title: 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.affiliation: Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 4a, 81675 Munich, Germany. philipp.yu@staff.uni-marburg.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Yu
authors.forename: Ute
authors.initials: U
authors.lastname: Wellmann
authors.forename: Sandra
authors.initials: S
authors.lastname: Kunder
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Luise
authors.initials: L
authors.lastname: Jennen
authors.forename: Neil
authors.initials: N
authors.lastname: Dear
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Winkler
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D013163:Splenomegaly / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D051217:Toll-Like Receptor 9; D004247:DNA; D051966:Phospholipase C gamma