G-rich DNA suppresses systemic lupus.
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.
Patole
Prashant S
PS
Medical Policlinic, Ludwig-Maximilians-University Munich, Germany.
Zecher
Daniel
D
Pawar
Rahul D
RD
Gröne
Hermann-Josef
HJ
Schlöndorff
Detlef
D
Anders
Hans-Joachim
HJ
D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D019175:DNA Methylation; D015226:Dinucleoside Phosphates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008181:Lupus Nephritis / Q000276:immunology* / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000517:prevention & control; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*
D015226:Dinucleoside Phosphates; D009838:Oligodeoxyribonucleotides; C015772:CpG dinucleotide