The modern view of atherosclerosis is of a chronic inflammatory disorder. In accord with this paradigm, the process of uninhibited influx of fat to the vessel wall results from an ‘adequate’ response to various forms of injury (i.e. turbulence, infections, modified lipoproteins). This idea has been further extended by several groups, to assume that the atherosclerotic lesion can be the target of an autoimmune mediated attack. According to this hypothesis, the site of initiation of the plaque should bear/express the target autoantigen, whereas concomitantly a respective immune response is generated in the periphery. The examples illuminating this notion are β2GPI as a target autoantigen, HSP60/65 an oxidized-LDL.
Herein we present evidence to support the involvement of autoimmune mechanisms in atherogenesis based on the experience from experimental models and human studies.
Ross R . Atherosclerosis-an inflammatory condition . N Eng J Med1999; 340: 115–126 .
2.
Libby P , Hansson GK . Involvement of the immune system in human atherogenesis: Current knowledge and unanswered questions . Lab Invest1991; 64: 5–11 .
3.
Wick G , Schett G , Amberger A et al. Is atherosclerosis an immunologically mediated disease?Immunol Today1995; 16: 27–33 .
4.
George J , Harats D , Gilburd B , Shoenfeld Y . Emerging cross-regulatory roles of immunity and autoimmunity in atherosclerosis . Immunol Res1996; 155: 315–322 .
5.
Plump AS , Smith JD , Hayek T et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein-E deficient mice created by homologous recombination in ES cells . Cell1992; 71: 343–353 .
6.
Ishibashi S , Brown MS , Goldstein JL et al. Hypercholesterolemia in LDL receptor knockout mice and its reversal by adenovirus mediated gene delivery . J Clin Invest1993; 92: 883–893 .
7.
Roselaar SE , Kakkanathu PX , Daugherty A . Lymphocyte populatons in atherosclerotic lesions of apo-E 7 = 7 and LDL recepto 7 = 7 mice; Decresing density with disease progression . Arterioscler Thromb Vasc Biol1996; 16: 1013–1018 .
Libby P , Egan D , Scarlatos S . Roles of infectious agents in atherosclerosis and restenosis. An assessment of the evidence and need for future research . Circulation1997; 96: 4095–4103 .
10.
Ridker PM . Inflammation, infection and cardiovascular risk: how good is the clinical evidence . Circulation1998; 98: 1671–1974 .
11.
Matsuura E , Igarashi Y , Fujimoto M et al. Heterogeneity of anticardioloipin antibodies defined by the anticardiolipin cofactor . J Immunol1992; 148: 3885–3891 .
12.
Shoenfeld Y , Gharavi A , Koike T . β2GPI in the antiphospholipid (Hughes) syndrome: from a cofactor to an autoantigen-from induction to prevention of antiphospholipid syndrome . Lupus1998; 7: 503–506 .
13.
Hughes GRV . The antiphospholipid syndrome: ten years on . Lancet1993; 342: 341–341 .
14.
George J , Shoeneld Y . The antiphospholipid (Hughes) syndrome: a crossroads of autoimmunity and atherosclerosis . Lupus1997; 6: 559–560 .
15.
Simantov R , LaSala JM , Lo SK et al. Activation of cultured endothelial cells by antiphospholipid antibodies . J Clin Invest1995; 96: 2211–2219 .
16.
George J , Blank M , Levy Y et al. Differential effects of anti-β2GPI antibodies on endothelial cells and on the manifestations of experimental antiphospholipid syndrome . Circulation1998; 97: 900–906 .
17.
Geore J , Blank M , Gilburd B et al. Immunologic characterization an dfunctional properties of murine antibodies raised against deleted mutants of β2-glycoprotein I . Int Immunol1997; 9: 913–913 .
18.
George J , Afek A , Gilburd B et al. Induction of early atherosclerosis in LDL receptor deficient mice immunized with beta 2 glycoprotein I . Circulation1998; 15: 1108–1115 .
19.
Afek A , George J , Shoenfeld Y et al. Enhanced atherosclerosis in ApoE deficient mice by immunization with β2-glycoprotein I . Pathobiology1999; 67: 19–25 .
20.
George J , Harats D , Gilburd et al. Immunolocalization of b2-glycoprotein I (apolipoprotein H) to human atherosclerosis plaques: potential implications for lesion progression . Circulation1999; 99: 2227–2230 .
21.
George J , Afek A , Gilburd B et al. Atherosclerosis in LDL receptor knockout mice is accelerated by immunization with anticardiolipin antibodies . Lupus1997; 6: 723–729 .
22.
George J , Harats D , Gilburd B et al. Atherosclerosis related markers in systemicLupus8: 220–226 .
23.
George J , Ahmed A , Adler Y et al. The prediction of coronary atherosclerosis employing artificial neural networks. Qutr J Med (In press).
24.
Witztum J , Steinberg D . Role of oxidized low density lipoprotein in atherogenesis . J Clin Invest1991; 88: 1785–1792 .
25.
Salonen JT , Yla-Herttuala S , Yamamoto R . Antibodies against oxidized LDL and the progression of carotid atherosclerosis . Lancet1992; 339: 883–887 .
26.
Bergmark C , Wu R , De Faire U et al. Patients with early onset peripheral vascular disease have increased levels of antibodies against oxidized LDL . Arterioscler Thromb Vasc Biol1995; 15: 441–445 .
27.
Puurunen M , Manttari M , Mannine Vesa et al. Antibodies against oxidized low density lipoprotein predicting myocardial infarction . Arch Intern Med1994; 154: 2605–2609 .
28.
George J , Harats D , Bakshi E et al. Anti-oxidized-low density lipoprotein antibody determination as a predictor of restenosis following percutaneous transluminal coronary angioplasty . Immunol Lett1999; 68: 263–266 .
29.
Stemme S , Faber B , Holm J . T lymphocytes from himan athero sclerotic plaques recognize oxidized low density lipoprotein . Proc Natl Acad Sci USA1995; 92: 3893–3897 .
30.
Palinski W , Miller E , Witztum JL . Immunization of low density lipoprotein (LDL) deficient rabbits with homologeous malondialde-hyde-modified LDL reduces atherogenesis . Proc Natl Acad Sci USA1995; 92: 821–825 .
31.
George J , Afek A , Gilburd B et al. Hyperimmunization of apoE deficient mice with homologous MDA-low density lipoprotein suppresses early atherogenesis . Atherosclerosis1998; 138: 147–152 .
32.
Freigang S , Horkko S , Miller E et al. Immunization of LDL receptor deficient mice with homologous malondialdehyde modified and native LDL reduces atherosclerosis progression by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes . Arterioscler Thromb Vasc Biol1998; 18: 1972–1982 .
33.
George J , Blank M , Hojnik M et al. Oxidized low density lipoprotein (oxLDL) but not LDL aggravates the manifestations of antiphospholipid syndrome (APS) . Clin Exp Immunol1997; 108: 227–233 .
34.
Horkko S , Miller E , Dudl E et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids . J Clin Invest1996; 98: 815–825 .
35.
George J , Gilburd B , Langevitz P et al. β2-glycoprotein I containing immune complexes: association with thrombocytopenia and lipoprotein (a) levels . Lupus1999; 8: 116–120 .
Xu Q , Willeit J , Marosi M et al. Asociation of serum antibodies to heat shock protein 65 with carotid atherosclerosis . Lance1993; 341: 255–259 .
38.
Xu Q , Dietrich H , Steiner HJ et al. Induction of arteriosclerosis in normocholesterolemic mice rabbits by immunization with heat shock protein 65 . Arterioscler Thromb1992; 12: 789–799 .
39.
George J , Shoenfeld Y , Afek A et al. Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock protein 65 . Arterioscler Thromb Vasc Biol1999; 19: 505–510 .
