Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study

Ravandi, Amir; Boekholdt, S. Matthijs; Mallat, Ziad; Talmud, Philippa J.; Kastelein, John J.P.; Wareham, Nicholas J.; Miller, Elizabeth R.; Bénessiano, Joëlle; Tedgui, Alain; Witztum, Joseph L.; Khaw, Kay‐Tee; Tsimikas, Sotirios

doi:10.1194/jlr.m015776

Cited by 118 publications

(102 citation statements)

References 41 publications

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“…Furthermore, transfer of B-1 cells from sIgM -/-mice were incapable of such rescue, demonstrating that the IgMs were atheroprotective. In humans, IgM titers to epitopes of oxLDL are inversely associated with CVD in univariate analysis, also consistent with an atheroprotective role (84). The recent identification in humans of CD20 + CD27 + CD43 + B cells that spontaneously secrete IgM NAbs suggests an equivalent human B-1 cell population (85).…”

Section: B Cells and Ab Responses In Atherosclerosis B-1 Cells And Igsupporting

confidence: 50%

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Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Lichtman¹,

Binder²,

Tsimikas³

et al. 2013

J. Clin. Invest.

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176

171

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Many remarkable advances have improved our understanding of the cellular and molecular events in the pathogenesis of atherosclerosis. Chief among these is the accumulating knowledge of how the immune system contributes to all phases of atherogenesis, including well-known inflammatory reactions consequent to intimal trapping and oxidation of LDL. Advances in our understanding of the innate and adaptive responses to these events have helped to clarify the role of inflammation in atherogenesis and suggested new diagnostic modalities and novel therapeutic targets. Here we focus on recent advances in understanding how adaptive immunity affects atherogenesis.

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Section: B Cells and Ab Responses In Atherosclerosis B-1 Cells And Igsupporting

confidence: 50%

“…In humans, IgG titers to oxLDL are much more heterogeneous than in the murine models but in general correlate positively with CVD manifestations in univariate analyses (84,87). This has led some investigators to suggest that such IgGs are proatherogenic.…”

Section: B Cells and Ab Responses In Atherosclerosis B-1 Cells And Igmentioning

confidence: 99%

Adaptive immunity in atherogenesis: new insights and therapeutic approaches

Lichtman¹,

Binder²,

Tsimikas³

et al. 2013

J. Clin. Invest.

Self Cite

176

171

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“…It is possible that CFH may bind and mask some of these epitopes. It is also possible that these epitopes may be bound by autoantibodies to MDA-LDL that have been well characterized ( 36 ). Additionally, some of these epitopes may be transported out of the lesion wall on migrating macrophages or lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions

Dijk

Kolodgie

Ravandi

et al. 2012

Journal of Lipid Research

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143

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Oxidative pathways in the subendothelial space activate pro-infl ammatory, immunogenic, and atherogenic processes, resulting in endothelial dysfunction, plaque growth and destabilization, platelet activation, and thrombosis, ultimately leading to clinical events ( 1 ). A variety of oxidation-specifi c epitopes (OSE) are generated during oxidative modifi cation of plaque components. These epitopes are not only expressed on modifi ed lipoproteins but also on apoptotic cells and proteins in the extracellular matrix of atherosclerotic vessels ( 2 ).Extensive experimental data exists defi ning the role of oxidation in both progression and regression of atherosclerosis. Atherosclerotic lesions of hypercholesterolemic animal models, which represent primarily early and intermediate stage atherosclerosis, contain signifi cant amounts of OSE, often in proportion to plaque burden. OSE in the vessel wall of atherosclerotic animals can also be imaged with nuclear and magnetic resonance techniques using murine and human oxidation-specifi c antibodies, such as MDA2, E06, and IK17 ( 3-5 ). Dietary interventions in hypercholesterolemic animals that promote regression result in more rapid removal of OSE than apoB, which occurs prior to plaques diminishing signifi cantly in size, and is associated with markers of plaque stabilization, such Abstract The relationships between oxidation-specifi c epitopes (OSE) and lipoprotein (a) [Lp(a)] and progressive atherosclerosis and plaque rupture have not been determined. Coronary artery sections from sudden death victims and carotid endarterectomy specimens were immunostained for apoB-100, oxidized phospholipids (OxPL), apo(a), malondialdehyde-lysine (MDA), and MDA-related epitopes detected by antibody IK17 and macrophage markers. The presence of OxPL captured in carotid and saphenous vein graft distal protection devices was determined with LC-MS/MS. In coronary arteries, OSE and apo(a) were absent in normal coronary arteries and minimally present in early lesions. As lesions progressed, apoB and MDA epitopes did not increase, whereas macrophage, apo(a), OxPL, and IK17 epitopes increased proportionally, but they differed according to plaque type and plaque components. Apo(a) epitopes were present throughout early and late lesions, especially in macrophages and the necrotic core. IK17 and OxPL epitopes were strongest in late lesions in macrophagerich areas, lipid pools, and the necrotic core, and they were most specifi cally associated with unstable and ruptured plaques. Specifi c OxPL were present in distal protection devices. Human atherosclerotic lesions manifest a differential expression of OSEs and apo(a) as they progress, rupture, and become clinically symptomatic.

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“…Determination of Lp-PLA 2 mass and activity in plasma and density fractions and sPLA 2 mass and activity in plasma Plasma Lp-PLA 2 mass in plasma and density gradients were measured in a blinded fashion as previously described (PLAC® Test, diaDexus, Inc.) ( 20,21 ). The assay has a lower detection limit of 2 ng/ml and an interassay coeffi cient of variation (CV) of 6-7%.…”

Section: Lipid and Protein Analysismentioning

confidence: 99%

“…The specifi c activity of Lp-PLA 2 as the Lp-PLA 2 activity/mass ratio was determined by dividing the Lp-PLA 2 activity by the Lp-PLA 2 mass. Serum sPLA 2 type IIA mass and activity levels were measured only in plasma at the Paris Cardiovascular Research Center, as previously described ( 20,21 ).…”

Section: Lipid and Protein Analysismentioning

confidence: 99%