title: Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis.
abstract: Periodontal infections increase the risk of atherosclerotic vascular disease via partly unresolved mechanisms. Of the natural IgM Abs that recognize molecular mimicry on bacterial epitopes and modified lipid and protein structures, IgM directed against oxidized low-density lipoprotein (LDL) is associated with atheroprotective properties. Here, the effect of natural immune responses to malondialdehyde-modified LDL (MDA-LDL) in conferring protection against atherosclerosis, which was accelerated by the major periodontopathogen Porphyromonas gingivalis, was investigated. LDL receptor-deficient (LDLR(-/-)) mice were immunized with mouse MDA-LDL without adjuvant before topical application challenge with live P. gingivalis. Atherosclerosis was analyzed after a high-fat diet, and plasma IgG and IgM Ab levels were measured throughout the study, and the secretion of IL-5, IL-10 and IFN-γ in splenocytes stimulated with MDA-LDL was determined. LDLR(-/-) mice immunized with MDA-LDL had elevated IgM and IgG levels to MDA-LDL compared with saline-treated controls. MDA-LDL immunization diminished aortic lipid depositions after challenge with P. gingivalis compared with mice receiving only P. gingivalis challenge. Immunization of LDLR(-/-) mice with homologous MDA-LDL stimulated the production of IL-5, implicating general activation of B-1 cells. Immune responses to MDA-LDL protected from the P. gingivalis-accelerated atherosclerosis. Thus, the linkage between bacterial infectious burden and atherogenesis is suggested to be modulated via natural IgM directed against cross-reactive epitopes on bacteria and modified LDL.
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland NordLab Oulu, Oulu University Hospital, Oulu, Finland pauliina.turunen@helsinki.fi.
authors.forename: S Pauliina
authors.initials: SP
authors.lastname: Turunen
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland NordLab Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kummu
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Harila
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Mattila
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Sahlman
authors.affiliation: Institute of Dentistry, University of Helsinki, Helsinki, Finland.
authors.forename: Pirkko J
authors.initials: PJ
authors.lastname: Pussinen
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Finland and Medical Research Center Oulu, Oulu, Finland NordLab Oulu, Oulu University Hospital, Oulu, Finland.
authors.forename: Sohvi
authors.initials: S
authors.lastname: Hörkkö
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000150:complications / Q000276:immunology*; D016866:Bacteroidaceae Infections / Q000150:complications / Q000276:immunology*; D003429:Cross Reactions; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D018985:Epitopes, B-Lymphocyte / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D008315:Malondialdehyde / Q000737:chemistry; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010518:Periodontitis / Q000150:complications / Q000276:immunology*; D016966:Porphyromonas gingivalis / Q000276:immunology*; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D016207:Cytokines; D018985:Epitopes, B-Lymphocyte; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D008315:Malondialdehyde
keywords: Natural antibodies; atherosclerosis; innate immunity; lipid peroxidation; malondialdehyde; periodontitis