Abstract
The pathogenicity of antibodies against β2-glycoprotein I (anti-β2GPI) depends on multiple factors such as subclass type, epitope binding and avidity. Due to their large heterogeneity, their impact on antiphospholipid syndrome (APS) onset is still not fully clarified. We studied the binding characteristics of IgG anti-β2GPI with known avidity from sera of 201 autoimmune patients (87 with APS, 67 with APS associated with systemic lupus erythematosus (SLE), 47 with only SLE) to six β2GPI peptides corresponding to amino acid clusters on domains I–II, II, III and III–IV by indirect ELISA and evaluated their association with clinical features of APS. Peptides A (LKTPRV; domain I–II), B (KDKATF; domain IV) and C (TLRVYK; domain III) were derived from a hexapeptide phage display library previously shown to react with pathogenic monoclonal anti-β2GPI. Peptides D (NGPANSK; domain III), E (YNPLWFV; domain II) and F (KMDGNHP; domain III–IV) represent surface amino acid clusters on β2GPI. The percentage of patients positive for peptides were observed as follows: 30.3 % for peptide D, 28.90 % for B, 25.9 % for C, 24.9 % for E, 24.4 % for F and 10.0 % for A. The anti-peptide antibodies in studied serum samples were predominantly of heterogeneous avidity, followed by law avidity anti-peptide antibodies, whereas only a few were of high avidity. Positive and negative correlations were found between several anti-peptide antibodies and the rate of thrombosis. Our results indicated diverse reactivity of IgG anti-β2GPI to different epitopes on β2GPI. Classification of IgG anti-β2GPI into subgroups regarding epitope specificity and avidity could represent an additional tool in understanding their pathogenicity in APS.
Similar content being viewed by others
References
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306. doi:10.1111/j.1538-7836.2006.01753.x.
Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42(7):1309–11. doi:10.1002/1529-0131(199907)42:7<1309:AID-ANR1>3.0.CO;2-F.
Cervera R, Asherson RA. Antiphospholipid syndrome. In: Shoenfeld Y, Cervera R, Gershwin ME, editors. Diagnostic criteria in autoimmune diseases. Totowa: Humana Press; 2008. p. 9–14.
Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46(4):1019–27. doi:10.1002/art.10187.
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271–7.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7(6):330–9. doi:10.1038/nrrheum.2011.52.
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(4):192–9. doi:10.1038/ncprheum0740.
Espinosa G, Cervera R. Antiphospholipid syndrome: frequency, main causes and risk factors of mortality. Nat Rev Rheumatol. 2010;6(5):296–300. doi:10.1038/nrrheum.2010.47.
Artenjak A, Lakota K, Frank M, Cucnik S, Rozman B, Bozic B, et al. Antiphospholipid antibodies as non-traditional risk factors in atherosclerosis based cardiovascular diseases without overt autoimmunity. A critical updated review. Autoimmun Rev. 2012;11(12):873–82. doi:10.1016/j.autrev.2012.03.002.
Shoenfeld Y, Gerli R, Doria A, Matsuura E, Cerinic MM, Ronda N, et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation. 2005;112(21):3337–47. doi:10.1161/CIRCULATIONAHA.104.507996.
Lin F, Murphy R, White B, Kelly J, Feighery C, Doyle R, et al. Circulating levels of beta2-glycoprotein I in thrombotic disorders and in inflammation. Lupus. 2006;15(2):87–93.
Horstman LL, Jy W, Bidot CJ, Ahn YS, Kelley RE, Zivadinov R, et al. Antiphospholipid antibodies: paradigm in transition. J Neuroinflammation. 2009;6:3. doi:10.1186/1742-2094-6-3.
Lozier J, Takahashi N, Putnam FW. Complete amino acid sequence of human plasma beta 2-glycoprotein I. Proc Natl Acad Sci USA. 1984;81(12):3640–4.
Hunt JE, Simpson RJ, Krilis SA. Identification of a region of beta 2-glycoprotein I critical for lipid binding and anti-cardiolipin antibody cofactor activity. Proc Natl Acad Sci USA. 1993;90(6):2141–5.
Schwarzenbacher R, Zeth K, Diederichs K, Gries A, Kostner GM, Laggner P, et al. Crystal structure of human beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome. EMBO J. 1999;18(22):6228–39. doi:10.1093/emboj/18.22.6228.
Sodin-Semrl S, Frank M, Ambrožič A, Pavlič J, Šuštar V, Čučnik S, et al. Interactions of phospholipid binding proteins with negatively charged membranes: β2-glycoprotein I as a model mechanism. In: Leitmannova Liu A, editor. Advances in planar lipid bilayers and liposomes, 1st ed. Amsterdam: Elsevier; 2008. p. 243–73.
Agar C, van Os GM, Morgelin M, Sprenger RR, Marquart JA, Urbanus RT, et al. Beta2-glycoprotein I can exist in 2 conformations: implications for our understanding of the antiphospholipid syndrome. Blood. 2010;116(8):1336–43. doi:10.1182/blood-2009-12-260976.
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(5):1916–24. doi:10.1182/blood-2005-05-1943.
Wang MX, Kandiah DA, Ichikawa K, Khamashta M, Hughes G, Koike T, et al. Epitope specificity of monoclonal anti-beta 2-glycoprotein I antibodies derived from patients with the antiphospholipid syndrome. J Immunol. 1995;155(3):1629–36.
Kasahara H, Matsuura E, Kaihara K, Yamamoto D, Kobayashi K, Inagaki J, et al. Antigenic structures recognized by anti-beta2-glycoprotein I auto-antibodies. Int Immunol. 2005;17(12):1533–42. doi:10.1093/intimm/dxh330.
Mahler M, Norman GL, Meroni PL, Khamashta M. Autoantibodies to domain 1 of beta 2 glycoprotein 1: a promising candidate biomarker for risk management in antiphospholipid syndrome. Autoimmun Rev. 2012;12(2):313–7. doi:10.1016/j.autrev.2012.05.006.
Ambrozic A, Avicin T, Ichikawa K, Kveder T, Matsuura E, Hojnik M, et al. Anti-beta(2)-glycoprotein I antibodies in children with atopic dermatitis. Int Immunol. 2002;14(7):823–30.
Cucnik S, Kveder T, Krizaj I, Rozman B, Bozic B. High avidity anti-beta 2-glycoprotein I antibodies in patients with antiphospholipid syndrome. Ann Rheum Dis. 2004;63(11):1478–82. doi:10.1136/ard.2003.017939.
de Laat B, Derksen RH, de Groot PG. High-avidity anti-beta2 glycoprotein I antibodies highly correlate with thrombosis in contrast to low-avidity anti-beta2 glycoprotein I antibodies. J Thromb Haemost. 2006;4(7):1619–21. doi:10.1111/j.1538-7836.2006.02002.x.
Zager U, Irman S, Lunder M, Skarabot M, Musevic I, Hodnik V, et al. Immunochemical properties and pathological relevance of anti-beta2-glycoprotein I antibodies of different avidity. Int Immunol. 2011;23(8):511–8. doi:10.1093/intimm/dxr043.
Zager U, Lunder M, Čučnik S, Kveder T, Rozman B, Božič B. Immunodominant epitopes of beta2-glycoprotein I for high avidity antibodies. In: 8th International congress on autoimmunity. Granada, Spain: Geneva: Kenes International; 2012.
Blank M, Shoenfeld Y, Cabilly S, Heldman Y, Fridkin M, Katchalski-Katzir E. Prevention of experimental antiphospholipid syndrome and endothelial cell activation by synthetic peptides. Proc Natl Acad Sci USA. 1999;96(9):5164–8.
Cucnik S, Kveder T, Artenjak A, Ulcova Gallova Z, Swadzba J, Musial J, et al. Avidity of anti-beta2-glycoprotein I antibodies in patients with antiphospholipid syndrome. Lupus. 2012;21(7):764–5. doi:10.1177/0961203312440057.
Iverson GM, von Muhlen CA, Staub HL, Lassen AJ, Binder W, Norman GL. Patients with atherosclerotic syndrome, negative in anti-cardiolipin assays, make IgA autoantibodies that preferentially target domain 4 of beta2-GPI. J Autoimmun. 2006;27(4):266–71. doi:10.1016/j.jaut.2006.09.007.
Shoenfeld Y, Krause I, Kvapil F, Sulkes J, Lev S, von Landenberg P, et al. Prevalence and clinical correlations of antibodies against six beta2-glycoprotein-I-related peptides in the antiphospholipid syndrome. J Clin Immunol. 2003;23(5):377–83.
Cucnik S, Bozic B, Kveder T, Tomsic M, Rozman B. Avidity of anti-beta2-glycoprotein I and thrombosis or pregnancy loss in patients with antiphospholipid syndrome. Ann N Y Acad Sci. 2005;1051:141–7. doi:10.1196/annals.1361.055.
Cucnik S, Kveder T, Ulcova-Gallova Z, Swadzba J, Musial J, Valesini G, et al. The avidity of anti-beta2-glycoprotein I antibodies in patients with or without antiphospholipid syndrome: a collaborative study in the frame of the European forum on antiphospholipid antibodies. Lupus. 2011;20(11):1166–71. doi:10.1177/0961203311406308.
Artenjak A, Kozelj M, Lakota K, Cucnik S, Bozic B, Sodin-Semrl S. High avidity anti-b2-glycoprotein I antibodies activate human coronary artery endothelial cells and trigger peripheral blood mononuclear cell migration. Eur J Inflamm. 2013;11(2):385–96.
Favaloro EJ, Wong RC. Laboratory testing for the antiphospholipid syndrome: making sense of antiphospholipid antibody assays. Clin Chem Lab Med. 2011;49(3):447–61. doi:10.1515/CCLM.2011.064.
Cucnik S, Ambrozic A, Bozic B, Skitek M, Kveder T. Anti-beta2-glycoprotein I ELISA: methodology, determination of cut-off values in 434 healthy Caucasians and evaluation of monoclonal antibodies as possible international standards. Clin Chem Lab Med. 2000;38(8):777–83. doi:10.1515/CCLM.2000.111.
Avcin T, Ambrozic A, Bozic B, Accetto M, Kveder T, Rozman B. Estimation of anticardiolipin antibodies, anti-beta2 glycoprotein I antibodies and lupus anticoagulant in a prospective longitudinal study of children with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2002;20(1):101–8.
Banzato A, Pozzi N, Frasson R, De Filippis V, Ruffatti A, Bison E, et al. Antibodies to domain I of beta(2)glycoprotein I are in close relation to patients risk categories in antiphospholipid syndrome (APS). Thromb Res. 2011;128(6):583–6. doi:10.1016/j.thromres.2011.04.021.
Muller C, Thaler M, Schlichtiger A, Schreiegg A, Balling G, Steigerwald U, et al. beta2-glycoprotein I-derived peptides as antigenic structures for the detection of antiphospholipid antibodies. J Thromb Haemost. 2010;8(9):2073–5. doi:10.1111/j.1538-7836.2010.03987.x.
Metzger J, von Landenberg P, Kehrel M, Buhl A, Lackner KJ, Luppa PB. Biosensor analysis of beta2-glycoprotein I-reactive autoantibodies: evidence for isotype-specific binding and differentiation of pathogenic from infection-induced antibodies. Clin Chem. 2007;53(6):1137–43. doi:10.1373/clinchem.2006.079632.
Pierangeli SS, Blank M, Liu X, Espinola R, Fridkin M, Ostertag MV, et al. A peptide that shares similarity with bacterial antigens reverses thrombogenic properties of antiphospholipid antibodies in vivo. J Autoimmun. 2004;22(3):217–25. doi:10.1016/j.jaut.2004.01.002.
Acknowledgments
The study is in accordance with the Helsinki Declaration of 1975, revised in 1983 and was approved by the National Ethical Committee (No. 163/02/09). This work was funded by the National Research Program Grant No. P3-0314 from the Ministry of Higher Education, Science and Technology, Slovenia.
Conflict of interest
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Artenjak, A., Locatelli, I., Brelih, H. et al. Immunoreactivity and avidity of IgG anti-β2-glycoprotein I antibodies from patients with autoimmune diseases to different peptide clusters of β2-glycoprotein I. Immunol Res 61, 35–44 (2015). https://doi.org/10.1007/s12026-014-8578-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12026-014-8578-0