title: Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins.
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 approximately 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.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California 92093-0682, USA.shorkko@ucsd.edu
authors.forename: S
authors.initials: S
authors.lastname: Hörkkö
authors.forename: D A
authors.initials: DA
authors.lastname: Bird
authors.forename: E
authors.initials: E
authors.lastname: Miller
authors.forename: H
authors.initials: H
authors.lastname: Itabe
authors.forename: N
authors.initials: N
authors.lastname: Leitinger
authors.forename: G
authors.initials: G
authors.lastname: Subbanagounder
authors.forename: J A
authors.initials: JA
authors.lastname: Berliner
authors.forename: P
authors.initials: P
authors.lastname: Friedman
authors.forename: E A
authors.initials: EA
authors.lastname: Dennis
authors.forename: L K
authors.initials: LK
authors.lastname: Curtiss
authors.forename: W
authors.initials: W
authors.lastname: Palinski
authors.forename: J L
authors.initials: JL
authors.lastname: Witztum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D003300:Copper / Q000494:pharmacology; D004655:Emulsions / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D008054:Lipid Peroxides / Q000276:immunology; D008077:Lipoproteins, LDL / Q000276:immunology* / Q000378:metabolism; D008081:Liposomes / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D010743:Phospholipids / Q000276:immunology; D011485:Protein Binding
chemical_list: D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D001323:Autoantibodies; D004655:Emulsions; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D008081:Liposomes; D010743:Phospholipids; C099252:oxidized low density lipoprotein; D003300:Copper