Download PDF
Hamostaseologie 2019; 39(02): 188-194
DOI: 10.1055/s-0038-1675355
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Cofactor-Independent Antiphospholipid Antibodies: Implications for Pathogenesis, Diagnosis, and Treatment of Antiphospholipid Syndrome

Karl J. Lackner
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
2   Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany
,
Nadine Müller-Calleja
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany
2   Center for Translational Vascular Biology, University Medical Center Mainz, Mainz, Germany
3   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
› Author Affiliations
Further Information

Publication History

23 June 2018

24 August 2018

Publication Date:
12 November 2018 (online)

Also available at
    Permissions and Reprints

Abstract

The antiphospholipid syndrome (APS) has occupied haemostaseologists, rheumatologists and obstetricians since its initial description 35 years ago. Its name has been coined because of the antibodies against phospholipids which were the common property of affected patients. In particular, the pathogenesis of APS has been intensively studied after the early discovery that it was possible to induce the clinical manifestations in animals by transfer of antiphospholipid antibodies (aPL). In recent years, it has become clear that aPL are not only structurally heterogeneous but also have different pathogenic properties. This review will focus on the relevance of antigenic specificity of aPL in terms of pathogenesis, diagnosis, and perhaps treatment of APS.

Zusammenfassung

Das Antiphospholipidsyndrom (APS) beschäftigt Hämostaseologen, Rheumatologen und Geburtshelfer seit seiner ersten Beschreibung vor 35 Jahren. Sein Name wurde durch die Antikörper gegen Phospholipide geprägt, die bei den betroffenen Patienten gefunden wurden. Insbesondere nachdem frühzeitig erkannt worden war, dass die klinischen Manifestationen bei Tieren durch Übertragung von Antiphospholipid Antikörpern (aPL) induziert werden können, wurde die Pathogenese des APS intensiv untersucht. In den letzten Jahren wurde deutlich, dass aPL nicht nur strukturell heterogen sind, sondern auch unterschiedliche pathogene Eigenschaften aufweisen. Diese Übersichtsarbeit konzentriert sich auf die Relevanz der Antigenspezifität von aPL in Bezug auf Pathogenese, Diagnose und möglicherweise Behandlung von APS.

Keywords

antiphospholipid antibodies - antiphospholipid syndrome - β2-glycoprotein I - lupus anticoagulant

Schlüsselwörter

Antiphospholipid-Antikörper - Antiphospholipid-Syndrom - β2-Glycoprotein I - Lupus Antikoagulanz
 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Schreiber K, Sciascia S, de Groot PG. , et al. Antiphospholipid syndrome. Nat Rev Dis Primers 2018; 4: 17103
    CrossrefPubMedGoogle Scholar
  • 3 Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med 2018; 378 (21) 2010-2021
    CrossrefPubMedGoogle Scholar
  • 4 Harris EN, Gharavi AE, Boey ML. , et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet 1983; 2 (8361): 1211-1214
    PubMedGoogle Scholar
  • 5 Firkin BG, Howard MA, Radford N. Possible relationship between lupus inhibitor and recurrent abortion in young women. Lancet 1980; 2 (8190): 366
    PubMedGoogle Scholar
  • 6 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 (11) 4120-4124
    CrossrefPubMedGoogle Scholar
  • 7 Galli M, Comfurius P, Maassen C. , et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335 (8705): 1544-1547
    CrossrefPubMedGoogle Scholar
  • 8 Matsuura E, Igarashi Y, Fujimoto M, Ichikawa K, Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336 (8708): 177-178
    PubMedGoogle Scholar
  • 9 Arvieux J, Roussel B, Jacob MC, Colomb MG. Measurement of anti-phospholipid antibodies by ELISA using beta 2-glycoprotein I as an antigen. J Immunol Methods 1991; 143 (02) 223-229
    CrossrefPubMedGoogle Scholar
  • 10 de Groot PG, Urbanus RT. The significance of autoantibodies against β2-glycoprotein I. Blood 2012; 120 (02) 266-274
    PubMedGoogle Scholar
  • 11 Pengo V, Tripodi A, Reber G. , et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7 (10) 1737-1740
    CrossrefPubMedGoogle Scholar
  • 12 Reynaud Q, Lega J-C, Mismetti P. , et al. Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis. Autoimmun Rev 2014; 13 (06) 595-608
    CrossrefPubMedGoogle Scholar
  • 13 Lockshin MD, Kim M, Laskin CA. , et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012; 64 (07) 2311-2318
    CrossrefPubMedGoogle Scholar
  • 14 Alessandri C, Conti F, Pendolino M, Mancini R, Valesini G. New autoantigens in the antiphospholipid syndrome. Autoimmun Rev 2011; 10 (10) 609-616
    CrossrefPubMedGoogle Scholar
  • 15 Mulliez SM, De Keyser F, Verbist C. , et al. Lupus anticoagulant-hypoprothrombinemia syndrome: report of two cases and review of the literature. Lupus 2015; 24 (07) 736-745
    CrossrefPubMedGoogle Scholar
  • 16 Branch DW, Dudley DJ, Mitchell MD. , et al. Immunoglobulin G fractions from patients with antiphospholipid antibodies cause fetal death in BALB/c mice: a model for autoimmune fetal loss. Am J Obstet Gynecol 1990; 163 (1, Pt 1): 210-216
    CrossrefPubMedGoogle Scholar
  • 17 Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci U S A 1991; 88 (08) 3069-3073
    CrossrefPubMedGoogle Scholar
  • 18 de Groot PG. The antiphospholipid syndrome finally fathomed?. Blood 2018; 131 (19) 2091-2092
    CrossrefPubMedGoogle Scholar
  • 19 von Landenberg C, Lackner KJ, von Landenberg P, Lang B, Schmitz G. Isolation and characterization of two human monoclonal anti-phospholipid IgG from patients with autoimmune disease. J Autoimmun 1999; 13 (02) 215-223
    CrossrefPubMedGoogle Scholar
  • 20 Prinz N, Häuser F, Lorenz M, Lackner KJ, von Landenberg P. Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody. Immunobiology 2011; 216 (1-2): 145-151
    CrossrefPubMedGoogle Scholar
  • 21 Prinz N, Clemens N, Strand D. , et al. Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood 2011; 118 (08) 2322-2332
    PubMedGoogle Scholar
  • 22 Prinz N, Clemens N, Canisius A, Lackner KJ. Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells. Lessons from the antiphospholipid syndrome. Thromb Haemost 2013; 109 (03) 525-531
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Müller-Calleja N, Köhler A, Siebald B. , et al. Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome. Thromb Haemost 2015; 113 (05) 1071-1083
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Lackner KJ, Manukyan D, Müller-Calleja N. Endosomal redox signaling in the antiphospholipid syndrome. Curr Rheumatol Rep 2017; 19 (04) 20
    CrossrefPubMedGoogle Scholar
  • 25 Müller-Calleja N, Lackner KJ. Mechanisms of cellular activation in the antiphospholipid syndrome. Semin Thromb Hemost 2018; 44 (05) 483-492
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Manukyan D, Müller-Calleja N, Jäckel S. , et al. Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice. J Thromb Haemost 2016; 14 (05) 1011-1020
    CrossrefPubMedGoogle Scholar
  • 27 Fischer C, Buschmann K, Blank M. , et al. Identification of a peptide mimicking the binding pattern of an antiphospholipid antibody. Immunobiology 2006; 211 (09) 695-699
    CrossrefPubMedGoogle Scholar
  • 28 Ikematsu W, Luan FL, La Rosa L. , et al. Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice. Arthritis Rheum 1998; 41 (06) 1026-1039
    CrossrefPubMedGoogle Scholar
  • 29 Girardi G, Berman J, Redecha P. , et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112 (11) 1644-1654
    CrossrefPubMedGoogle Scholar
  • 30 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Pierangeli SS, Liu SW, Anderson G, Barker JH, Harris EN. Thrombogenic properties of murine anti-cardiolipin antibodies induced by beta 2 glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies. Circulation 1996; 94 (07) 1746-1751
    CrossrefPubMedGoogle Scholar
  • 32 Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013; 368 (11) 1033-1044
    CrossrefPubMedGoogle Scholar
  • 33 Müller-Calleja N, Hollerbach A, Häuser F, Canisius A, Orning C, Lackner KJ. Antiphospholipid antibody induced cellular responses depend on epitope specificity: implications for treatment of antiphospholipid syndrome. J Thromb Haemost 2017; 15: 2367-2376
    CrossrefPubMedGoogle Scholar
  • 34 Devreese KMJ, Ortel TL, Pengo V, de Laat B. ; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
    CrossrefPubMedGoogle Scholar
  • 35 Manukyan D, Rossmann H, Schulz A. , et al. Distribution of antiphospholipid antibodies in a large population-based German cohort. Clin Chem Lab Med 2016; 54 (10) 1663-1670
    PubMedGoogle Scholar
  • 36 Montaruli B, De Luna E, Mengozzi G. , et al. Anti-cardiolipin and anti-β2-glycoprotein I antibodies: normal reference ranges in northwestern Italy. Lupus 2012; 21 (07) 799-801
    CrossrefPubMedGoogle Scholar
  • 37 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 (03) 217-225
    CrossrefPubMedGoogle Scholar
  • 38 Blank M, Baraam L, Eisenstein M. , et al. β2-Glycoprotein-I based peptide regulate endothelial-cells tissue-factor expression via negative regulation of pGSK3β expression and reduces experimental-antiphospholipid-syndrome. J Autoimmun 2011; 37 (01) 8-17
    CrossrefPubMedGoogle Scholar
  • 39 Agostinis C, Durigutto P, Sblattero D. , et al. A non-complement-fixing antibody to β2 glycoprotein I as a novel therapy for antiphospholipid syndrome. Blood 2014; 123 (22) 3478-3487
    CrossrefPubMedGoogle Scholar
  • 40 Kolyada A, Porter A, Beglova N. Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome. Blood 2014; 123 (07) 1090-1097
    CrossrefPubMedGoogle Scholar
  • 41 Mineo C, Lanier L, Jung E. , et al. Identification of a monoclonal antibody that attenuates antiphospholipid syndrome-related pregnancy complications and thrombosis. PLoS One 2016; 11 (07) e0158757
    CrossrefPubMedGoogle Scholar
  • 42 Zandman-Goddard G, Pierangeli SS, Gertel S, Blank M. Tolerogenic dendritic cells specific for β2-glycoprotein-I domain-I, attenuate experimental antiphospholipid syndrome. J Autoimmun 2014; 54: 72-80
    CrossrefPubMedGoogle Scholar
  • 43 Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev 2015; 14 (04) 358-362
    CrossrefPubMedGoogle Scholar
  • 44 Lefkou E, Mamopoulos A, Dagklis T, Vosnakis C, Rousso D, Girardi G. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J Clin Invest 2016; 126 (08) 2933-2940
    CrossrefPubMedGoogle Scholar
  • 45 Canaud G, Bienaimé F, Tabarin F. , et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med 2014; 371 (04) 303-312
    CrossrefPubMedGoogle Scholar
  • 46 Meroni PL, Macor P, Durigutto P. , et al. Complement activation in antiphospholipid syndrome and its inhibition to prevent rethrombosis after arterial surgery. Blood 2016; 127 (03) 365-367
    CrossrefPubMedGoogle Scholar
  • 47 Müller-Calleja N, Ritter S, Hollerbach A, Falter T, Lackner KJ, Ruf W. Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies. Blood Adv 2018; 2 (09) 979-986
    CrossrefPubMedGoogle Scholar
  • 48 Erkan D, Salmon JE. The role of complement inhibition in thrombotic angiopathies and antiphospholipid syndrome. Turk J Haematol 2016; 33 (01) 1-7
    PubMedGoogle Scholar
  • 49 Müller-Calleja N, Manukyan D, Canisius A, Strand D, Lackner KJ. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Ann Rheum Dis 2017; 76 (05) 891-897
    CrossrefPubMedGoogle Scholar