Q J Med 1999; 92: 57-59
© 1999 Association of Physicians
Commentary |
Atheroma: links with antiphospholipid antibodies, Hughes syndrome and lupus
From the Institute of Lipid and Atherosclerosis Research, 1 Department of Medicine `B' and Research Unit of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel, and 2 The Rayne Institute, St. Thomas Hospital, London, UK
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Antiphospholipid antibodies (aPL) are found in a variety of autoimmune diseases, and are thought to predispose to arterial and venous thrombosis. These antibodies, when investigated in different assays in vitro, activate endothelial cells and promote uptake of modified LDL to macrophages. These observations suggest that aPL can contribute to atheroma development by targeting some of the sequential steps that constitute early atherogenesis. If substantiated by large-scale clinical trials, the pro-atherogenic properties of aPL may merit screening and intervention programs in selected populations.
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In 1993, the Lancet carried an article by Vaarala and colleagues which suggested that some antiphospholipid antibodies were capable of cross-reacting with oxidized low-density lipoprotein (oxLDL).1 This finding focused attention on the reports of accelerated arterial disease seen in individuals with the antiphospholipid (Hughes) syndrome, and has provided a new line of atheroma research.2 Since the description of the syndrome in 1983,3 it has been clear that its many features include venous and arterial thrombosis. This propensity, both to arterial thrombosis and accelerated arterial disease, had of course, long been recognized in lupus, and a variety of hypotheses had been put forward—notably as an effect of long-term steroid therapy. It now seems likely that the strongest arterial risk factor, both in SLE and in Hughes syndrome (antiphospholipid syndrome) is the presence of antiphospholipid antibodies (aPL). Further, it is clear that there are `subjects' of aPL with different specificities—some (predominantly those requiring the co-factor ß2GPI for binding) being more strongly associated with thrombosis. A more recent clinical observation was that aPL cross-reacted with oxLDL were more closely associated with arterial than with venous thrombosis.4 If proved correct, this observation has implications, not only for therapy in lupus and in Hughes syndrome, where arterial disease (especially stroke), is currently treated with warfarin to a high INR,5 but also more broadly in terms of the pathogenesis and prophylaxis of atheroma.
The formation of atheroma is increasingly recognized as an inflammatory process in the arterial wall, including the accumulation of macrophages and activated T-lymphocytes.6 A high oxidative capacity in the arterial wall leads to oxidation-mediated endothelial injury and to a vital decrease in the physiological function of the endothelium.7 It is an attractive working hypothesis, therefore, to assume that antibody responses to oxidized plasma proteins, such as oxLDL, ß2GPI, prothrombin or heat-shock proteins may influence this inflammatory reaction and the associated thrombotic risk in atherosclerosis.
The association of `autoimmune' aPL with thrombotic events has been documented so consistently that their causal role in establishing a prothrombotic state is highly suggested. Indeed, well-conducted clinical trials have shown that the occurrence of aPL can be considered as an independent risk factor for myocardial infarctions8 and cerebral strokes.9 These findings have prompted an elaborate effort by many investigators to determine the mechanism by which aPL induce thrombosis. Activation of endothelium cells10 and platelets,11 and induction of tissue factor12 have all been suggested as possible mechanisms for the prothrombotic diathesis. An interesting point which relates to these findings is the requirement of ß2GPI for the mentioned functional properties, further emphasizing ß2GPI targeting by aCL.
The issue of target recognition of aCL is apparently more complex than initially thought. Other than binding ß2GPI, aCL were shown by several authors to cross-react with oxLDL1 and some have even suggested that the true target of some aCL may actually reside in neo-epitopes appearing within phospholipids upon their oxidation.13 These observations bear particular relevance to the study of the interrelations between aCL and atherosclerosis, since oxLDL is considered a major immunogen contributing to the progression of the plaque.7 To confound the issue further, it has been reported that the immune response to modified forms of LDL may either have protective,14 or deleterious15 effects on atherosclerosis development, implying that cross-reactivity of aCL with oxLDL may have opposing effects.
In a recent study, ß2GPI-reactive aPL were shown to enhance the uptake in vitro of oxidized lipoproteins to macrophages, leading us to speculate that these antibodies may have a role in atherosclerosis.16 The modern view of the atherosclerotic process is based on the assumption that the early stages of fatty streak formation are the result of monocyte adherence to endothelial cells at sites of local tissue stress.6 Subsequently, the adherent monocytes turn to macrophages expressing the scavenger receptor which allows for an unregulated influx of oxidized LDL to these cells.
Each of the steps constituting early atherosclerosis can actually be influenced by aPL. Endothelial cell activation can be triggered by aCL in vitro. The effect is mediated by upregulation of adhesion molecules on the surface of the cultured endothelial cells.10 As mentioned above, aCL can also increase the uptake of oxidized LDL by monocytes.16 Moreover, since thrombotic events are considered as part of the atherosclerotic process, the creation of a prothrombotic `atmosphere' by aCL can contribute to atherogenesis.
We have recently tested the hypothesis that aCL induced by immunization with human ß2GPI affect atherosclerosis.17 Indeed, transgenic mice lacking the LDL receptor were found to develop accelerated atherosclerosis upon immunization with ß2GPI. This animal model substantiated the link between the anti-ß2GPI response and atherosclerosis.18 However, if aPL can be found to possess proatherogenic properties, population screening programs may characterize risk groups which may, in the future, benefit from regimens aimed at reducing antibody titers or to intervening with its atherogenic effects.
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Notes |
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Address correspondence to Professor Y. Shoenfeld, Department of Medicine `B', Sheba Medical Center, Tel-Hashomer 52621, Israel. e-mail: shoenfel{at}post.tau.ac.il
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References |
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TopSummaryIntroductionReferences |
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1. Vaarala O, Alfthan G, Jauhiainen M, Leirisalo-Repo M, Aho Knd Palosuo T. Crossreaction between antibodies to oxidized low-density lipoprotein and to cardiolipin in systemic lupus erythematosus. Lancet 1993; 2:923–5.
2. Vaarala O. Antiphospholipid antibodies and atherosclerosis. Lupus 1996; 5:442–7.[Web of Science][Medline]
3. Hughes GRV. The antiphospholipid syndrome: ten years on. Lancet 1993; 342:341.[Web of Science][Medline]
4. Cuadrado MJ, Tinahones F, Khamashta MA, Camps MT, DeRamon E, Gomez-Zumaquero JM, Mujic F, Hughes GRV. Antiphospholipid anti-beta2 glycoprotein I anti anti-oxidized LDL antibodies and the risk of APS related features. Abstract. ACR meeting, Washington DC, 1997.
5.
Khamashta MA, Cuadrado MJ, Mujic F, Taub N, Hunt BJ, Hughes GRV. The management of thrombosis in the antiphospholipid syndrome. N Engl J Med 1995; 332:993–7.
6. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362:801–9.[Medline]
7. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet 1994; 344:793–5.[Web of Science][Medline]
8.
Vaarala O, Manttari M, Manninen V, Tenkanen L, Puurunen M, Aho K, Palosuo T. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91:23–7.
9.
The Antiphospholipid Antibodies and Stroke Study (APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology 1993; 43:2069–73.
10. Simantov R, LaSala JM, Lo SK, Gharavi AE, Sammaritano LR, Salmon JE, Silverstein RL. Activation of cultured endothelial cells by antiphospholipid antibodies. J Clin Invest 1995; 96:2211–19.
11.
Shi W, Chong BH, Chesterman CN. ß2-glycoprotein-I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants. Blood 1993; 81:1255–62.
12. Kornberg A, Blank M, Kaufman S, Shoenfeld Y. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J Immunol 1994; 153:1328–32.[Abstract]
13. Horkko S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, Terkeltaub R, Pierangeli SS, Branch DW, Palinski W, Witztum JL. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. J Clin Invest 1996; 98:815–25.[Web of Science][Medline]
14.
Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA. 1995; 92:821–5.
15. Klimov AM, Denisenko AD, Popov AV, et al. Lipoprotein-antibody immune complexes; their catabolism and role in foam cell formation. Atherosclerosis 1985; 58:1–15.[Web of Science][Medline]
16. Hasunuma Y, Matsuura E, Makita Z, Katahira T, Nishi S, Koike T. Involvement of ß2 glycoprotein I and anticardiolipin antibodies in oxidatively modified low density lipoprotein uptake by macrophages. Clin Exp Immunol 1997; 107:569–74.[Web of Science][Medline]
17. Shaish A, George J, Afek A, Gilburd B, Levkovitz H, Goldberg I, Shoenfeld Y, Harats D. Induction of early atherosclerosis in LDL-receptor deficient mice immunized with beta 2 glycoprotein I. Abstract. XIth Symposium on Atherosclerosis, Paris, 1997:39.
18.
George J, Afek A, Gilburd B, Blank M, Levy Y, Aron-Maor A, Levkovitz H, Shaish A, Goldberg I, Kopolovic J, Harats D, Shoenfeld Y. Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I. Circulation 1998; 98:1108–15.
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