DNA hypomethylation is crucial for apoptotic DNA to induce systemic lupus erythematosus-like autoimmune disease in SLE-non-susceptible mice

Abstract

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. © The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.