Bispecific Abs against modified protein and DNA with oxidized lipids
| Autor: | Yusuke Kishi, Yoshihisa Ishii, Takeshi Tsubata, Emi Tatsuda, Tsukasa Matsuda, Kazuyo Toyoda, Nobutaka Hattori, Koji Uchida, Satoru Yamaguchi, Yoshichika Kawai, Takahiro Adachi, Yoshinari Takasaki, Mitsugu Akagawa, Sohei Ito, Takahiro Shibata, Kousuke Ishino |
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| Rok vydání: | 2006 |
| Předmět: |
Stereochemistry
Molecular Sequence Data Deoxyribonucleosides Stereoisomerism Cross Reactions Crystallography X-Ray medicine.disease_cause Epitope Adduct DNA Adducts Epitopes Immunoglobulin Fab Fragments Mice chemistry.chemical_compound Antibodies Bispecific medicine Animals Lupus Erythematosus Systemic Amino Acid Sequence Peptide sequence Histidine Autoantibodies Aldehydes Multidisciplinary Chemistry Molecular Mimicry Protein primary structure Antibodies Monoclonal Proteins DNA Biological Sciences Lipids Molecular mimicry Biochemistry Antibodies Antinuclear Lipid Peroxidation Oxidation-Reduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 103:6160-6165 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0600865103 |
| Popis: | 4-Hydroxy-2-nonenal (HNE), a racemic mixture of 4R- and 4S-enantiomers, is a major product of lipid peroxidation and is believed to be largely responsible for the cytopathological effects observed during oxidative stress. HNE reacts with histidine to form a stable HNE-histidine Michael addition-type adduct possessing three chiral centers in the cyclic hemiacetal structure. We have previously raised the mAbs, anti-RmAb 310 and anti-SmAb S412, that enantioselectively recognized theR-HNE-histidine andR-HNE-histidine adducts, respectively, and demonstrated the presence of both epitopesin vivo. In the present study, to further investigate the anti-HNE immune response, we analyzed the variable genes and primary structure of these Abs and found that the sequence of R310 was highly homologous to anti-DNA autoantibodies, the hallmark of systemic lupus erythematosus. An x-ray crystallographic analysis of the R310 Fab fragment showed that theR-HNE-histidine adduct binds to a hydrophobic pocket in the antigen-binding site. Despite the structural identity to the anti-DNA autoantibodies, however, R310 showed only a slight crossreactivity with the native double-stranded DNA, whereas the Ab immunoreactivity was dramatically enhanced by the treatment of the DNA with 4-oxo-2-nonenal (ONE), an analog of HNE. Moreover, the 7-(2-oxo-heptyl)-substituted 1,N2-etheno-type ONE-2′-deoxynucleoside adducts were identified as alternative epitopes of R310. Molecular mimicry between theR-HNE-histidine configurational isomers and the ONE-DNA base adducts is proposed for the dual crossreactivity. |
| Databáze: | OpenAIRE |
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