Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE

Int Immunol. 2006 Aug;18(8):1211-9. doi: 10.1093/intimm/dxl067. Epub 2006 Jun 23.


The generation of anti-DNA auto-antibodies is characteristic for the human autoimmune condition systemic lupus erythematosus (SLE) and its animal models. However, the contribution of the toll-like receptor (TLR) system of innate immunity receptors and, in particular, TLR9 to this B cell-mediated autoimmune process remains controversial. Here we report that in a novel murine model of SLE, based on hyper-reactive B cell activation mediated by mutant phospholipase Cg2, the genetic deficiency of TLR9 does not protect from spontaneous anti-DNA auto-antibody formation and glomerulonephritis. On the contrary, disease induction is aggravated and additional nucleolar antibody specificity develops in autoimmune TLR9-deficient mice. In vitro studies demonstrate that, in autoimmune-prone mice, dual signaling via the B cell receptor and non-CpG DNA results in synergistic B cell activation in a TLR9-independent manner. These results suggest that engagement of a TLR9-independent DNA activation pathway may promote autoimmunity, while TLR9 signaling can ameliorate SLE-like immune pathology in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / biosynthesis
  • Antibodies, Antinuclear / immunology
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology
  • B-Lymphocytes / immunology
  • DNA / immunology
  • Disease Models, Animal
  • Female
  • Glomerulonephritis / enzymology
  • Glomerulonephritis / genetics
  • Glomerulonephritis / immunology*
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / enzymology
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / immunology
  • Splenomegaly / immunology
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / immunology*


  • Antibodies, Antinuclear
  • Autoantibodies
  • Toll-Like Receptor 9
  • DNA
  • Phospholipase C gamma