Abstract
The aberrant activity of CD4+ T cells in patients with systemic lupus erythematosus (SLE) is associated with DNA hypomethylation of the regulatory regions in CD11a and CD70 genes. Our previous studies demonstrated that Gadd45a contributes to the development of SLE by promoting DNA demethylation in CD4+ T cells. In this study, we identified proteins that bind to Gadd45a in CD4+ T cells during SLE flare by using the method of co-immunoprecipitation and mass spectrometry, High mobility group box protein 1 (HMGB1) is one of identified proteins. Furthermore, gene and protein expression of HMGB1 was significantly increased in SLE CD4+ T cells compared to controls, and HMGB1 mRNA was correlated with CD11a and CD70 mRNA. A significant, positive correlation was found between HMGB1 mRNA and SLEDAI for SLE patients. Our data demonstrate that HMGB1 binds to Gadd45a and may be involved in DNA demethylation in CD4+ T cells during lupus flare.
Highlights
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that affects multiple organ systems
We previously demonstrated that inhibition of DNA methylation in T cells resulted in the demethylation of regulatory sequences and increased gene expression of CD11a (ITGAL) and CD70 (TNFSF7) [2,3,4]
We identified proteins that bind to Gadd45a in SLE CD4+ T cells that may assist in DNA demethylation
Summary
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that affects multiple organ systems. We previously demonstrated that inhibition of DNA methylation in T cells resulted in the demethylation of regulatory sequences and increased gene expression of CD11a (ITGAL) and CD70 (TNFSF7) [2,3,4]. Increased expression of these genes results in T-cell autoreactivity and autoantibody production by the B lymphocyte lineage. The molecular mechanisms that mediate gene demethylation in SLE CD4+ T cell are not fully understood, but it is possible that growth arrest and DNA damage-inducible gene (Gadd45a/Gadd45) may contribute since increased expression of Gadd45a gene has been shown to repress DNA methylation, and factors that induce lupus flare such as ultraviolet have been shown to promote DNA demethylation in SLE CD4+ T cells [5,6,7]
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