Analyses of Toll-like receptors regulating innate antibody response against microbial lipids

调节针对微生物脂质的先天抗体反应的 Toll 样受体的分析

• 批准号: 16390142
• 负责人: MIYAKE Kensuke
• 金额: $ 9.47万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390142/
• 关键词: innate immunity; endotoxin; Toll-like receptor; natural antibody; Lipopolysaccharide; MD-2

Antibody responses have an important role in defense against microbial infection. Two distinct antibodies were produced during infection, innate antibodies such as IgM and IgG3 and T-dependent antibodies including IgG2a and IgG2b. The former is produced in an T-independent manner in response to lipopolysaccharides or lipopeptides. In the present study, we examined how production of innate antibodies were regulated. Radioprotective 105/MD-1 is expressed on the B cell surface and structurally related to Toll-like receptors. We previously showed that RP105 is required for B cell responses to LPS. In this project, we showed that RP105 is also required for B cell response to TLR2 ligand, lipopeptide. Moreover, serum IgG3 is specifically low in RP105 mice. To reveal a mechanism by which RP105 induces serum IgG3, we studied expression of the γ3 germline transcript, which is constitutively expressed in splenic B cells. Intrerestingly, the constitutive expression of the γ3 germline transcript was impaired in RP105^<-/-> mice. Moreover, reduced serum IgG3 was also seen in MD-1^<-/-> mice and TLR2^<-/->TLR4^<-/-> mice. These results suggest that RP105/MD-1 and TLR2/4 work in concert for inducing serum IgG3. These results suggest that B cells are responding to TLR2/4 ligands without any apparent infection. Given that TLR2/4 respoind not only to microbial ligands but also to endogenous ligands, TLR2/4 and RP105/MD-1 may have a role in B cell response to endogenous self ligands as well as to microbial ligands. IgG3 was shown to be pathogenic in lupus nephritis, we are going to study roles for TLR2/4 and RP105/MD-1 in lupus nephritis.

抗体反应在防御微生物感染过程中发挥着重要作用，即先天性抗体（例如 IgM 和 IgG3）以及 T 依赖性抗体（包括 IgG2a 和 IgG2b）。前者以 T 依赖性方式产生。在本研究中，我们研究了辐射防护 105/MD-1 在 B 细胞表面和结构上的表达是如何调节的。我们之前表明，B 细胞对 LPS 的反应需要 RP105。此外，我们还表明，B 细胞对 TLR2 配体脂肽的反应也需要 RP105。为了揭示 RP105 诱导血清 IgG3 的机制，我们研究了在脾 B 中组成型表达的 γ3 种系转录物的表达。有趣的是，RP105^-/- 小鼠中 γ3 种系转录物的组成型表达受损，而且在 MD-1^-/- 小鼠和 TLR2^-/- 小鼠中也观察到血清 IgG3 减少。 >TLR4^</-/-> 小鼠。这些结果表明 RP105/MD-1 和 TLR2/4 协同作用，诱导血清 IgG3。在没有任何明显感染的情况下对 TLR2/4 配体作出反应 鉴于 TLR2/4 不仅对微生物配体有反应，而且对内源性配体也有反应，因此 TLR2/4 和 RP105/MD-1 可能在 B 细胞对内源性自身配体的反应中发挥作用。以及微生物配体 IgG3 已被证明在狼疮性肾炎中具有致病性，我们将研究 TLR2/4 和 的作用。狼疮性肾炎中的 RP105/MD-1。

项目成果

The Radioprotective 105/MD-1 Complex Links Toll-like Receptor 2 (TLR2) and TLR4/MD-2 in Antibody Response to Microbial Membranes.

辐射防护 105/MD-1 复合物在微生物膜抗体反应中与 Toll 样受体 2 (TLR2) 和 TLR4/MD-2 相关联。

• 发表时间: 2005
• 期刊: J.Immunol. 174
• 作者: Nagai Y;et al.;Nagai Y
• 通讯作者: Nagai Y

Endotoxin recognition molecules, Toll-like receptor 4-MD-2.

内毒素识别分子，Toll样受体4-MD-2。

• 发表时间: 2004
• 期刊: Semin Immunol. 16
• 作者: Nagai Y;et al.;Nagai Y;Inamine A;Nagaoka K;Shinohara H.;Miyake K.
• 通讯作者: Miyake K.

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling.

• DOI: 10.1084/jem.20041817
• 发表时间: 2005-02-07
• 期刊: The Journal of experimental medicine
• 作者: Shinohara H;Inoue A;Toyama-Sorimachi N;Nagai Y;Yasuda T;Suzuki H;Horai R;Iwakura Y;Yamamoto T;Karasuyama H;Miyake K;Yamanashi Y
• 通讯作者: Yamanashi Y

Agonistic Antibody to Toll-like receptor 4/MD-2 Protects Mice From Acute Lethal Hepatitis Induced by Tumor Necrosis Factor-α

Toll 样受体 4/MD-2 激动性抗体可保护小鼠免受肿瘤坏死因子-α 诱导的急性致死性肝炎

• 发表时间: 2006
• 期刊: Journal of Immunology 176
• 作者: 赤司祥子

The Radioprotective 105/MD-1 Complex Links Toll-like Receptor 2 (TLR2) and TLR4/MD-2 in Antibody Response to Microbial Membranes

辐射防护 105/MD-1 复合物在微生物膜抗体反应中与 Toll 样受体 2 (TLR2) 和 TLR4/MD-2 相关

• 发表时间: 2005
• 期刊: J.Immunol. 174
• 作者: Nagai Y;et al.
• 通讯作者: et al.