Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice
Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice
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DOI：
10.1093/intimm/dxn049
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发表时间：
2008-07-01
影响因子：
4.4
通讯作者：
Miyake, Kensuke
中科院分区：
文献类型：
--
作者：
Kobayashi, Toshihiko;Takahashi, Koichiro;Miyake, Kensuke
toll样受体（TLRs）在感知微生物产物和触发免疫反应中起着至关重要的作用。最近的报道表明，TLR7和TLR9在激活自身反应性B细胞中起重要作用。除TLR7和TLR9外，小鼠B细胞还表达TLR2、TLR4和结构相关的Radioprotective105 （RP105）。我们之前已经证明，RP105在抗体对TLR2/4配体的反应中与TLR2/4协同作用。我们在这里报道了B细胞被TLR2/4和RP105组成性激活。这种B细胞的激活是通过γ - 3生殖系转录物和血清IgG3的产生来揭示的，两者都因缺乏RP105或TLR2/4而受损。在无菌或抗生素处理的小鼠中，血清IgG3没有改变，这表明微生物菌群对B细胞的持续激活几乎没有贡献。缺乏依赖rp105的B细胞激活改善了狼疮易发MRL/lpr小鼠的疾病进展。与MRL/lpr小鼠相比，RP105(-/-) MRL/lpr小鼠淋巴腺病/脾肿大较少，存活时间更长。虽然肾小球肾炎和自身抗体的产生没有改变，但血液尿素氮的改善和肾动脉炎发生率的降低表明，在没有RP105的情况下，肾功能得到了改善。我们的研究结果表明，依赖rp105的强直B细胞活化在MRL/lpr小鼠中具有致病作用。
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.