Oxidized LDL/β2-glycoprotein I complexes: new aspects in atherosclerosis

Abstract

β₂-glycoprotein I (β₂GPI) is a major antigenic target for antiphospholipid antibodies. Oxidized low-density lipoprotein (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it colocalizes with β₂GPI and immunoreactive lymphocytes. oxLDL/β₂GPI complexes appeared in the blood circulation of patients with diseases, such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis, diabetes mellitus and chronic renal diseases. Thus, the complexes may be associated with systemic and chronic inflammation of the vasculature. IgG anti-oxLDL/β₂GPI complexes autoantibodies and their immune complexes were detected only in SLE/APS patients and in its animal model and were strongly associated with arterial thrombosis. The oxLDL/β₂GPI complexes were internalized by macrophages via IgG anti-β₂GPI antibody-mediated phagocytosis. In contrast, IgM anti-oxLDL antibodies derived from hyperlipidemic mice reduced the incidence of atherosclerosis. The distribution patterns of IgG and IgM anti-oxLDL antibodies in patients suggest the different roles of these antibodies.

Keywords

antiphospholipid syndrome (APS)atherosclerosis autoantibody β2-glycoprotein I (β2GPI)oxidized low-density lipoprotein (oxLDL)

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References

Steinbrecher UP , Parthasarathy S , Leake DS , Witztum JL , Steinberg D. Modification of low-density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low-density lipoprotein phospholipids . Proc Natl Acad Sci USA 1984; 81: 3883-3887 .

Steinberg D , Parthasarathy S , Carew TE , Khoo JC , Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity . N Engl J Med 1989, 320: 915-924 .

Steinberg D. Low-density lipoprotein oxidation and its pathobiological significance . J Biol Chem 1997, 272: 20963-20966 .

Hughes GRV , Harris EN , Gharavi AE. The anticardiolipin syndrome . J Rheumatol 1986; 13: 486-489 .

Harris EN , Gharavi AE , Boey ML et al. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus . Lancet 1983, 2: 1211-1214 .

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: β2-glycoprotein I (apolipoprotein H) . Proc Natl Acad Sci USA 1990; 87: 4120-4124 .

Galli M , Comfurius P , Maassen C et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor . Lancet 1990; 335: 1544-1547

Matsuura E , Igarashi Y , Fujimoto M , Ichikawa K , Koike T. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease . Lancet 1990; 336: 177-178 .

Matsuura E , Igarashi Y. Fujimoto M et al. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor . J Immunol 1992; 148: 3885-3891 .

10.

Matsuura E , Igarashi Y , Yasuda T , Triplett DA , Koike T. Anticardiolipin antibodies recognize β2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface . J Exp Med 1994; 179: 457-462 .

11.

George J , Harats D , Gilburd B et al. Immunolocalization of β2-glycoprotein I(apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression . Circulation 1999; 99: 2227-2230 .

12.

Vaarala O , Alfthan G , Jauhiainen M et al. Crossreaction between antibodies to oxidised low-density lipoprotein and to cardiolipin in systemic lupus erythematosus . Lancet 1993; 341: 923-925 .

13.

Tinahones FJ , Cuadrado MJ , Khamashta MA et al. Lack of cross reaction between antibodies to β2-glycoprotein-I and oxidized low-density lipoprotein in patients with antiphospholipid syndrome . Br J Rheumatol 1998; 37: 746-749 .

14.

Romero FI , Amengual O , Atsumi T et al. Arterial disease in lupus and secondary antiphospholipid syndrome: association with anti-β2-glycoprotein I antibodies but not with antibodies against oxidized low-density lipoprotein . Br J Rheumatol 1998; 37: 883-888 .

15.

Kobayashi K , Kishi M , Atsumi T et al. Circulating oxidized LDL forms complexes with β2-glycoprotein I: implication as an atherogenic autoantigen . J Lipid Res 2003; 44: 716-726 .

16.

Hasunuma Y , Matsuura E , Makita Z et al. Involvement of β2-glycoprotein I and anticardiolipin antibodies in oxidatively modified low-density lipoprotein uptake by macrophages . Clin Exp Immunol 1997; 107: 569-573 .

17.

Kobayashi K , Matsuura E , Liu Q et al. A specific ligand for β2-glycoprotein I mediates autoantibody-dependent uptake of oxidized low density lipoprotein by macrophages . J Lipid Res 2001; 42: 697-709 .

18.

Liu Q , Kobayashi K , Inagaki J et al. v-carboxyl variants of 7- ketocholesteryl esters are ligands for β2-glycoprotein I and mediate antibody-dependent uptake of oxidized LDL by macrophages . J Lipid Res 2002; 43: 1486-1495 .

19.

Chang MK , Bergmark C , Laurila A et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition . Proc Natl Acad Sci USA 1999; 96: 6353-6358 .

20.

Horkko S , Bird DA , Miller E et al. Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins . J Clin Invest 1999; 103: 117-128 .

21.

Binder CJ , Horkko S , Dewan A et al. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL . Nat Med 2003; 9: 736-743 .

22.

Rose N , Afanasyeva M. Autoimmunity: busting the atheorsclerotic plaque . Nat Med 2003; 9: 641-642 .

23.

Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other “antiphospholipid” autoantibodies . Blood 1994; 84: 2854-2867 .

24.

Vaarala O. Antiphospholipid antibodies in myocardial infarction . Lupus 1998; 7: S132-S134 .

25.

Brey RL , Abbott RD Curb JD et al. b2-glycoprotein I dependent anticardiolipin antibodies and the risk of ischemic stroke and myocardial infarction . Stroke 2001; 32: 1701-1706 .

26.

Tsutsumi A , Matsuura E , Ichikawa K et al. Antibodies to β2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus . Arthritis Rheum 1996; 39: 1466-1474 .

27.

Lopez LR , Dier KJ , Lopez D , Merrill JT , Fink CA. Anti-β2-glycoprotein I and antiphosphatidylserine antibodies are predictors of arterial thrombosis in patients with antiphospholipid syndrome . Am J Clin Pathol 2004; 121: 142-149 .

28.

Petri M. Autoimmune thrombosis. In Asherson RA , Cervera R , Piette J , Schoenfeld Y , eds. The antiphospholipid syndrome, Amsterdam: Elsevier Science , 2002: 11-20.

29.

Wahl DG , Guillemin F , de Maistre E et al. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus: a meta analysis . Lupus 1997; 6: 467-473 .

30.

Khamashta MA , Cuadrado MJ , Mujic F et al. The management of thrombosis in the antiphospholipid-antibody syndrome . N Engl J Med 1995; 332: 993-997 .