Autoantibodies against N-homocysteinylated proteins in humans: implications for atherosclerosis.

Abstract

Homocysteine (Hcy)-thiolactone mediates protein N-homocysteinylation in humans. Protein N-linked Hcy comprises a major pool of Hcy in human blood, greater that the "total" Hcy pool. N-homocysteinylated proteins are structurally different, compared with native proteins, and are thus likely to be recognized as neoself antigens and induce an autoimmune response. This study was undertaken to provide evidence for anti-Nepsilon-Hcy-Lys-protein antibody and to examine associations between the antibody level, Hcy, and stroke in humans. ELISA was used to quantify anti-Nepsilon-Hcy-Lys-protein antibodies in human serum. We found that autoantibodies that specifically recognize Nepsilon-Hcy-Lys epitope on Hcy-containing proteins occur in humans. Serum levels of anti-Nepsilon-Hcy-Lys-protein autoantibodies positively correlate with plasma total Hcy levels, but not with plasma cysteine or methionine levels. In a group of exclusively male patients with stroke, mean level of anti-Nepsilon-Hcy-Lys-protein autoantibodies was approximately 50% higher than in a group of healthy subjects. These findings support a hypothesis that Nepsilon-Hcy-Lys-protein is a neoself antigen, which may contribute to immune activation, an important modulator of atherogenesis.