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Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid–protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins
Sohvi Hörkkö, … , Wulf Palinski, Joseph L. Witztum
Sohvi Hörkkö, … , Wulf Palinski, Joseph L. Witztum
Published January 1, 1999
Citation Information: J Clin Invest. 1999;103(1):117-128. https://doi.org/10.1172/JCI4533.
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Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid–protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins

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Abstract

We recently cloned monoclonal IgM autoantibodies which bind to epitopes of oxidized low-density lipoprotein (OxLDL) from apoE-deficient mice (EO– autoantibodies). We now demonstrate that those EO– autoantibodies that were originally selected for binding to copper-oxidized low-density lipoproteins (CuOx-LDL), also bound both to the oxidized protein and to the oxidized lipid moieties of CuOx-LDL. The same EO– autoantibodies showed specific binding to products of oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine (OxPAPC) and to the specific oxidized phospholipid, 1-palmitoyl-2-(5-oxovaleroyl)-phosphatidyl-choline (POVPC), whereas oxidation of fatty acids (linoleic or arachidonic acid) or cholesteryl esters (cholesteryl-oleate or cholesteryl-linoleate) did not yield any binding activity. Those EO– autoantibodies that bound to oxidized phospholipids (e.g., EO6) inhibited the binding and degradation of CuOx-LDL by mouse peritoneal macrophages up to 91%, whereas other IgM EO– autoantibodies, selected for binding to malondialdehyde (MDA)-LDL, had no influence on binding of either CuOx-LDL or MDA-LDL by macrophages. F(ab′)2 fragments of EO6 were equally effective as the intact EO6 in preventing the binding of CuOx-LDL by macrophages. The molar ratios of IgM to LDL needed to maximally inhibit the binding varied from ∼8 to 25 with different CuOx-LDL preparations. Finally, a POVPC–bovine serum albumin (BSA) adduct also inhibited CuOx-LDL uptake by macrophages. These data suggest that oxidized phospholipid epitopes, present either as lipids or as lipid-protein adducts, represent one class of ligands involved in the recognition of OxLDL by macrophages, and that apoE-deficient mice have IgM autoantibodies that can bind to these neoepitopes and inhibit OxLDL uptake.

Authors

Sohvi Hörkkö, David A. Bird, Elizabeth Miller, Hiroyuki Itabe, Norbert Leitinger, Ganesamoorthy Subbanagounder, Judith A. Berliner, Peter Friedman, Edward A. Dennis, Linda K. Curtiss, Wulf Palinski, Joseph L. Witztum

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Figure 1

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(a) Immunoassay showing binding of natural monoclonal autoantibodies fro...
(a) Immunoassay showing binding of natural monoclonal autoantibodies from apoE-deficient mice (EO1–EO17), a murine MAB from mice immunized with homogenates of human atheromatous plaque (DLH3) and MDA2 (a murine MAB to MDA-lysine), to BSA, native LDL, LDL oxidized with copper for 16 h (CuOx-LDL), and MDA-modified LDL (MDA-LDL). The antigens were plated at 10 μg/ml overnight (4°C), and the purified antibodies were incubated with antigen at 10 μg/ml for 1 h (room temperature). The amount of antibody bound was then measured with alkaline phosphatase–labeled goat anti–mouse IgM (or anti-IgG for MDA2) antibody using chemiluminescent technique. Each bar is the mean of triplicate determinations. (b) Competition immunoassay showing binding of a fixed and limiting dilution of biotinylated EO6 MAB to immobilized CuOx-LDL in the presence of increasing amounts of nonimmune mouse IgM, EO6, and MAB DLH3. LDL, low-density lipoproteins; MAB, monoclonal antibody; MDA, malondialdehyde; RLU, relative light units.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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