DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice
1Department of Immunology, Institute for Immunobiology and Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai Medical College, Fudan University, 2Immunology Division, E-Institutes of Shanghai Universities and 3Institute of Biomedical Science, Fudan University, Shanghai, P.R. China.
Correspondence to: S. Xiong, Professor and Director, Department of Immunology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, P.R. China. E-mail: sdxiongfd{at}126.com
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Abstract |
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Objectives. Systemic lupus erythematosus (SLE) is characterized by serological presence of anti-double-stranded DNA (dsDNA) antibodies and its pathogenesis remains unclarified. Our previous work found that syngeneic activated lymphocyte-derived DNA (ALD-DNA) induced SLE-like autoimmune disease in the SLE-non-prone BALB/c mice. Here, the biological and chemical characteristics of the somatic DNA were focused upon to investigate their contribution to the autoimmunity induction to provide clues for the understanding of the pathogenesis of SLE in non-susceptible strains.
Methods. Induction of anti-dsDNA antibodies, glomerulonephritis and proteinuria was evaluated in BALB/c mice after subcutaneous immunization with apoptotic DNA (annexin-V+) extracted from concanavalin A or UV-treated apoptotic splenocytes or necrotic DNA from necrotic splenocytes. The hypomethylated apoptotic DNA and the normal DNA were then methylated and demethylated, respectively, by CpG methylase or 5-azacytidine treatment to re-evaluate their immunogenicity in BALB/c mice.
Results. It was apoptotic but not necrotic DNA that induced SLE-like autoimmune disease and the level of apoptotic DNA was associated with the level of anti-dsDNA antibodies. The apoptotic DNA exhibited significantly lower methylation levels than the normal DNA. Methylation of the hypomethylated apoptotic DNA significantly impaired its ability to induce anti-dsDNA antibodies and proteinuria, while demethylation of the normal or necrotic DNA endowed them with the immunogenicity to induce the SLE-like syndrome.
Conclusions. Our study provides direct evidence showing that DNA hypomethylation is essential for apoptotic DNA to induce SLE-like autoimmune disease in non-susceptible mice, which may help in elucidating the pathogenesis of SLE.
KEY WORDS: Systemic lupus erythematosus, Anti-dsDNA antibody, Apoptosis, Hypomethylation
Submitted 20 June 2007;
revised version accepted 7 September 2007.
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