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G-Rich DNA Suppresses Systemic Lupus

Prashant S. Patole^*, Daniel Zecher^*, Rahul D. Pawar^*, Hermann-Josef Gröne, Detlef Schlöndorff^* and Hans-Joachim Anders^*

^* Medical Policlinic, Ludwig-Maximilians-University Munich, Germany; and Division of Molecular and Cellular Pathology, German Cancer Research Center, Heidelberg, Germany

Address correspondence to: Dr. Hans-Joachim Anders, Medizinische Poliklinik der LMU, Pettenkoferstrasse 8a, 80336 Munich, Germany. Phone: +49-89-2180-75846; Fax: +49-89-2180-75860; hjanders{at}med.uni-muenchen.de

Received for publication June 27, 2005. Accepted for publication August 1, 2005.

Whereas the role of immune complexes in mediating renal cell and immune cell activation is well established, the contribution of sequence-specific immunomodulatory actions of the chromatin part remains unclear. Toll-like receptor-9 (TLR-9) mediates immunostimulatory effects of unmethylated microbial CpG-DNA. It was hypothesized that hypomethylated CpG-DNA in vertebrates may have similar effects and may contribute to disease progression in lupus nephritis. A synthetic G-rich DNA, known to block CpG-DNA effects, was used in this study. In macrophages, G-rich DNA suppressed CpG-DNA–but not LPS-induced production of CCL5 in a dose-dependent manner. Injections of G-rich DNA suppressed lymphoproliferation induced by CpG-DNA injections in mice. In MRL^lpr/lpr mice with lupus nephritis, labeled G-rich DNA co-localized to glomerular immune complexes and was taken up into endosomes of TLR-9–positive infiltrating macrophages. Eleven-week-old MRL^lpr/lpr mice that received injections of either saline or G-rich DNA for 13 wk revealed decreased lymphoproliferation and less autoimmune tissue injury in lungs and kidneys as compared with saline-treated controls. G-rich DNA reduced the levels of serum dsDNA-specific IgG2a as well as the renal immune complex deposits. This was consistent with the blocking effect of G-rich DNA on CpG-DNA–induced proliferation of B cells that were isolated from MRL^lpr/lpr mice. As oligodeoxyribonucleotide 2114–treated MRL^lpr/lpr mice were not exposed to exogenous CpG-DNA, these effects should relate to a blockade of CpG motifs in endogenous DNA. It is concluded that adjuvant activity of self-DNA contributes to the pathogenesis of lupus nephritis. Modulating the CpG-DNA–TLR-9 pathway may offer new opportunities for the understanding and treatment of lupus.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673