G-rich DNA suppresses systemic lupus

J Am Soc Nephrol. 2005 Nov;16(11):3273-80. doi: 10.1681/ASN.2005060658. Epub 2005 Sep 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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