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International Immunology Advance Access published online on May 19, 2008
International Immunology, doi:10.1093/intimm/dxn049
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice

Toshihiko Kobayashi1,2, Koichiro Takahashi1, Yoshinori Nagai1,6, Takuma Shibata1, Masako Otani3, Shozo Izui3, Shizuo Akira4, Yoshiyuki Gotoh5, Hiroshi Kiyono5 and Kensuke Miyake1

1 Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, Japan
2 Japan Society for the Promotion of Science, Tokyo, Japan
3 Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
4 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
5 Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
6 Present address: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama, Japan

Correspondence to: Correspondence to: K. Miyake; E-mail: kmiyake{at}ims.u-tokyo.ac.jp

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 {gamma}3 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.

Keywords: autoimmunity, B cells, innate immunity

Transmitting editor: K. Inaba

Received 4 February 2008, accepted 22 April 2008.


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