; 84 (03) 388-395
- 36 Giles I, Pericleous C, Liu X. , et al. Thrombin binding predicts the effects of sequence changes in a human monoclonal antiphospholipid antibody on its in vivo biologic actions. J Immunol 2009; 182 (08) 4836-4843
- 37 Agostinis C, Durigutto P, Sblattero D. , et al. A non-complement-fixing antibody to b2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood 2014; 123 (22) 3478-3487
- 38 Ioannou Y, Romay-Penabad Z, Pericleous C. , et al. In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I: proof of concept. J Thromb Haemost 2009; 7 (05) 833-842
- 39 Pericleous C, Ruiz-Limón P, Romay-Penabad Z. , et al. Proof-of-concept study demonstrating the pathogenicity of affinity-purified IgG antibodies directed to domain I of b2-glycoprotein I in a mouse model of anti-phospholipid antibody-induced thrombosis. Rheumatology (Oxford) 2015; 54 (04) 722-727
- 40 Colasanti T, Alessandri C, Capozzi A. , et al. Autoantibodies specific to a peptide of b2-glycoprotein I cross-react with TLR4, inducing a proinflammatory phenotype in endothelial cells and monocytes. Blood 2012; 120 (16) 3360-3370
- 41 Iverson GM, Matsuura E, Victoria EJ, Cockerill KA, Linnik MD. The orientation of beta2GPI on the plate is important for the binding of anti-beta2GPI autoantibodies by ELISA. J Autoimmun 2002; 18 (04) 289-297
- 42 Pelkmans L, Kelchtermans H, de Groot PG. , et al. Variability in exposure of epitope G40-R43 of domain i in commercial anti-beta2-glycoprotein I IgG ELISAs. PLoS One 2013; 8 (08) e71402
- 43 Dienava-Verdoold I, Boon-Spijker MG, de Groot PG. , et al. Patient-derived monoclonal antibodies directed towards beta2 glycoprotein-1 display lupus anticoagulant activity. J Thromb Haemost 2011; 9 (04) 738-747
- 44 Devreese K, Kelchtermans H, de Laat B. Differences in sensitivity of two automated panels for anticardiolipin and anti-beta2glycoprotein I antibodies in the laboratory diagnosis of antiphospholipid syndrome due to the exposure of domain I epitope of beta2 glycoprotein I on the solid phase. [abstract]. Thromb Haemost 2014; 12 (S1): 55
- 45 Roggenbuck D, Borghi MO, Somma V. , et al. Antiphospholipid antibodies detected by line immunoassay differentiate among patients with antiphospholipid syndrome, with infections and asymptomatic carriers. Arthritis Res Ther 2016; 18 (01) 111
- 46 Pozzi N, Banzato A, Bettin S, Bison E, Pengo V, De Filippis V. Chemical synthesis and characterization of wild-type and biotinylated N-terminal domain 1-64 of beta2-glycoprotein I. Protein Sci 2010; 19 (05) 1065-1078
- 47 Banzato A, Pozzi N, Frasson R. , et al. Antibodies to domain I of b(2)glycoprotein I are in close relation to patients risk categories in antiphospholipid syndrome (APS). Thromb Res 2011; 128 (06) 583-586
- 48 Pericleous C, Ferreira I, Borghi O. , et al. Measuring IgA anti-b2-glycoprotein I and IgG/IgA anti-domain I antibodies adds value to current serological assays for the antiphospholipid syndrome. PLoS One 2016; 11 (06) e0156407
- 49 Ioannou Y, Giles I, Lambrianides A. , et al. A novel expression system of domain I of human beta2 glycoprotein I in Escherichia coli. BMC Biotechnol 2006; 6: 8
- 50 Mahler M, Albesa R, Zohoury N. , et al. Autoantibodies to domain 1 of beta 2 glycoprotein I determined using a novel chemiluminescence immunoassay demonstrate association with thrombosis in patients with antiphospholipid syndrome. Lupus 2016; 25 (08) 911-916
- 51 Meneghel L, Ruffatti A, Gavasso S. , et al. Detection of IgG anti-domain I beta2 glycoprotein I antibodies by chemiluminescence immunoassay in primary antiphospholipid syndrome. Clin Chim Acta 2015; 446: 201-205
- 52 Mondejar R, González-Rodríguez C, Toyos-Sáenz de Miera FJ. , et al. Role of antiphospholipid score and anti-b2-glycoprotein I domain I autoantibodies in the diagnosis of antiphospholipid syndrome. Clin Chim Acta 2014; 431: 174-178
- 53 Pengo V, Ruffatti A, Tonello M. , et al. Antiphospholipid syndrome: antibodies to domain 1 of b2-glycoprotein 1 correctly classify patients at risk. J Thromb Haemost 2015; 13 (05) 782-787
- 54 De Craemer AS, Musial J, Devreese KM. Role of anti-domain 1-b2 glycoprotein I antibodies in the diagnosis and risk stratification of antiphospholipid syndrome. J Thromb Haemost 2016; 14 (09) 1779-1787
- 55 Agmon-Levin N, Seguro L, Rosário C. , et al. Anti-β2GP1-Domain-1 Antibodies Are a Marker Of APS Severity. [abstract]. Arthritis Rheum 2013; 65 (Suppl. 10) 1
- 56 Zhang S, Wu Z, Chen S. , et al. Evaluation of the diagnostic potential of antibodies to beta2-glycoprotein 1 domain 1 in Chinese patients with antiphospholipid syndrome. Sci Rep 2016; 6: 23839
- 57 Andreoli L, Chighizola CB, Nalli C. , et al. Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against b2 -glycoprotein i domain 1 and domain 4/5: ratio of anti-domain 1 to anti-domain 4/5 as a useful new biomarker for antiphospholipid syndrome. Arthritis Rheumatol 2015; 67 (08) 2196-2204
- 58 Zuily S, de Laat B, Mohamed S. , et al; TAC(I)T investigators. Validity of the global anti-phospholipid syndrome score to predict thrombosis: a prospective multicentre cohort study. Rheumatology (Oxford) 2015; 54 (11) 2071-2075
- 59 Akhter E, Shums Z, Norman GL, Binder W, Fang H, Petri M. Utility of antiphosphatidylserine/prothrombin and IgA antiphospholipid assays in systemic lupus erythematosus. J Rheumatol 2013; 40 (03) 282-286
- 60 Arvieux J, Renaudineau Y, Mane I, Perraut R, Krilis SA, Youinou P. Distinguishing features of anti-beta2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome. Thromb Haemost 2002; 87 (04) 599-605
- 61 Rodríguez-García V, Ioannou Y, Fernández-Nebro A, Isenberg DA, Giles IP. Examining the prevalence of non-criteria anti-phospholipid antibodies in patients with anti-phospholipid syndrome: a systematic review. Rheumatology (Oxford) 2015; 54 (11) 2042-2050
- 62 Otomo K, Atsumi T, Amengual O. , et al. Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 2012; 64 (02) 504-512
- 63 Cousins L, Pericleous C, Khamashta M. , et al. Antibodies to domain I of b-2-glycoprotein I and IgA antiphospholipid antibodies in patients with ‘seronegative’ antiphospholipid syndrome. Ann Rheum Dis 2015; 74 (01) 317-319
- 64 Mekinian A, Bourrienne MC, Carbillon L. , et al. Non-conventional antiphospholipid antibodies in patients with clinical obstetrical APS: prevalence and treatment efficacy in pregnancies. Semin Arthritis Rheum 2016; 46 (02) 232-237
- 65 Despierres L, Beziane A, Kaplanski G. , et al. Contribution of anti-b2glycoprotein I IgA antibodies to the diagnosis of anti-phospholipid syndrome: potential interest of target domains to discriminate thrombotic and non-thrombotic patients. Rheumatology (Oxford) 2014; 53 (07) 1215-1218
- 66 Artenjak A, Locatelli I, Brelih H. , et al. Immunoreactivity and avidity of IgG anti-b2-glycoprotein I antibodies from patients with autoimmune diseases to different peptide clusters of b2-glycoprotein I. Immunol Res 2015; 61 (1-2): 35-44
- 67 Mullen MT, Messé SR, Kasner SE. , et al. Anti-phosphatidylserine-prothrombin antibodies are associated with outcome in a TIA cohort. Front Neurol 2012; 3: 137
- 68 Filippidou N, Krashias G, Pericleous C. , et al. The association between IgG and IgM antibodies against cardiolipin, b2-glycoprotein I and domain I of b2-glycoprotein I with disease profile in patients with multiple sclerosis. Mol Immunol 2016; 75: 161-167
- 69 Marrie RA, Cohen J, Stuve O. , et al. A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: overview. Mult Scler 2015; 21 (03) 263-281
- 70 Peeters PJ, Bazelier MT, Uitdehaag BM, Leufkens HG, De Bruin ML, de Vries F. The risk of venous thromboembolism in patients with multiple sclerosis: the Clinical Practice Research Datalink. J Thromb Haemost 2014; 12 (04) 444-451
- 71 Cieśla M, Wypasek E, Undas A. IgA antiphospholipid antibodies and anti-domain 1 of Beta 2 glycoprotein 1 antibodies are associated with livedo reticularis and heart valve disease in antiphospholipid syndrome. Adv Clin Exp Med 2014; 23 (05) 729-733
- 72 Pengo V, Ruffatti A, Tonello M. , et al. Antibodies to domain 4/5 (Dm4/5) of b2-glycoprotein 1 (b2GP1) in different antiphospholipid (aPL) antibody profiles. Thromb Res 2015; 136 (01) 161-163
- 73 Andreoli L, Nalli C, Motta M. , et al. Anti-b2-glycoprotein I IgG antibodies from 1-year-old healthy children born to mothers with systemic autoimmune diseases preferentially target domain 4/5: might it be the reason for their ‘innocent’ profile?. Ann Rheum Dis 2011; 70 (02) 380-383
- 74 Ambrozic A, Avicin T, Ichikawa K. , et al. Anti-beta(2)-glycoprotein I antibodies in children with atopic dermatitis. Int Immunol 2002; 14 (07) 823-830
- 75 Forastiero R, Martinuzzo M, de Larrañaga G, Vega-Ostertag M, Pierangeli S. Anti-b2glycoprotein I antibodies from leprosy patients do not show thrombogenic effects in an in vivo animal model. J Thromb Haemost 2011; 9 (04) 859-861
- 76 Sciascia S, Khamashta MA, Bertolaccini ML. New tests to detect antiphospholipid antibodies: antiprothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies. Curr Rheumatol Rep 2014; 16 (05) 415
- 77 Murthy V, Willis R, Romay-Penabad Z. , et al. Value of isolated IgA anti-b2-glycoprotein I positivity in the diagnosis of the antiphospholipid syndrome. Arthritis Rheum 2013; 65 (12) 3186-3193
- 78 Andreoli L, Fredi M, Nalli C. , et al. Clinical significance of IgA anti-cardiolipin and IgA anti-b2glycoprotein I antibodies. Curr Rheumatol Rep 2013; 15 (07) 343
- 79 Lakos G, Favaloro EJ, Harris EN. , et al. International consensus guidelines on anticardiolipin and anti-b2-glycoprotein I testing: report from the 13th International Congress on Antiphospholipid Antibodies. Arthritis Rheum 2012; 64 (01) 1-10
- 80 Bertolaccini ML, Amengual O, Andreoli L. , et al. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev 2014; 13 (09) 917-930
- 81 Zandman-Goddard G, Pierangeli SS, Gertel S, Blank M. Tolerogenic dendritic cells specific for b2-glycoprotein-I domain-I, attenuate experimental antiphospholipid syndrome. J Autoimmun 2014; 54: 72-80
- 82 De Laat B, Derksen RH, Reber G. , et al. An international multicentre-laboratory evaluation of a new assay to detect specifically lupus anticoagulants dependent on the presence of anti-beta2-glycoprotein autoantibodies. J Thromb Haemost 2011; 9 (01) 149-153
- 83 Pengo V, Biasiolo A, Pegoraro C, Iliceto S. A two-step coagulation test to identify antibeta-glycoprotein I lupus anticoagulants. J Thromb Haemost 2004; 2 (05) 702-707
- 84 Devreese KM. A functional coagulation test to identify anti-beta2-glycoprotein I dependent lupus anticoagulants. Thromb Res 2007; 119 (06) 753-759