title: Multispecificity of immunoglobulin M antibodies raised against advanced glycation end products: involvement of electronegative potential of antigens.
abstract: BACKGROUND
  Advanced glycation end products (AGEs) can act as neoantigens to trigger immune responses.
  
  
  RESULTS
  Natural IgM antibodies against AGEs recognize multiple molecules, including DNA and chemically modified proteins.
  
  
  CONCLUSIONS
  There is a close relationship between the formation of AGEs and innate immune responses.
  
  
  CONCLUSIONS
  Our findings highlight AGEs and related modified proteins as a source of multispecific natural antibodies Advanced glycation end products (AGEs) are a heterogeneous and complex group of compounds that are formed when reducing sugars, such as dehydroascorbic acid, react in a nonenzymatic way with amino acids in proteins and other macromolecules. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect the extracellular and intracellular structure and function. In the present study, we studied the immune response to the dehydroascorbic acid-derived AGEs and provide multiple lines of evidence suggesting that the AGEs could be an endogenous source of innate epitopes recognized by natural IgM antibodies. Prominent IgM titers to the AGEs were detected in the sera of normal mice and were significantly accelerated by the immunization with the AGEs. Patients with systemic lupus erythematosus (SLE), a potentially fatal systemic autoimmune disease characterized by the increased production of autoantibodies, showed significantly higher serum levels of the IgM titer against the AGEs than healthy individuals. A progressive increase in the IgM response against the AGEs was also observed in the SLE-prone mice. Strikingly, a subset of monoclonal antibodies, showing a specificity toward the AGEs, prepared from normal mice immunized with the AGEs and from the SLE mice cross-reacted with the double-stranded DNA. Moreover, they also cross-reacted with several other modified proteins, including the acetylated proteins, suggesting that the multiple specificity of the antibodies might be ascribed, at least in part, to the increased electronegative potential of the proteins. These findings suggest that the protein modification by the endogenous carbonyl compounds, generating electronegative proteins, could be a source of multispecific natural antibodies.
authors.affiliation: Laboratories of Food and Biodynamics, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Chikazawa
authors.forename: Natsuki
authors.initials: N
authors.lastname: Otaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shibata
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyashita
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Kawai
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kitaura
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Matsuda
authors.forename: Koji
authors.initials: K
authors.lastname: Uchida
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology*; D000918:Antibody Specificity; D000941:Antigens / Q000737:chemistry / Q000276:immunology*; D003683:Dehydroascorbic Acid / Q000378:metabolism; D005260:Female; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007075:Immunoglobulin M / Q000737:chemistry / Q000276:immunology*; D007526:Isoelectric Point; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D020539:Sequence Analysis, Protein
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000941:Antigens; D017127:Glycation End Products, Advanced; D007075:Immunoglobulin M; D003683:Dehydroascorbic Acid
keywords: AGEs; Antibodies; Antigen; Glycation; Innate Immunity; Natural Antibodies; Protein Chemical Modification
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