title: Human monoclonal Fab and human plasma antibodies to carbamyl-epitopes cross-react with malondialdehyde-adducts.
abstract: Oxidized low-density lipoprotein (OxLDL) plays a crucial role in the development of atherosclerosis. Carbamylated LDL has been suggested to promote atherogenesis in patients with chronic kidney disease. Here we observed that plasma IgG and IgM antibodies to carbamylated epitopes were associated with IgG and IgM antibodies to oxidation-specific epitopes (ρ = 0·65-0·86, P < 0·001) in healthy adults, suggesting a cross-reaction between antibodies recognizing carbamyl-epitopes and malondialdehyde (MDA)/malondialdehyde acetaldehyde (MAA) -adducts. We used a phage display technique to clone a human Fab antibody that bound to carbamylated LDL and other carbamylated proteins. Anti-carbamyl-Fab (Fab106) cross-reacted with oxidation-specific epitopes, especially with MDA-LDL and MAA-LDL. We showed that Fab106 bound to apoptotic Jurkat cells known to contain these oxidation-specific epitopes, and the binding was competed with soluble carbamylated and MDA-/MAA-modified LDL and BSA. In addition, Fab106 was able to block the uptake of carbamyl-LDL and MDA-LDL by macrophages and stained mouse atherosclerotic lesions. The observed cross-reaction between carbamylated and MDA-/MAA-modified LDL and its contribution to enhanced atherogenesis in uraemic patients require further investigation.
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu, Finland; NordLab Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kummu
authors.forename: S Pauliina
authors.initials: SP
authors.lastname: Turunen
authors.forename: Piotr
authors.initials: P
authors.lastname: Prus
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lehtimäki
authors.forename: Marja
authors.initials: M
authors.lastname: Veneskoski
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.forename: Sohvi
authors.initials: S
authors.lastname: Hörkkö
mesh_terms: D000079:Acetaldehyde / Q000097:blood / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology*; D017209:Apoptosis; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001667:Binding, Competitive; D061505:Cell Surface Display Techniques; D003429:Cross Reactions; D004195:Disease Models, Animal; D000939:Epitopes; D006801:Humans; D056724:Immunity, Humoral; D007140:Immunoglobulin Fab Fragments / Q000097:blood / Q000276:immunology*; D019169:Jurkat Cells; D008077:Lipoproteins, LDL / Q000097:blood / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000097:blood / Q000276:immunology*; D051379:Mice; D010084:Oxidation-Reduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D008077:Lipoproteins, LDL; C039916:carbamyl-LDL; C569869:malondialdehyde-low density lipoprotein, human; D008315:Malondialdehyde; D000079:Acetaldehyde
keywords: antibody; atherosclerosis; carbamylation; cross-reaction; low-density lipoprotein