Several interpretations have been made regarding the specificity of antiphospholipid antibodies and antibodies against oxidized low-density lipoprotein (oxLDL), but these are still controversial. In the present study, we delineated specificity of these two types of antibodies and analyzed their regulatory effect on oxLDL and/or β 2-glycoprotein I (β2GPI) binding to macrophages. Scavenger receptor-mediated binding of oxLDL (or its β2GPI complexes) to macrophages was observed and the binding was partly prevented by β 2GPI. The IgG monoclonal anti-β2GPI antibody (WB-CAL-1), which was derived from NZW × BXSB F1 mouse (a model of antiphospholipid syndrome), significantly increased the oxLDL/β2GPI binding to macrophages. In contrast, IgM anti-oxLDL natural antibody, EO6 (derived from apoe -/- mouse), prevented the binding. Different antigenic specificity of these antibodies to oxLDL and its β2GPI complexes was also confirmed in TLC—ligand blot and ELISA. Thus, IgG anti-β2 GPI autoantibodies contribute to lipid metabolism (housekeeping of oxLDL by macrophages) whereas IgM natural anti-oxLDL antibodies may protect against atherogenesis. In addition, in vitro data suggest that relatively high dose of intravenous immunoglobulin preparations (mainly contain IgG anti-oxLDL antibodies) might also prevent atherogenesis by inhibiting the oxLDL binding to macrophages. Lupus (2007) 16, 929—938.
Matsuura E., Igarashi Y., Fujimoto M., Ichikawa K., Koike T.Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease . Lancet1990; 336: 177—178.
2.
Galli M., Comfurius P., Maassen C. et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet1990 ; 335: 1544—1547.
3.
McNeil HP , Simpson RJ, Chesterman CN, Krilis SAAnti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA1990; 87: 4120—4124.
4.
Bouma B., de Groot PG, van den Elsen JM et al. Adhesion mechanism of human β2-glycoprotein I to phospholipids based on its crystal structure. EMBO J1999 ; 18: 5166—5174.
Shoenfeld Y. , Gerli R., Doria A. et al. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation2005; 112: 3337—3347.
7.
George J., Harats D., Gilburd B. et al. Adoptive transfer of β2-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice . Circulation2000; 102: 1822—1827.
8.
Yla-Herttuala S., Palinski W., Rosenfeld ME et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest1989; 84: 1086—1095.
9.
Lehtimaki T. , Lehtinen S., Solakivi T. et al. Autoantibodies against oxidized low density lipoprotein in patients with angiographically verified coronary artery disease. Arterioscler Thromb Vasc Biol1999 ; 19: 23—27.
10.
Yasunobu Y. , Hayashi K., Shingu T., Yamagata T., Kajiyama G., Kambe M.Coronary atherosclerosis and oxidative stress as reflected by autoantibodies against oxidized low-density lipoprotein and oxysterols. Atherosclerosis2001; 155: 445—453.
11.
Zhang SH, Reddick RL, Piedrahita JA, Maeda N.Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science1992; 258: 468—471.
12.
Palinski W. , Horkko S., Miller E. et al. Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma . J Clin Invest1996; 98: 800-814.
13.
Shaw PX, Horkko S., Chang MK et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest2000; 105: 1731—1740.
14.
Itabe H., Takeshima E., Iwasaki H. et al. A monoclonal antibody against oxidized lipoprotein recognizes foam cells in atherosclerotic lesions. Complex formation of oxidized phosphatidylcholines and polypeptides. J Biol Chem1994; 269: 15274—15279.
15.
Friedman P. , Horkko S., Steinberg D., Witztum JL, Dennis EACorrelation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids. Importance of Schiff base formation and aldol concentration. J Biol Chem2002; 277: 7010—7020.
16.
Itabe H., Yamamoto H., Suzuki M. et al. Oxidized phosphatidylcholines that modify proteins. Analysis by monoclonal antibody against oxidized low density lipoprotein. J Biol Chem1996; 271: 33208—33217.
17.
Hasunuma Y. , Matsuura E., Makita Z., Katahira T., Nishi S., Koike T.Involvement of β2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages. Clin Exp Immunol1997 ; 107: 569—573.
18.
Kobayashi K. , Matsuura E., Liu Q. et al. A specific ligand for β2glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages. J Lipid Res2001; 42: 697—709.
19.
Liu Q., Kobayashi K., Furukawa J. et al. ω-Carboxyl variants of 7-ketocholesteryl esters are ligands for β2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages. J Lipid Res2002; 43: 1486—1495.
20.
Kobayashi K. , Kishi M., Atsumi T. et al. Circulating oxidized LDL forms complexes with β2-glycoprotein I: implication as an atherogenic autoantigen . J Lipid Res2003; 44: 716—726.
21.
Matsuura E. , Kobayashi K., Tabuchi M., Lopez LROxidative modification of low-density lipoprotein and immune regulation of atherosclerosis. Prog Lipid Res2006; 45: 466—486.
22.
Vaarala O., Alfthan G., Jauhiainen M., Leirisalo-Repo M., Aho K., Palosuo T.Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet1993; 341: 923—935.
23.
Wu R., Svenungsson E., Gunnarsson I., Haegerstrand-Gillis C. et al. Antibodies to adult human endothelial cells cross-react with oxidized low-density lipoprotein and β2-glycoprotein I (β 2-GPI) in systemic lupus erythematosus. Clin Exp Immunol1999; 115: 561—566.
24.
Hurez V., Kaveri SV, Kazatchkine MDNormal polyspecific immunoglobulin G (IVIg) in the treatment of autoimmune diseases. J Autoimmun1993; 6: 675—681.
25.
Righi A., Schiavon F., Jablonska S. et al. Intravenous immunoglobulins control scleromyxoedema. Ann Rheum Dis2002; 61: 59—61.
26.
Shoenfeld Y. , Katz U.IVIG therapy in autoimmunity and related disorders: our experience with a large cohort of patients. Autoimmunity2005; 38: 123—137.
27.
Yuan Z., Kishimoto C., Sano H., Shioji K., Xu Y., Yokode M.Immunoglobulin treatment suppresses atherosclerosis in apolipoprotein E-deficient mice via the Fc portion. Am J Physiol Heart Circ Physiol2003; 285: H899—H906.
28.
Igarashi M. , Matsuura E., Igarashi Y. et al. Human β2-glycoprotein I as an anticardiolipin cofactor determined using mutants expressed by a baculovirus system. Blood1996; 87: 3262—3270.
29.
Hashimoto Y. , Kawamura M., Ichikawa K. et al. Anticardiolipin antibodies in NZWxBXSB F1 mice. A model of antiphospholipid syndrome. J Immunol1992; 149: 1063—1068.
30.
Ichikawa K. , Khamashta MA, Koike T., Matsuura E., Hughes GRV.β2-Glycoprotein I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome. Arthritis Rheum1994; 37: 1453—1461.
31.
Havel RJ, Eder HA, Bragdon JHThe distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest1955; 34: 1345—1353.
32.
Matsuura E. , Inagaki J., Kasahara H. et al. Proteolytic cleavage of β 2glycoprotein I: reduction of antigenicity and the structural relationship . Int Immunol2000; 12: 1183—1192.
33.
Matsuura E. , Igarashi Y., Yasuda T., Triplett DA, Koike T.Anticardiolipin antibodies recognize β 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med1994; 179: 457—462.
34.
Kasahara H. , Matsuura E., Kaihara K. et al. Antigenic structures recognized by anti-β2-glycoprotein I autoantibodies. Int Immunol2005; 17: 1533—1542.
35.
Kuwana M., Matsuura E., Kobayashi K. et al. Binding of β2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells. Blood2005 ; 105: 1552—1557.
36.
Yamaguchi Y. , Seta N., Kaburaki J., Kobayashi K., Matsuura E., Kuwana M.Excessive exposure to anionic surfaces maintains autoantibody response to β 2-glycoprotein in patients with antiphospholipid syndrome. Blood (in press).
37.
Binder CJ, Horkko S., Dewan A. et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med2003; 9: 736—743.
38.
Shoenfeld Y. , Krause I.IVIG for autoimmune, fibrosis, and malignant conditions: our experience with 200 patients. J Clin Immunol2004; 24: 107—114.
Wu R., Shoenfeld Y., Sherer Y. et al. Anti-idiotypes to oxidized LDL antibodies in intravenous immunoglobulin preparations—possible immunomodulation of atherosclerosis. Autoimmunity2003; 36: 91—97.
