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

Abstract

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.

• Authors: Philipp Yu, Ute Wellmann, Sandra Kunder, Leticia Quintanilla-Martinez, Luise Jennen, Neil Dear, Kerstin Amann, Stefan Bauer, Thomas H Winkler, Hermann Wagner
• Journal: International immunology (Int Immunol) Vol. 18 Issue 8 Pg. 1211-9 (Aug 2006) ISSN: 0953-8178 [Print] England
• PMID: 16798839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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