Patients With Early-Onset Peripheral Vascular Disease Have Increased Levels of Autoantibodies Against Oxidized LDL

Bergmark, Claes; Wu, Ruihua; Fairé, Ulf dé; Lefvert, Ann‐Kari; Swedenborg, Jesper

doi:10.1161/01.atv.15.4.441

Cited by 243 publications

(110 citation statements)

References 29 publications

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“…We have recently made an investigation of antibodies against oxLDL in patients who were operated on because of severe peripheral atherosclerosis before the age of 50 years. In this study, the presence of antibodies discriminated better between the patients and healthy control individuals than any of the conventional risk factors smoking, hypertension and diabetes [53]. There are, however, also studies that fail to show any correlation between the antibodies and atherosclerosis [13,18], and the question of the pathogenic role ofthe antibodies is far from solved.…”

Section: Discussionmentioning

confidence: 58%

Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL

Wu¹,

Lefvert²

1995

Clinical and Experimental Immunology

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SUMMARY Circulating antibodies against oxLDL are present in several inflammatory and autoimmune conditions. Such antibodies are also present in patients with atherosclerosis, although the pathogenic significance of the antibodies is still not known. We have characterized the antibodies with regard to isotype, subclass, affinity and effect on macrophage uptake of oxLDL. Antibodies of IgG and IgM isotype were most common and found both in patients with atherosclerosis and in normal individuals. The subclass of IgG antibodies was mainly IgG2 and IgG3. Scatchard analyses of IgG and IgM antibodies showed that IgG antibodies were heterogeneous with regard to affinity, whereas only one population of high‐affinity antibodies was found in the IgM antibody population. The high‐affinity populations had an average equilibrium constant (KO) of 8.84 × 109 M−1 for IgG antibodies and of 1.65 × 109 M−1 for IgM antibodies. Incubation of 125I‐oxLDL with purified IgG and IgM from sera with high amounts of antibodies enhanced the uptake of 125I‐oxLDL in the monocyte‐like U937 cell line. Antibody preparations from sera containing no anti‐oxLDL antibodies and from sera with antibodies against LDL had less effect on this uptake. The increased uptake was competitively decreased by adding unlabelled oxLDL. This study shows that antibodies against oxLDL are mainly IgG2. IgG3 and IgM. Both IgG and IgM antibodies have a high affinity for the antigen and increase the uptake of oxLDL in a monocyte‐like ceil line.

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Section: Discussionmentioning

confidence: 58%

Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL

Wu¹,

Lefvert²

1995

Clinical and Experimental Immunology

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“…10 Several studies demonstrated an increased titer of oxLDLAbs in patients with atherosclerotic coronary artery disease (CAD), 9,[11][12][13] acute myocardial infarction (MI), 14 and cerebral or peripheral artery disease. 15,16 In contrast, other studies found no such positive relationship between oxLDLAb titers and cardiovascular (CV) phenotypes. 17,18 Of interest, oxLDLAbs were detected in healthy individuals, 19 and a negative (inverse) association between total serum cholesterol and anti-OxLDLAb titers was reported in the general population.…”

mentioning

confidence: 93%

Antibodies to Oxidized Low-Density Lipoproteins and Angiographically Assessed Coronary Artery Disease in White Patients

et al. 2003

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Background-Low-density lipoprotein (LDL) can be oxidatively modified by reactive oxygen species, thus generating oxLDL. The latter induce formation of specific antibodies (oxLDLAb), which are detectable in patients with atherosclerosis, in which they might play a pathogenic or a protective role. Thus, we aimed to investigate the association of antibodies with oxidized LDLs (oxLDL) (oxLDLAbs) with coronary artery disease (CAD) and acute coronary syndromes. Methods and Results-In a cross-sectional study of 529 consecutive patients undergoing quantitative coronary angiography for suspected CAD, we measured the titer of IgG oxLDLAbs by ELISA. With regression analysis techniques, we also investigated the determinants of oxLDLAb titer and the association of oxLDLAbs with CAD severity. We found no significant differences of oxLDLAb titer between groups of patients without and with different CAD severity. The oxLDLAb titer was 18.6 enzyme units (EU) (11.5 to 25.7 EU/mL) (mean, 95% CI) in patients without CAD; 16.8 EU (9.6 to 24.2 EU) in patients with stenosis Ͻ50%; and 19.9 EU (15 to 24.8 EU), 17.2 (13.8 to 20.6 EU), and 14.7 EU (12.1 to 17.3 EU) in those with in 1-, 2-, or 3-vessel Ն50% stenosis, respectively. Similarly, no differences of oxLDLAb titer between patients without and with acute coronary syndrome were found. The oxLDLAb titer correlated weakly with aging and with serum total, LDL, and HDL cholesterol and plasma homocysteine levels; however, only age and HDL cholesterol remained significant predictors of the oxLDLAb titer at a stepwise regression analysis. Conclusions-The results of this study, which was adequately powered from the statistical standpoint, provided no evidence for an association of IgG oxLDLAb titer with angiographically assessed CAD in whites. (Circulation. 2003; 108:2467-2472.)

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“…Circulating autoantibodies against oxidized LDLs are also abundant in humans and have been shown to correlate with severity of disease in cardiovascular patients. [13][14][15][16] These findings suggest the possibility of developing new treatments against atherosclerosis based on selective activation of atheroprotective immune responses against oxidized LDL antigens.Oxidation of LDL is associated with formation of reactive aldehydes, such as malondialdehyde (MDA), that form covalent adducts with lysine and histidine residues in apoB. 17,18 These haptenized peptide sequences become targets for the immune system.…”

mentioning

confidence: 95%

mentioning

confidence: 95%

Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences

Fredrikson

Söderberg

Lindholm

et al. 2003

ATVB

236

164

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Objective-LDL oxidation is believed to play an important role in the development of atherosclerosis, and oxidized LDL particles have been shown to become targets for the immune system. Immunization of animals with oxidized LDL results in reduction of atherosclerosis, suggesting an atheroprotective effect of this immune response. Methods and Results-Using a polypeptide library covering the complete sequence of apoB-100, a large number of native and malondialdehyde-modified peptide sequences in apoB-100 that are recognized by antibodies in human plasma were identified. We report here that immunization with apoB-100 peptide sequences, against which high levels of IgG and IgM antibodies are present in healthy human controls, reduce atherosclerosis in apoE-null mice by about 60%.Immunizations with these peptides were also found to increase the collagen content of subvalvular lesions. Conclusions-These studies have identified peptide sequences in apoB-100 that induce immune responses, which inhibits atherosclerosis. This suggests a way of developing an immunization therapy for coronary heart disease. Key Words: apolipoproteins Ⅲ atherosclerosis Ⅲ immunization Ⅲ mice Ⅲ peptides A ccumulation, aggregation, and modification of LDL particles in the arterial intima are believed to be among the most important initiating factors in atherosclerosis. 1,2 Oxidative modification of LDLs trapped in the vascular extracellular matrix is associated with generation of a number of highly reactive compounds, such as lysophosphatidylcholine, lipid peroxides, aldehydes, and oxysterols, that cause cell damage and local inflammation. 2,3 In general terms, the development of raised fibromuscular plaques can be said to represent a repair response to the vascular injury and oxidized lipids may be one factor causing such injury. 4 Several protective mechanisms exist to limit injury caused by oxidatively damaged LDL particles. One involves the removal of oxidized LDL by macrophage scavenger receptors. 5,6 Recent studies suggest a second protective mechanism involving specific immune responses against epitopes present in oxidized LDLs. These were initially identified in studies of hypercholesterolemic rabbits, in which immunization with oxidized LDL was found to reduce atherosclerosis by 40% to 60%. 7,8 Similar observations were subsequently also made in apoE-null and LDL receptor-null mice, 9 -11 as well as in balloon-injured hypercholesterolemic rabbits. 12 In apoE-null mice, induction of hypercholesterolemia by a high-fat diet results in a dramatic increase in autoantibodies against oxidized LDLs. Circulating autoantibodies against oxidized LDLs are also abundant in humans and have been shown to correlate with severity of disease in cardiovascular patients. [13][14][15][16] These findings suggest the possibility of developing new treatments against atherosclerosis based on selective activation of atheroprotective immune responses against oxidized LDL antigens.Oxidation of LDL is associated with formation of reactive aldehydes, such as malondi...

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Patients With Early-Onset Peripheral Vascular Disease Have Increased Levels of Autoantibodies Against Oxidized LDL

Cited by 243 publications

References 29 publications

Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL

Autoantibodies against oxidized low density lipoproteins (oxLDL): characterization of antibody isotype, subclass, affinity and effect on the macrophage uptake of oxLDL

Antibodies to Oxidized Low-Density Lipoproteins and Angiographically Assessed Coronary Artery Disease in White Patients

Inhibition of Atherosclerosis in ApoE-Null Mice by Immunization with ApoB-100 Peptide Sequences

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