title: T-cell recognition of lipid peroxidation products breaks tolerance to self proteins.
abstract: Peroxidation of polyunsaturated fatty acids in lipoproteins and cell membrane phospholipids occurs in many situations in the body, both under normal and pathological conditions. Low-density lipoprotein is particularly prone to oxidation and is believed to be a pathogenetic component in atherogenesis. Both antibody responses and T-cell responses to oxidatively modified lipoproteins have been demonstrated in humans as well as in animal models. However, little is known about how these responses arise or how T cells recognize these antigens. In the present study, mice were immunized with homologous albumin covalently modified with a series of defined aldehydes which are known to be generated during lipid peroxidation. T-cell hybridomas from immunized animals demonstrated major histocompatibility complex-restricted and protein sequence-dependent responses to modified albumin, but not to native albumin. In addition to the response to modified epitopes, some aldehyde modifications resulted in strong antibody responses also to the non-modified protein. This T-cell-dependent break of tolerance constitutes a novel pathway for induction of autoimmunity by lipid peroxidation. The findings have implications in many situations where lipid peroxidation products are generated, including atherosclerosis and inflammatory and infectious diseases.
authors.affiliation: Cardiovascular Research Unit, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
authors.forename: D M
authors.initials: DM
authors.lastname: Wuttge
authors.forename: M
authors.initials: M
authors.lastname: Bruzelius
authors.forename: S
authors.initials: S
authors.lastname: Stemme
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D005260:Female; D006825:Hybridomas; D007376:Interleukin-2 / Q000276:immunology; D015227:Lipid Peroxidation; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017634:Self Tolerance / Q000187:drug effects*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000447:Aldehydes; D000941:Antigens; D007376:Interleukin-2