Atherogenic Oxidized Low-Density Lipoprotein/β2-Glycoprotein I (oxLDL/β2GPI) Complexes in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Abstract

Oxidized low-density lipoprotein (oxLDL) interacts in vitro with β ₂-glycoprotein I (β ₂GPI) via LDL-derived specific ligands forming oxLDL/β ₂GPI complexes. Circulating oxLDL/β ₂GPI complexes have been demonstrated in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Autoimmune vascular inflammation and oxidative stress contribute to oxLDL/β ₂GPI complex formation. Immunohistochemical staining of atherosclerotic lesions suggest that these complexes are formed in the arterial wall and released into circulation. The demonstration of antibodies to oxLDL/β ₂GPI complexes indicates that these complexes are immunogenic, and the coexistence of complexes and antibodies suggest an active pro-thrombotic/pro-atherogenic role in the development of autoimmune vascular complications. Circulating oxLDL/β ₂GPI complexes can be measured by ELISA using a monoclonal antibody specific to complexed human β ₂GPI to capture β ₂GPI bound to oxLDL. An enzyme-conjugated monoclonal antibody to human Apo B 100 allows the specific detection of oxLDL/β ₂GPI complexes. OxLDL/β ₂GPI complexes were common in SLE and APS patients suggesting an underlying process of inflammation and oxidation. Using oxLDL/β ₂GPI complexes as capture antigen, antibodies to oxLDL/β ₂GPI can be measured by ELISA. Serum levels of IgG anti-oxLDL/β ₂GPI antibodies were significantly higher in SLE patients with APS compared to SLE controls without APS. Further, high titers of these IgG antibodies were observed in APS patients with a history of arterial thrombosis. The presence of circulating oxLDL/β ₂GPI complexes and IgG antibodies to these complexes indicates significant vascular injury and oxidative stress as well as an active role in autoimmune-mediated atherothrombosis.

Keywords

antiphospholipid antibodies autoimmunity oxidized-LDL antibodies

Get full access to this article

View all access options for this article.

References

Ross R. Atherosclerosis: an inflammatory disease . N Engl J Med 1999; 340: 115-126 .

Steinberg D. Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime . Nature Med 2002; 8: 1211-1217 .

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

Ames PRJ , Alves J , Murat I , Isenberg DA , Nourooz-Zadeh J. Oxidative stress in systemic lupus erythematosus and allied conditions with vascular involvement . Rheumatology 1999; 38: 529-534 .

Pratico D , Ferro D , Iuliano G et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation . Blood 1999; 93: 3401-3407 .

Lambert M , Boullier A , Hachulla E et al. Paraoxonase activity is dramatically decreased in patients positive for anticardiolipin antibodies . Lupus 2000; 9: 299-300 .

Delgado Alves J , Ames PR , Donohue S et al. Antibodies to high-density lipoprotein and β2-glycoprotein I are inversely correlated with Paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome . Arthritis Rheum 2002; 46: 2686-2694 .

McMurray HF , Parthasarathy S , Steinberg D. Oxidatively modified low-density lipoprotein is a chemoattractant for human T lymphocytes . J Clin Invest 1993; 92: 1004-1008 .

Salonen JT , Yla-Herttuala S , Yamamoto R et al. Autoantibodies against oxidized LDL and progression of carotid atherosclerosis . Lancet 1992; 339: 883-887 .

10.

Virella G , Atchley DH , Koskinen S , Zheng D , Lopes-Virella M. Pro-atherogenic and pro-inflammatory properties of immune complexes prepared with purified human oxLDL antibodies and human oxLDL . Clin Immunol 2002; 105: 81-92 .

11.

Yla-Herttuala S , Palinski W , Rosenfeld ME et al. Evidence for presence of oxidatively modified low-density lipoprotein in atherosclerotic lesions of rabbit and man . J Clin Invest 1989; 85: 1086-1095 .

12.

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

13.

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

14.

Brey RL , Abbott RD , Curb JD et al. β2-glycoprotein I dependent anti-cardiolipin antibodies and the risk of ischemic stroke and myocardial infarction . Stroke 2001; 32: 1701-1706 .

15.

Ward MM. Premature morbidity from cardiovascular and cerebrovascular diseases in women with systemic lupus erythematosus . Arthritis Rheum 1999; 42: 338-346 .

16.

Aranow C , Ginzler EM. Epidemiology of cardiovascular disease in systemic lupus erythematosus . Lupus 2000; 9: 166-169 .

17.

Esdaile JM , Abrahamowicz M , Grodzicky T et al. Traditional Framing-ham risk factors fail to fully account for accelerated atherosclerosis in systemic lupus erythematosus . Arthritis Rheum 2001; 44: 2331-2337 .

18.

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 Immunol 1997; 107: 569-573 .

19.

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 .

20.

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

21.

Matsuura E , Kobayashi K , Koike T , Shoenfeld Y , Khamashta MA , Hughes GRV. Oxidized low-density lipoprotein as a risk factor of thrombosis in antiphospholipid syndrome . Lupus 2003; 12: 550-554 .

22.

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 .

23.

Lopez D , Garcia-Valladares I , Palafox-Sanchez C et al. Oxidized low-density lipoprotein/β2-glycoprotein I complexes and autoantibodies to oxLig-1/β2-glycoprotein I in patients with systemic lupus erythematosus and antiphospholipid syndrome . Am J Clin Pathol 2004; 121: 426-436 .

24.

Lopez D , Kobayashi K , Merrill JT , Matsuura E , Lopez LR. IgG autoantibodies against β2-glycoprotein I complexed with a lipid ligand derived from oxidized low-density lipoprotein are associated with arterial thrombosis in antiphospholipid syndrome . Clin Dev Immunol 2003; 10: 203-211 .

25.

Lopez LR , Simpson DF , Hurley BL , Matsuura E. OxLDL/β2GPI complexes and autoantibodies in patients with systemic lupus erythematosus, systemic sclerosis, and antiphospholipid syndrome: pathogenic implications for vascular involvement . Ann N Y Acad Sci 2005; 1051: 313-322 .

26.

Tan EM , Choen AS , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271-1277 .

27.

Wilson WA , Gharavi AE , Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop . Arthritis Rheum 1999; 42: 1309-1311 .

28.

Hashimoto Y , Kawamura M , Ichikawa K et al. Anticardiolipin antibodies in NZW × BXSB F1 mice. A model of antiphospholipid syndrome . J Immunol 1992; 149: 1063-1068 .

29.

Ichikawa K , Khamashta MA , Koike T et al. β2-Glycoprotein I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome . Arthritis Rheum 1994; 37: 1453-1461 .

30.

Finlayson JS , Mushinski JF. Separations of subfractions of human β 2- glycoprotein I . Biochim Biophys Acta 1967; 147: 413-420 .

31.

Havel RJ , Eder HA , Bragdon JH. The distribution and chemical composition of ultracentifugally separated lipoproteins in human serum . J Clin Invest 1955; 43: 1345-1353 .

32.

Parthasarathy S , Fong LG , Quinn MT , Steinberg D. Oxidative modification of LDL: comparison between cell-mediated and copper-mediated modification . Eur Heart J 1990; 11 (Suppl E): 83-87 .

33.

Morgan PE , Sturgess AD , Davies M. Increased levels of serum protein oxidation and correlation with disease activity in systemic lupus erythematosus . Arthritis Rheum 2005; 52: 2869-2879 .

34.

Frostegard J , Svenungsson E , Wu R et al. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations . Arthritis Rheum 2005; 52: 192-200 .

35.

Geroge J , Blank M , Hojnik M et al. Oxidized low-density lipoprotein (oxLDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS) . Clin Exp Immunol 1997; 108: 277-333 .

36.

Shoenfeld Y , Wu R , Dearing LD , Matsuura E. Are anti-oxidized low-density lipoprotein antibodies pathogenic or protective ? Circulation 2004; 110: 2552-2558 .

37.

Lopez LR , Salazar-Paramo M , Palafox-Sanchez C , Hurley BL , Matsuura E , Garcia De La Torre I. Oxidized low-density lipoprotein and β 2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis . Lupus 2006; 15: 80-86 .