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J. Biol. Chem., Vol. 282, Issue 35, 25769-25778, August 31, 2007

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Protein-bound 4-Hydroxy-2-nonenal

AN ENDOGENOUS TRIGGERING ANTIGEN OF ANTI-DNA RESPONSE^*

Kazuyo Toyoda, Ritsuko Nagae, Mitsugu Akagawa, Kosuke Ishino, Takahiro Shibata, Sohei Ito, Noriyuki Shibata^¶, Tomoko Yamamoto^¶, Makio Kobayashi^¶, Yoshinari Takasaki^||, Tsukasa Matsuda, and Koji Uchida¹

From the Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan, the School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan, the ^¶Departments of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan, and the ^||Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo 113-8421, Japan

Several lines of evidence indicate that the nonenzymatic oxidative modification of proteins and the subsequent accumulation of the modified proteins have been found in cells during aging and oxidative stress and in various pathological states, including premature diseases, muscular dystrophy, rheumatoid arthritis, and atherosclerosis. Our previous work suggested the existence of molecular mimicry between antibodies raised against hydroxy-2-nonenal (HNE)-modified protein and anti-DNA autoantibodies, a serologic hallmark of systemic lupus erythematosus (SLE). In the present study, we investigated the possible involvement of HNE-modified proteins as the endogenous source of the anti-DNA antibodies. Accumulation of the antigen recognized by the antibody against the HNE-modified protein was observed in the nucleus of almost all of the epidermal cells from patients with autoimmune diseases, including SLE. The SLE patients also showed significantly higher serum levels of the anti-HNE titer than healthy individuals. To determine if a specific anti-DNA response could be initiated by the HNE-derived epitopes, we immunized BALB/c mice with the HNE-modified protein and observed a progressive increase in the anti-DNA response. Moreover, we generated the monoclonal antibodies, showing recognition specificity toward DNA, and found that they can bind to two structurally distinct antigens (i.e. the native DNA and protein-bound 4-oxo-2-nonenal). The findings in this study provide evidence to suspect an etiologic role for lipid peroxidation in autoimmune diseases.

Received for publication, April 11, 2007 , and in revised form, June 1, 2007.

^* This work was supported by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology and by the Center of Excellence (COE) Program in the 21st Century in Japan (to K. U.), by a research grant from the Institute for Advanced Research, Nagoya University (to K. U.), and by the COE Program in the 21st Century in Japan (to K. U. and T. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. Tel.: 81-52-789-4127; Fax: 81-52-789-5741; E-mail: uchidak{at}agr.nagoya-u.ac.jp.

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