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Thromb Haemost 1996; 76(03): 354-360
DOI: 10.1055/s-0038-1650583
Original Article
Schattauer GmbH Stuttgart

Phosphatidylethanolamine Induces Specific Conformational Changes in the Kininogens Recognizable by Antiphosphatidylethanolamine Antibodies[*]

Toshitaka Sugi
1   The Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis, IN, USA
2   The Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan
,
John A McIntyre
1   The Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis, IN, USA
› Author Affiliations
Further Information

Publication History

Received 16 April 1996

Accepted after resubmission 04 June 1996

Publication Date:
10 July 2018 (online)

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Summary

Autoantibodies to the zwitterionic phospholipid (PL), phosphatidylethanolamine (PE) have been described in patients with thrombotic diseases. Recently, we reported that many antiphosphatidylethanolamine antibodies (aPE) are not specific for PE per se, but are directed to plasma proteins which can bind PE, for example, high molecular weight kininogen (HK), low molecular weight kininogen (LK) and/or proteins in complex with HK, factor XI or prekallikrein. In the ELISA, we now show that intact HK binds to all PL tested. By using a monoclonal antibody (mAb) to the HK light chain, binding to cardiolipin (CL) was highest followed by phosphatidylserine (PS), PE and phosphatidylcholine (PC). By contrast, LK bound best to PE, with lesser amounts binding to PC and CL. Many aPE recognize only a kininogen-PE complex and neither PE nor kininogen when they are tested independently. We now report that these aPE are specific for the kininogen-PE complex as they do not recognize the kininogens when the latter are presented on other PL substrates. This indicates that PE induces unique antigenic conformational changes in the kininogens which are not induced when the kininogens bind to other PL. The kininogens bind to platelets and endothelial cells through an as yet undefined receptor. Since PE is a normal constituent of the outer layer of cell and platelet plasma membranes, it is available for the kininogens to bind. In vitro studies showed that purified IgG which bound kininogen-PE complexes in ELISA also caused platelets to undergo irreversible aggregation when stimulated by subthreshold concentrations of bovine thrombin.

* Supported in part by a grant from the Showalter Foundation


 

  • References

  • 1 McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol 1991; 49: 193-280
    PubMedGoogle Scholar
  • 2 Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome. J Rheumatol 1986; 13: 486-489
    PubMedGoogle Scholar
  • 3 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682-698
    CrossrefPubMedGoogle Scholar
  • 4 Triplett DA. Obstetrical complications associated with antiphospholipid antibodies. In: Immunological Obstetrics Coulam CB, Faulk WP, McIntyre JA. (eds) New York: W. W. Norton; 1992: 377-403
  • 5 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: P2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA 1990; 87: 4120-4124
    CrossrefPubMedGoogle Scholar
  • 6 Galli M, Comfurius P, Massen C, Hemker HC, De Baets MH, van Breda-Vriesman PJC, Barbui T, Zwaal RFA, Bevers EM. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544-1547
    CrossrefPubMedGoogle Scholar
  • 7 Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988; 72: 512-529
    PubMedGoogle Scholar
  • 8 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RFA. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629-632
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Oosting JD, Derksen RHWM, Bobbink IWG, Hackeng TM, Bouma BN, DeGroot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism?. Blood 1993; 81: 2618-2625
    PubMedGoogle Scholar
  • 10 Zwaal RFA, Hemker HC. Blood cell membranes and haemostasis. Haemostasis 1982; 11: 12-39
    PubMedGoogle Scholar
  • 11 Bevers EM, Comfurius P, Zwaal RFA. Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys. Acta 1983; 736: 57-66
    CrossrefPubMedGoogle Scholar
  • 12 Staub HL, Harris EN, Khamashta MH, Savidge G, Chahade WH, Hughes GRV. Antibody to phosphatidylethanolamine in a patient with lupus anticoagulant and thrombosis. Ann Rheum Dis 1989; 48: 166-169
    CrossrefPubMedGoogle Scholar
  • 13 Karmochkine M, Cacoub P, Piette JC, Godear P, Boffa MC. Antiphosphatidyl ethanolamine antibody as the sole antiphospholipid antibody in systemic lupus erythematosus with thrombosis. Clin Exp Rheumatol 1992; 10: 603-605
    PubMedGoogle Scholar
  • 14 Karmochkine M, Berard M, Piette JC, Cacoub P, Ailland MF, Harlet JR, Godeau P, Boffa MC. Antiphosphatidylethanolamine antibodies in systemic lupus erythematosus. Lupus 1993; 157-160
    PubMedGoogle Scholar
  • 15 Boffa MC, Berard M, Sugi T, McIntyre JA. Kininogen reactivity of antiphosphatidylethanolamine antibodies found as the sole antiphospholipid antibodies in thrombosis and vascular cutaneous disease. J Rheumatol 1996 (in press)
    Google Scholar
  • 16 Sugi T, McIntyre JA. Autoantibodies to phosphatidylethanolamine (PE) recognize a kininogen-PE complex. Blood 1995; 86: 3083-3089
    CrossrefPubMedGoogle Scholar
  • 17 Schmaier AH, Zuckerberg A, Silverman C, Kuchibholta J, Tsuzynski GP, Colman RW. High molecular weight kininogen. A secreted platelet protein. J Clin Invest 1983; 71: 1477-1489
    PubMedGoogle Scholar
  • 18 Schmaier AH, Smith PM, Purdon AD, White JG, Colman RW. High molecular weight kininogen: Localization in the unstimulated and activated platelet and activation by a platelet calpain(s). Blood 1986; 67: 119-130
    PubMedGoogle Scholar
  • 19 Greengard JS, Griffin JH. Receptors for high molecular weight kininogen on stimulated washed human platelets. Biochemistry 1984; 23: 6863-6869
    CrossrefPubMedGoogle Scholar
  • 20 Gustafson EJ, Schutsky D, Knight L, Schmaier AH. High molecular weight kininogen binds to unstimulated platelets. J Clin Invest 1986; 78: 310-318
    CrossrefPubMedGoogle Scholar
  • 21 Schmaier AH, Kuo A, Lundberg D, Murray S, Cines DB. Expression of high molecular weight kininogen on human umbilical vein endothelial cells. J Biol Chem 1988; 263: 16327-16333
    PubMedGoogle Scholar
  • 22 Van Iwaarden F, deGroot PG, Bouma GN. The binding of high molecular weight kininogen to cultured human endothelial cells. J Biol Chem 1988; 263: 4698-4703
    PubMedGoogle Scholar
  • 23 Meloni FJ, and Schmaier AH. Low molecular weight kininogen binds to platelets to modulate thrombin-induced platelet activation. J Biol Chem 1991; 266: 6786
    PubMedGoogle Scholar
  • 24 Weisel JW, Nagaswami C, Woodhead JL, De La Cadena RA, Page JD, Colman RW. The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interaction with pre-kallikrein, as determined by electron microscopy. J Biol Chem 1994; 269: 10100-10106
    PubMedGoogle Scholar
  • 25 Puri RN, Zhou F, Hu CJ, Colman RF, Colman RW. High molecular weight kininogen inhibits thrombin-induced platelet aggregation and cleavage of aggregin by inhibiting binding of thrombin to platelets. Blood 1991; 77: 500-507
    PubMedGoogle Scholar
  • 26 McNeil HP, Krilis SA, Chesterman CN. Purification of antiphospholipid antibodies using a new affinity method. Thromb Res 1988; 52: 641-648
    CrossrefPubMedGoogle Scholar
  • 27 Johnson DA, Salvesen G, Brown MA, Barrett AJ. Rapid isolation of human kininogens. Thromb Res 1987; 48: 187-193
    CrossrefPubMedGoogle Scholar
  • 28 Komiya M, Kato H, Suzuki T. Bovine plasma kininogens. III. Structural comparison of high molecular weight and low molecular weight kininogens. J Biochem 1974; 76: 833-845
    PubMedGoogle Scholar
  • 29 Han YN, Komiya M, Iwanaga S, Suzuki T. Studies on the primary structure of bovine high-molecular-weight kininogen: Amino acid sequence of a fragment (“histidine-rich peptide”) released by plasma kallikrein. J Biochem 1975; 77: 55-68
    PubMedGoogle Scholar
  • 30 Scott CF, Silver LD, Schapira M, Colman RW. Cleavage of human high molecular weight kininogen markedly enhances its coagulant activity: Evidence that this molecule exists as a procofactor. J Clin Invest 1984; 73: 954-962
    CrossrefPubMedGoogle Scholar
  • 31 Jian T, Muller-Estel W, Schmaier AH. Domain 3 of kininogens contains a cell-binding site and a site that modifies thrombin activation of platelets. J Biol Chem 1992; 267: 3712-3717
    PubMedGoogle Scholar
  • 32 Reddigari SR, Kuna P, Miragliotta G, Shibayama Y, Nishikawa K, Kaplan A. Human high molecular weight kininogen binds to human umbilical vein endothelial cells via its heavy and light chains. Blood 1993; 81: 1306-1311
    PubMedGoogle Scholar
  • 33 Meloni FJ, Gustafson EJ, Schmaier AH. High molecular weight kininogen binds to platelets by its heavy and light chains and when bound has altered susceptibility to kallikrein cleavage. Blood 1992; 79: 1233-1244
    CrossrefPubMedGoogle Scholar
  • 34 Kunapuli SP, Colman RW. Platelet-kininogen interactions. Platelets 1993; 4: 61-65
    CrossrefPubMedGoogle Scholar
  • 35 Wachtfogel YT, DeLa CadenaRA, Kunapuli SP, Rick L, Miller M, Schultze RL, Altieri DC, Edington TS, Colman RW. High molecular weight kininogen binds to Mac-1 on neutrophils by its heavy chain (domain 3) and its light chain (domain 5). J Biol Chem 1994; 269: 19307-19312
    PubMedGoogle Scholar
  • 36 De La Cadena RA, Wyshock EG, Walz DA, Colman RW. Structural determinants of the binding of human high molecular weight kininogen (HK) to platelet thrombospondin (TSP). Thromb Haemost 1992; 65: 699
    PubMedGoogle Scholar