G-rich DNA suppresses systemic lupus.

Abstract

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.

• Authors: Prashant S Patole, Daniel Zecher, Rahul D Pawar, Hermann-Josef Gröne, Detlef Schlöndorff, Hans-Joachim Anders
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 16 Issue 11 Pg. 3273-80 (Nov 2005) ISSN: 1046-6673 [Print] United States
• PMID: 16176997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dinucleoside Phosphates
• Oligodeoxyribonucleotides
• cytidylyl-3'-5'-guanosine

Topics

• Animals
• Autoimmune Diseases (prevention & control)
• B-Lymphocytes (drug effects, immunology)
• Cell Line
• DNA Methylation
• Dinucleoside Phosphates (antagonists & inhibitors, pharmacology)
• Lupus Nephritis (immunology, prevention & control)
• Lymphocyte Activation (drug effects)
• Lymphoproliferative Disorders (immunology, prevention & control)
• Macrophages (physiology)
• Mice
• Mice, Mutant Strains
• Oligodeoxyribonucleotides (pharmacology)