title: Natural antibodies of newborns recognize oxidative stress-related malondialdehyde acetaldehyde adducts on apoptotic cells and atherosclerotic plaques.
abstract: Malondialdehyde acetaldehyde (MAA) adducts are generated under oxidative stress and shown to be highly immunogenic. Our aim was to investigate the recognition of MAA adducts by human natural antibodies in newborns before or at the time of full-term pregnancy. Plasma samples of pre-term (n = 11) and full-term (n = 36) newborns were enriched in specific IgM binding to MAA adducts compared with the maternal plasma IgM levels. Umbilical cord blood lymphocyte phage display library was generated to clone Fabs that specifically recognized MAA adducts without cross-reactivity to malondialdehyde. Fab clones from the antibody libraries of the pre-term and full-term newborns showed high sequence homology to the germline genes encoding the variable regions of antibodies, confirming that these Fabs represented the natural antibody repertoire of human fetuses. The MAA-specific umbilical cord blood Fabs bound to apoptotic human endothelial cells and the binding was efficiently competed with MAA adducts. The MAA-specific Fabs also recognized epitopes on advanced atherosclerotic lesions, and the uptake of infrared (IR)-labeled MAA-low-density lipoprotein by mouse J774A.1 macrophages was significantly reduced in the presence of these Fabs. In conclusion, MAA adducts were identified as one of the major antigenic targets for human natural antibodies already before the time of birth. MAA-specific natural antibodies are suggested to regulate apoptotic cell clearance starting from fetal development and to participate in the immunomodulation of atherosclerosis development during adulthood.
authors.affiliation: Department of Medical Microbiology and Immunology, Institute of Diagnostics, Faculty of Medicine, University of Oulu, 90014 Oulu, Finland.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Wang
authors.forename: S Pauliina
authors.initials: SP
authors.lastname: Turunen
authors.forename: Outi
authors.initials: O
authors.lastname: Kummu
authors.forename: Marja
authors.initials: M
authors.lastname: Veneskoski
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lehtimäki
authors.forename: Antti E
authors.initials: AE
authors.lastname: Nissinen
authors.forename: Sohvi
authors.initials: S
authors.lastname: Hörkkö
mesh_terms: D000079:Acetaldehyde / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D007231:Infant, Newborn; D008297:Male; D008315:Malondialdehyde / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology*; D019151:Peptide Library; D010587:Phagocytosis; D058226:Plaque, Atherosclerotic / Q000276:immunology*; D011108:Polymers / Q000378:metabolism*; D011247:Pregnancy; D015202:Protein Engineering; D013548:Sweden
chemical_list: D007140:Immunoglobulin Fab Fragments; D007075:Immunoglobulin M; D019151:Peptide Library; D011108:Polymers; D008315:Malondialdehyde; D000079:Acetaldehyde
keywords: innate immunity; oxidized low-density lipoprotein; phage display; reactive aldehydes