Antibodies against lysophosphatidylcholine and oxidized LDL in patients with SLE

Abstract

Lysophosphatidylcholine (LPC) is present in oxidized low density lipoprotein (oxLDL), which is implicated in atherosclerosis. Antibodies to cardiolipin (aCL) and oxLDL (aoxLDL) have been shown to crossreact. LPC is formed by hydrolysis of phosphatidylcholine (PC) in LDL and cell membranes, induced by phospholipase A2 or by oxidation. We here demonstrate the presence of enhanced antibody levels to LPC in 184 patients with SLE as compared to 85 healthy, age-matched controls. The antibody reactivity to LPC was not specifically related to oxidation of the fatty acid moiety in LPC, since LPC containing only the saturated fatty acid palmitic acid showed equivalent antibody levels as LPC containing unsaturated fatty acids. aPC were significantly lower as compared to aLPC, indicating that hydrolysis of PC at the sn-2 position increases the antigenic potential of the molecule. β-glycoprotein 1 was a cofactor for aCL, but not for aoxLDL or aLPC, and the antigenicity of these compounds is therefore not directly related to β2GP1.

There was a close correlation between aoxLDL, aCL and aLPC and both LPC and oxLDL competitively inhibited aCL-binding to CL. LPC, oxLDL and CL thus display a common antigenic site, which could be formed by removal of a fatty acid at the sn-2 position, possibly due to the activity to phospholipase A2 and/or oxidation. This study indicates the potential role of LDL-oxidation and phospholipase A2 in SLE.

Keywords

SLE phospholipid antibodies oxidized LDL lysophosphatidylcholine cardiovascular disease

References

Shapiro S . The lupus anticoagulant/antiphospholipid syndrome . Annu Rev Med 1996; 47: 533–553 .

Hojnik M , George J , Ziporen L , Schoenfeld Y . Heart valve involvement (Libman–Sacks endocarditis) in the antiphospholipid syndrome . Circulation 1996; 93: 1579–1587 .

Harris EN , Pierangeli SS . Antiphospholipid antibodies and the antiphospholipid syndrome . Springer Semin Immunopathol 1994; 16: 223–245 .

McNeil HP , Simpson RJ , Chesterman CN , Krilis SA . Anti-phospho-lipid 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 1990; 87: 4120–4124 .

Hörkkö S et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids . J Clin Inv 1996; 98: 815–825 .

Steinberg D et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity . N Eng J Med 1989; 320: 915–924 .

Frostegård J et al. Oxidized low-density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937 . Proc Natl Acad Sci USA 1990; 87: 904–908 .

Frostegård J et al. Induction of T cell activation by oxidized low density lipoprotein . Arteriosclerosis and Thrombosis 1992; 12: 461–467 .

Huang YH , Rönnelid J , Frostegård J . Oxidized LDL induces enhanced antibody formation and MHC class II dependent IFN-gamma production in lymphocytes from healthy individuals . Arterioscl, Thromb and Vasc Biol 1995; 15: 1577–1583 .

10.

Gladman DD . Prognosis of systemic lupus erythematosus and factors that affect it . Curr Op Rheum 1990; 2: 694–702 .

11.

Sturfelt G et al. Cardiovascular disease in systemic lupus erythematosus, a study of 75 patients from a defined population . Medicine 1992; 71: 216–223 .

12.

Petri M , Perez-Gutthann S , Spence D and Hochberg MC. Risk factors for coronary artery disease in patients with systemic lupus erythematosus . Am J Med 1992; 93: 513–519 .

13.

Drenkard C , Villa AR , Alarcón-Segovia D , Pérés-Vazquez ME . Influence of the antiphospholipid syndrome in the survival of patients with systemic lupus erythematosus . J Rheumatol 1994; 21: 1067–1072 .

14.

Ginsburg KS et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis . Ann Intern Med 1992; 117: 997–1002 .

15.

Manzi S et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study . Am J Epidem 1997; 145: 408–415 .

16.

Belmont M , Abramson B , Lie JT . Pathology and pathogenesis of vascular injury in systemic lupus erythematosus . Arthritis & Rheumatism 1996; 39: 9–22 .

17.

Vaarala O et al. Crossreaction between antibodies to oxidised lowdensity lipoprotein and to cardiolipin in systemic lupus erythematosus . Lancet 1993; 341: 923–925 .

18.

Salonen JT et al. Autoantibody against oxidized LDL and progression of carotid atherosclerosis . Lancet 1992; 339: 883–887 .

19.

Quinn MT , Parthasarathy S , Steinberg D . Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis . Proc Natl Acad Sci 1988; 85: 2805–2809 .

20.

Liu M , Subbaiah PV . Hydrolysis and transesterification of platelet-activating factor by lecithin-cholesterol acyltransferase . Proc Natl Acad Sci USA 1994; 91: 6035–6039 .

21.

Wu R , Huang Y , Schäfer-Elinder L , Frostegård J . Lysophosphatidylcholine is involved in the antigenicity of oxLDL . Arteriosclerosis, Thrombosis and Vasc Biol 1998; 18: 626–630 .

22.

Schäfer-Elinder L et al. Presence of different isoforms of phospholipase A2 in tissue slices from atherosclerotic carotid plaque . Arteriosclerosis, Thrombosis and Vasc Biol 1997; 17: 2257–2262 .

23.

Tan EM et al. The 1982 revised criteria for classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271–1277 .

24.

Havel RJ , Eder HA , Bragdon JH . The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum . J Clin Invest 1955; 34: 1345–1353 .

25.

Lowry O , Rosebrough NJ , Farr AL , Randall RJ . Protein measurement with the Folin phenol reagent . J Biol Chem 1951; 193: 265–275 .

26.

Wu R , Lefvert AK . Autoantibodies against oxidized low density lipoprotein: characterization of antibody isotyp, subclass, affinity and effect on the macrophage uptake of oxLDL . Clin Exp Immunol 1995; 102: 174–180 .

27.

Harris EN , Gharavi AE , Patel SP , Hughes GRV . Evaluation of the anticardiolipin antibody test: report of an international workshop held 4 April 1986 . Clin Exp Immunol 1986; 68: 215–222 .

28.

Nityanand S et al. Antibodies against endothelial cells and cardiolipin in young patients with peripheral atherosclerotic disease . J Int Med 1995; 238: 437–443 .

29.

Olee T et al. A monoclonal IgG anticardiolipin antibody from a patient with the antiphospholipid syndrome is thrombogenic in mice . Proc Natl Acad Sci 1996; 93: 8606–8611 .

30.

McDonald J , Stewart J , Urowitz M , Gladman D . Peripheral vascular disease in patients with systemic lupus erythematosus . Ann Rheum Dis 1992; 51: 56–60 .

31.

Haider Y , Roberts WC . Coronary arterial disease in systemic lupus erythematosus . Am J Medicine 1981; 70: 775–781 .

32.

Pruzanski W et al. Serum phospholipase A2 correlates with disease activity in rheumatoid arthritis . J Rheumatol 1988; 15: 1351–1355 .

33.

Pruzanski W et al. Circulating Group II phospholipase A2 activity and antilipocortin antibodies in systemic lupus erythematosus . Correlative study with disease activity. J Rheum 1994; 21: 252–257 .

34.

Pruzanski W , Vadas P . Phospholipase A2<Eth>A mediator between proximal and distal effectors of inflammation . Immunology Today 1991; 12: 143–146 .

35.

Studnicka-Benke A , Steiner G , Petera P , Smolen JS . Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus . Brit J Rheumatol 1996; 35: 1067–1074 .

36.

Qamar T , Gharavi AE , Levy RA , Lockshin MD . Lysophosphatidylethanolamine is the antigen to which apparent antibody to phosphatidylethanolamine binds . J Clin Immunol 1990; 10: 200–203 .

37.

Hörkkö S et al. The epitopes for some antiphospholipid antibodies are adducts of oxidized phospholipid and b2 glycoprotein 1 (and other proteins) . Proc Natl Acad Sci 1997; 94: 10356–10361 .

38.

Sambrano GR , Parthasarathy S , Stenberg D . Recognition of oxidatively damaged erythrocytes by a macrophage receptor with specificity for oxidized low density lipoprotein . Proc Natl Acad Sci 1994; 91: 3265–3269 .