International Immunology Advance Access originally published online on June 23, 2006
International Immunology 2006 18(8):1211-1219; doi:10.1093/intimm/dxl067
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Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE
1 Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 4a, 81675 Munich, Germany
2 Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany
3 Institute of Pathology, GSF-National Research Center for Environment and Health, Ingolstädter Landstrasse1, 85764 Neuherberg, Germany
4 Division of Clinical Sciences, University of Sheffield, Royal Hallamshire Hospital, Beech Hill Road, Sheffield S10 2RX, UK
5 Division of Nephropathology, Institute for Pathology, University Erlangen-Nürnberg Krankenhausstrasse 8-10, 91054 Erlangen, Germany
6 Institute of Immunology, Philipps-University Marburg, Hans-Meerwein Strasse 3, 35037 Marburg, Germany
Correspondence to: P. Yu; E-mail: philipp.yu{at}staff.uni-marburg.de
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.
Keywords: autoimmunity, B cells, innate immunity, systemic lupus erythematosus
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