Autoantibodies against modified low density lipoprotein. Nonlipid factor of blood plasma that stimulates foam cell formation.

Orekhov, Alexander N.; Tertov, V.V.; Kabakov, Alexander E.; Adamova, I. Yu.; Pokrovsky, S.; Смирнов, В. Н.

doi:10.1161/01.atv.11.2.316

Cited by 76 publications

(47 citation statements)

References 56 publications

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“…We have previously demonstrated that circulating autoantibodies to OxLDL penetrate atherosclerotic lesions and form immune complexes with OxLDL, 60 which could enhance the uptake of OxLDL by macrophages via Fc receptors or phagocytosis. 14,61 However, the marked discrepancy between antibody titers in the MDA-LDL and LDL groups does not support a major role for this mechanism, either.…”

Section: Discussionmentioning

confidence: 86%

“…12 By analogy, OxLDL present in atherosclerotic lesions triggers a humoral immune response in vivo, and autoantibodies binding to various epitopes of OxLDL have been described in humans, rabbits, and mice. 1,[13][14][15][16] Extensive data have since accumulated suggesting that the titers of such antibodies may be of diagnostic and/or prognostic value (reviewed in Reference 17). In a Finnish population in whom carotid atherosclerosis was followed by ultrasound over a 2-year period, the titer of autoantibody binding to MDA-LDL was significantly greater in subjects with rapid progression of atherosclerosis than in control subjects with minimal progression.…”

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confidence: 99%

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Immunization of LDL Receptor–Deficient Mice With Homologous Malondialdehyde-Modified and Native LDL Reduces Progression of Atherosclerosis by Mechanisms Other Than Induction of High Titers of Antibodies to Oxidative Neoepitopes

Freigang

Hörkkö

Miller

et al. 1998

ATVB

288

194

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Abstract-We and others previously showed that immunization of rabbits with different forms of oxidized low density lipoprotein (LDL) significantly reduced atherogenesis. We now investigated the effect of continued immunization on atherosclerosis in LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice to determine whether a similar reduction of atherosclerosis occurred in murine models and whether this was due to humoral immune responses, ie, formation of high titers of antibodies to oxidation-specific epitopes. Three groups of LDLR Ϫ/Ϫ mice were repeatedly immunized with homologous malondialdehyde-modified LDL (MDA-LDL), native LDL, or phosphate-buffered saline (PBS) for 7 weeks. Extensive hypercholesterolemia and accelerated atherogenesis were then induced by feeding a cholesterol-rich diet for 17 weeks, during which immunizations were continued. Binding of immunoglobulin (Ig) M and IgG antibodies, as well as IgG1 and IgG2a isotypes, to several epitopes of oxidized LDL were followed throughout the study. After 24 weeks of intervention, atherosclerosis in the aortic origin was significantly reduced by 46.3% and 36.9% in mice immunized with MDA-LDL and native LDL, respectively, compared with PBS (133 558 and 157 141 versus 248 867 m 2 per section, respectively). However, the humoral immune response to oxidative neoepitopes in the MDA-LDL group was very different from that of the LDL or PBS group. IgG antibody binding to MDA-LDL and other epitopes of oxidized LDL, such as oxidized phospholipid (cardiolipin), oxidized cholesterol, or oxidized cholesteryl linoleate, but not native LDL, increased markedly in mice immunized with MDA-LDL, but not in mice immunized with native LDL or PBS. In the MDA-LDL group, both T helper cell (Th)2-dependent IgG1 antibody and Th1-dependent IgG2a antibody binding to oxidative neoepitopes increased significantly over time. The fact that mice immunized with both MDA-LDL and native LDL had a significant reduction in atherosclerosis, whereas only the MDA-LDL group developed very high titers of antibodies to oxidation-specific epitopes, suggests that the antiatherogenic effect of immunization is not primarily dependent on very high titers of antibodies to oxidation-specific epitopes but is more likely to result from the activation of cellular immune responses. (Arterioscler Thromb Vasc Biol. 1998;18:1972-1982

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Section: Discussionmentioning

confidence: 86%

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confidence: 99%

Immunization of LDL Receptor–Deficient Mice With Homologous Malondialdehyde-Modified and Native LDL Reduces Progression of Atherosclerosis by Mechanisms Other Than Induction of High Titers of Antibodies to Oxidative Neoepitopes

Freigang

Hörkkö

Miller

et al. 1998

ATVB

288

194

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“…6,7 Indeed, modified LDL present in atherosclerotic lesions can trigger an autoimmune response in vivo, and auto-Abs (mainly IgG1 and IgG3) to oxidized LDL have been found in blood and plaques. 4,8,9 These results suggest that the clearance of LDLcontaining ICs by macrophage Fc␥Rs contributes to foamcell development in vivo.Previous studies found functional evidence of Fc␥Rs in monocytic cells from atherosclerotic patients, and differential expression of Fc␥Rs in the proliferative areas of human lesions. 10 -12 Moreover, the beneficial effect of immunomodulation in atherosclerosis has recently been reported.…”

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confidence: 79%

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confidence: 79%

Fcγ Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice

Hernández-Vargas

Ortiz-Muñoz

López-Franco

et al. 2006

Circulation Research

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Abstract-IgG Fc receptors (Fc␥Rs) play a role in activating the immune system and in maintaining peripheral tolerance, but their role in atherosclerosis is unknown. We generated double-knockout (DKO) mice by crossing apolipoprotein E-deficient mice (apoE Ϫ/Ϫ ) with Fc␥R ␥ chain-deficient mice (␥ Ϫ/Ϫ ). The size of atherosclerotic lesions along the aorta was approximately 50% lower in DKO compared with apoE Ϫ/Ϫ control mice, without differences in serum lipid levels. The macrophage and T-cell content of lesions in the DKO were reduced by 49Ϯ6% and 56Ϯ8%, respectively, compared with the content in apoE Ϫ/Ϫ lesions. Furthermore, the expression of monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated on Activated Normal T-cell Expressed and Secreted), and intercellular adhesion molecule-1 (ICAM-1) and the activation of nuclear factor-B (NF-B) were significantly reduced in aortic lesions from DKO mice. In vitro, vascular smooth muscle cells (VSMCs) from both ␥ Ϫ/Ϫ and DKO mice failed to respond to immune complexes, as shown by impaired chemokine expression and NF-B activation. ApoE Ϫ/Ϫ mice have higher levels of activating Fc␥RI and Fc␥RIIIA, and inhibitory Fc␥RIIB, compared with wild-type mice. The DKO mice express only the inhibitory Fc␥RIIB receptor. We conclude that Fc␥R deficiency limits development and progression of atherosclerosis. In addition to leukocytes, Fc␥R activation in VSMCs contributes to the inflammatory process, in part, by regulating chemokine expression and leukocyte invasion of the vessel wall. These results underscore the critical role of Fc␥Rs in atherogenesis and support the use of immunotherapy in the treatment of this disease. Key Words: Fc receptors Ⅲ atherosclerosis Ⅲ double-knockout mice Ⅲ immune complexes A therosclerosis is a chronic inflammatory disease of the arterial wall characterized by progressive accumulation of lipids, cells, and extracellular matrix. In recent years, the immune processes associated to atherogenesis have received considerable attention. Studies in both humans and animals have demonstrated that atheromatous lesions at all stage of development contain a wide variety of cells and molecules characteristic of immune system, such as macrophages, lymphocytes, CD40, interferon-␥, major histocompatibility complex-II, complement, and antibodies (Abs). [1][2][3][4] In addition, congenital deficiency of macrophages, T and B lymphocytes, or even the inhibition of their mediators has resulted in the reduction of atherosclerotic lesion. 1,3 One of the critical steps in atherogenesis is the accumulation within the arterial intima of cholesteryl ester-laden foam cells, many of them derived from macrophages, whose formation is ultimately dependent on the uptake of various forms of low-density lipoproteins (LDLs). 1,2 Although emphasis has been placed on scavenger receptors, foam-cell development may also be influenced by lipoprotein interaction with other receptors, such as LDL receptors, very-low-density lipoprotein (VLDL) receptors, and IgG Fc (Fc␥Rs) receptors. 5 Diff...

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“…During oxidative modification of LDL, highly reactive lipid peroxidation products, such as malondialdehyde (MDA), 1 form adducts with free amino groups of lysines and other amino acids of apo B. Modified apo B is highly immunogenic (5-7), and circulating autoantibodies to epitopes of oxidized LDL (OxLDL), such as MDA-lysine, have been demonstrated in the plasma of humans, rabbits, and mice (6,(8)(9)(10). A number of studies have suggested that higher titers of these autoantibodies are found in patients with increased carotid atherosclerosis, coronary artery disease, diabetes, peripheral vascular disease, hypertension, and preeclampsia (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.

Palinski¹,

Hörkkö²,

Miller³

et al. 1996

J. Clin. Invest.

525

446

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Many reactive products may be formed when LDL undergoes lipid peroxidation, which in turn can react with lipids, apoproteins, and proteins, generating immunogenic neoepitopes. Autoantibodies recognizing model epitopes of oxidized low density lipoprotein, such as malondialdehydelysine, occur in plasma and in atherosclerotic lesions of humans and animals. Because apo E-deficient mice develop particularly high titers of such autoantibodies, we used their spleens to clone 13 monoclonal antibodies to various epitopes of oxidized LDL ("E0 antibodies"). Binding and competitive RIAs demonstrated significant differences in fine specificity even between E0 antibodies initially selected for binding to the same screening antigen. For example, some E0 antibodies selected for binding to malondialdehyde-LDL also recognized copper oxidized LDL, acrolein-LDL, or LDL modified by arachidonic or linoleic acid oxidation products. Circulating IgG and IgM autoantibodies binding to copper-oxidized LDL, 4-hydroxynonenal-LDL, acrolein-LDL, and LDL modified with arachidonic or linoleic acid oxidation products were found in apo E-deficient mice, suggesting that the respective antigens are formed in vivo. Epitopes recognized by some of the E0 monoclonal antibodies were also found on human circulating LDL. Each of the E0 monoclonal antibodies immunostained rabbit and human atherosclerotic lesions, and some of them yielded distinct staining patterns in advanced lesions. Together, this suggests that the natural monoclonal antibodies recognize different epitopes of complex structures formed during oxidation of lipoproteins, or epitopes formed independently at different lesion sites. Our data demonstrate that a profound immunological response to a large number of different epitopes of oxidized lipoproteins occurs in vivo. The availability of "natural" monoclonal autoantibodies should facilitate the identification of specific epitopes inducing this response.( J. Clin. Invest. 1996. 98:800-814.)

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Autoantibodies against modified low density lipoprotein. Nonlipid factor of blood plasma that stimulates foam cell formation.

Cited by 76 publications

References 56 publications

Immunization of LDL Receptor–Deficient Mice With Homologous Malondialdehyde-Modified and Native LDL Reduces Progression of Atherosclerosis by Mechanisms Other Than Induction of High Titers of Antibodies to Oxidative Neoepitopes

Immunization of LDL Receptor–Deficient Mice With Homologous Malondialdehyde-Modified and Native LDL Reduces Progression of Atherosclerosis by Mechanisms Other Than Induction of High Titers of Antibodies to Oxidative Neoepitopes

Fcγ Receptor Deficiency Confers Protection Against Atherosclerosis in Apolipoprotein E Knockout Mice

Cloning of monoclonal autoantibodies to epitopes of oxidized lipoproteins from apolipoprotein E-deficient mice. Demonstration of epitopes of oxidized low density lipoprotein in human plasma.

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