title: Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice.
abstract: Toll-like receptors (TLRs) have a crucial role in sensing microbial products and triggering immune responses. Recent reports have indicated that TLR7 and TLR9 have an important role in activating autoreactive B cells. In addition to TLR7 and TLR9, mouse B cells express TLR2, TLR4 and structurally related Radioprotective105 (RP105). We have previously shown that RP105 works in concert with TLR2/4 in antibody response to TLR2/4 ligands. We here report that B cells are constitutively activated by TLR2/4 and RP105. Such B cell activation was revealed by the gamma3 germ line transcript and serum IgG3 production, both of which were impaired by the lack of RP105 or TLR2/4. Serum IgG3 was not altered in germ-free or antibiotics-treated mice, suggesting that the microbial flora hardly contributes to the continuous activation of B cells. The lack of RP105-dependent B cell activation ameliorated disease progression in lupus-prone MRL/lpr mice. RP105(-/-) MRL/lpr mice showed less lymphoadenopathy/splenomegaly and longer survival than MRL/lpr mice. Whereas glomerulonephritis and auto-antibody production were not altered, improvement in blood urea nitrogen and lower incidence of renal arteritis indicated that renal function was ameliorated in the absence of RP105. Our results suggest that RP105-dependent tonic B cell activation has a pathogenic role in MRL/lpr mice.
authors.affiliation: Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagai
authors.forename: Takuma
authors.initials: T
authors.lastname: Shibata
authors.forename: Masako
authors.initials: M
authors.lastname: Otani
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005921:Glomerulonephritis / Q000097:blood / Q000276:immunology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; D007074:Immunoglobulin G; C490500:Ly78 protein, mouse; D051193:Toll-Like Receptors