title: Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9-deficient mice.
abstract: Accumulating evidence supports the idea that TLR7 and TLR9 play pathogenic and protective roles, respectively, in the development of murine systemic lupus erythematosus (SLE). However, the molecular mechanism responsible for the accelerated development of SLE resulting from the deletion of TLR9 and the respective contributions of TLR7 and TLR9 to the development of different autoimmune responses against nuclear and non-nuclear autoantigens implicated in lupus nephritis have not been well defined. In the present study, we addressed these questions by assessing the effect of the TLR9 and/or TLR7 deletion on the production of various autoantibodies and the development of lupus nephritis in C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus (B6.Nba2). TLR9-deficient B6.Nba2 mice displayed increased production of autoantibodies against nuclear antigens, serum retroviral gp70 and glomerular matrix antigens, and developed a markedly accelerated form of lupus nephritis. Enhanced disease was associated with functionally upregulated expression of TLR7, as documented by an increased TLR7-dependent activation of B cells and plasmacytoid dendritic cells. Notably, disease exacerbation in TLR9-deficient mice was completely suppressed by the deletion of TLR7. Our results indicate that TLR7 has a pivotal role in a wide variety of autoimmune responses against DNA- and RNA-containing nuclear antigens, retroviral gp70 and glomerular matrix antigens implicated in murine SLE, and that enhanced TLR7 activity is critical for the accelerated development of SLE in TLR9-deficient lupus-prone mice.
authors: Department of Pathology and Immunology, University of Geneva, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
authors: Marie-Laure
authors: ML
authors: Santiago-Raber
authors: Isabelle
authors: I
authors: Dunand-Sauthier
authors: Tianfu
authors: T
authors: Wu
authors: Quan-Zhen
authors: QZ
authors: Li
authors: Satoshi
authors: S
authors: Uematsu
authors: Shizuo
authors: S
authors: Akira
authors: Walter
authors: W
authors: Reith
authors: Chandra
authors: C
authors: Mohan
authors: Brian L
authors: BL
authors: Kotzin
authors: Shozo
authors: S
authors: Izui
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D018450:Disease Progression; D050533:Glomerular Basement Membrane / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051199:Toll-Like Receptor 7 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency*
chemical_list: D034961:Antigens, Nuclear; D001323:Autoantibodies; D001324:Autoantigens; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9