Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies

Abstract

Atherosclerosis is a process initiated by accumulation of macrophages in distinct areas of endothelial cell damage and uptake of large amounts of lipids. Recently, it has been shown that the immune system plays an active part in the progression of the atherosclerotic plaque although its precise role has not yet been elucidated.

Anticardiolipin antibodies (aCL) are generally found in the sera of patients with the antiphospholipid syndrome (APS) and are associated with a prothrombotic state. Several authors have demonstrated that aCL can activate platelets and endothelial cells as well as increase oxidized low density lipoprotein (LDL) uptake by macrophages. In the present study we sought to assess the effect of immunization with aCL (Ab1, leading to the production of mouse aCL-Ab3) on the progression of atherosclerosis. Two groups of 8-weeks old female LDL-receptor knockout mice (n = 13 per group) were immunized with IgG purified from the serum of an APS patient or with normal human IgG, respectively. The aCL immunized mice developed high titres of 'self' aCL (detected using the standard aCL ELISA) as compared with the normal human IgG immunized mice, whereas no differences were noted between both study groups with respect to the serum lipid levels. The extent of fatty streak formation was significantly higher in the aCL immunized mice in comparison with the human IgG injected mice (mean aortic lesion size of 5308 ± 471 μm² vs 1027 ± 184 μm², respectively, P < 0.01). The immunohistochemical analysis of the atherosclerotic plaques from both mouse groups did not display differences in cellular composition.

The results of the study show that mouse aCL induced by immunization with human aCL from an APS patient enhance atherogenesis in LDL-RKO mice and imply that these antibodies may play a role in atherosclerosis development in patients with the APS.

Keywords

atherosclerosis anticardiolipin antibodies autoimmunity antiphospholipid syndrome oxidized LDL

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References

Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-809.

Libby P. , Hansson GK Involvement of the immune system in human atherogenesis:current knowledge and unanswered questions. Lab Invest 1991; 64: 5-15.

Wick G. et al. Is atherosclerosis an immunologically mediated disease? Immunol Today 1995; 16: 27-33.

George J. , Harats D. , Gilburd B. , Shoenfeld Y. Emerging cross-regulatory roles of immunity and autoimmunity in atherosclerosis . Immunol Res 1996; 155: 315-322.

Shoenfeld Y. , Isenberg DA The mosaic of autoimmunity. Immunol Today 1989; 10: 123-126.

Shoenfeld Y. Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB J 1994 ; 8: 1296-1303.

Shoenfeld Y. , George J. Induction of autoimmunity: a role for the idiotypic network. Ann NY Acad Sci 1997; 815: 343-349.

Bakimer R. et al. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest 1992; 89: 1558-1563.

Blank M. , Tincani A. , Shoenfeld Y. Induction of experimental antiphospholipid syndrome in naive mice with purified antiphoshphatidylserine antibodies. J Rheumatol 1994; 21: 100-104.

10.

Hughes Grv. The antiphospholipid syndrome: ten years on . Lancet 1993; 342, 341-344.

11.

Khamashta MA , Hughes Grv. Antiphospholipid syndrome. A common cause of thrombosis. Br Med J 1993; 307: 883-884.

12.

Simantov R. et al. Activation of cultured endothelial cells by antiphopholipid antibodies. J Clin Invest 1995; 96: 2211—2219.

13.

Del Papa N. et al. Endothelial cells as target for antiphospholipid antibodies. Arthritis Rheum 1997; 3: 551—561.

14.

La Tonqueze M. et al. Role of β2-glycoprotein 1 in the antiphospholipid antibody binding to endothelial cells. Lupus 1995; 4: 179—186.

15.

Hasunuma Y. et al. Involvement of β2 glycoprotein 1 and anticardiolipin antibodies in oxidatively modified low density lipoprotein uptake by macrophages. Clin Exp Immunol 1997 ; 107: 569-573.

16.

Pierangeli SS , Harris EN Induction of phospholipid binding antibodies in mice and rabbits by immunization with human beta 2 glycoprotein 1 or anticardiolipin antibodies alone. Clin Exp Immunol 1993; 93: 269-272.

17.

Pierangeli SS et al. Thrombogenic properties of murine anticardiolipin antibodies induced by β2-glycoprotein 1 and human immunoglobulin G antiphospholipid antibodies. Circulation 1996; 94: 1746-1751.

18.

Vaarala O. et al. Affinity purified cardiolipin binding antibodies show heterogeneity in their binding to oxidized low density lipoprotein. Clin Exp Immunol 1996; 104: 269-274.

19.

Horkko S. et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. J Clin Invest 1996 ; 98: 815—825.

20.

Witztum JL The oxidation hypothesis of atherosclerosis. Lancet 1994; 344: 793-795.

21.

Ishibashi S. et al. Hypercholesterolemia in LDL receptor knockout micc and its reversal by adenovirus mediated gene delivery. J Clin Invest 1993; 92: 883-893.

22.

Xu Q. et al. Induction of arteriosclerosis in normocholesterolemic mice rabbits by immunization with heat shock protein 65. Arterioscler Thromb 1992; 12: 789—799.

23.

George J. et al. Oxidized low density lipoprotein (oxLDL) but not LDL aggravates the manifestations of antiphospholipid syndrome (APS). Clin Exp Immunol 1997; 108: 227-233.

24.

Paigen B. et al. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 1987; 68: 231—240.

25.

Rubin EM et al. Inhibition of early atherogenesis in transgenic mice by human apoplipoprotein A-I. Nature 1991; 353: 265-267.

26.

Qiao JH et al. Pathology of atheromatous lesions in inbred and genetically engineered mice: genetic determinations of arterial calcification. Arterioscler Thromb 1994; 14: 1480-1497.

27.

Vaarala O. et al. Anticardiolipin antibodies and the risk of myocardial infarction in a prospective cohort of middle aged men. Circulation 1995; 91: 23-27.

28.

The Antiphospholipid Antibodies and Stroke Study (APASS) Group. Anticardiolipin antibodies are an independent risk factor for first ischemic stroke. Neurology 1993; 43: 2069—2073.

29.

Matsuura E. et al. Heterogeneity of anticardioloipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885-3891.

30.

Matsuura E. et al. Anticardiolipin antibodies recognize β 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457.

31.

Puurunen M. et al. Antibody against oxidized LDL predicting myocardial infarction. Arch Intern Med 1994 ; 154: 2605—2609.