Dynamism of B cell development

B 细胞发育的动态

• 批准号: 14370110
• 负责人: KARASUYAMA Hajime
• 金额: $ 7.23万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370110/
• 关键词: B cell development; pre B cell receptor; μH chain; surrogate light chain; signal transduction; quality check; immunodeficiency; autoimmune deseases; 遺伝子再構成; 大型プレB細胞; チロシンリン酸化; NKκB; Srcファミリーキナーゼ; PKC

All the genes so far identified till now, which mutations cause B cell-less primary immunodeficiency encode components of preB cell receptor or molecules involved in preB cell receptor signaling. This clearly indicates that preB cell receptor plays a pivotal role in B cell development. However, it remains to be determined how preB cell receptor regulates early B cell development in bone marrow. In this study, we employed our original system to analyze early B cell development and examined the expression pattern of preB cell receptor in B cell precursors, the signaling pathways of preB cell receptor and the quality check of p11 chain through preB cell receptor. It was clearly demonstrated by using highly sensitive immunofluorescence that the surface expression of preB cell receptor was confined to the large preB cell stage of B cell (levelopment m both humans and mice. This finally settled the confusion regarding the preB cell receptor expression. Two distinct pathways of preB cell receptor signahng were identified. One is dependent on Src family kinases, and the other is dependent on Syk. Activation of NFκ3 was observed only in the former pathway. Novel molecules designated TPP36 and TPP32 were identified as tyrosine-phosphorylated by Abl in preB cells. In order to clarify the mechanism of H chain selection at the early stage of B cell development, we have established a novel system to dlstlngnLsh preB cells with preB cell receptor and those without preB cell receptor ih vivo and found that as much as two-thirds of H chains pro(luced at the preB cell stage are incal)able of associating with surrogate L chain to form preB cell receptor. Our recent data suggest that the malfunction of μH chain quality check results in immunodeficiency and autoimmune diseases.

到目前为止，所有导致 B 细胞非原发性免疫缺陷的基因都编码前 B 细胞受体或参与前 B 细胞受体信号传导的分子，这清楚地表明前 B 细胞受体在 B 细胞发育中发挥着关键作用。 preB 细胞受体如何调节骨髓中的早期 B 细胞发育仍有待确定。在本研究中，我们使用我们的原始系统来分析早期 B 细胞发育，并检查了前 B 细胞受体在 B 细胞前体中的表达模式、信号通路。前B细胞受体通过前B细胞受体进行p11链的质量检查通过使用高灵敏的免疫荧光清楚地证明前B细胞受体的表面表达仅限于B细胞的大前B细胞阶段（在人和小鼠中均如此）。前 B 细胞受体表达存在两种不同的途径，一种依赖于 Src 家族激酶，另一种依赖于 Syk 激活，仅在前者中观察到。命名为 TPP36 和 TPP32 的新分子被 Abl 在 preB 细胞中鉴定为酪氨酸磷酸化。 为了阐明 B 细胞发育早期阶段的 H 链选择机制，我们建立了一个新的系统来分离 preB 细胞。体内研究了前B细胞受体和那些没有前B细胞受体的细胞，发现多达三分之二的H链（在前​​B细胞阶段阐明）能够我们最近的数据表明，μH 链质量检查的故障会导致免疫缺陷和自身免疫性疾病。

项目成果

Maezawa, Y, Nakajima, H., Kumano, K., Kubo, S., Karasnyama H, Iwamoto, J.: "Role of IgE in Th2 cell-mediated allergic airway inflammation."International Archives of Allergy and Immunology. 131(Suppl 1). 2-6 (2003)

Maezawa, Y、Nakajima, H.、Kumano, K.、Kubo, S.、Karasn​​yama H、Iwamoto, J.：“IgE 在 Th2 细胞介导的过敏性气道炎症中的作用。”国际过敏与免疫学档案馆。

Sato, E., et al.: "Chronic inflammation in skin can be induced in IgE transgenic mice by a singlde challenge of multivalent antigen"J. Allergy Clin. Immunol.. 111. 143-148 (2003)

Sato, E., et al.：“通过多价抗原的单次攻击可以在 IgE 转基因小鼠中诱导皮肤慢性炎症”J.

烏山 一: "「B細胞の初期分化」標準免疫学第2版(谷口克, 宮坂昌之編)"医学書院. 9 (2002)

Hajime Karasuyama：“‘B 细胞的初始分化’标准免疫学第 2 版（由 Masaru Taniguchi 和 Masayuki Miyasaka 编辑）”Igaku Shoin 9 (2002)。

Maezawa, Y., Nakajima, H., Kumano, K., Kubo, S., Karasuyama, H., Iwamoto, I.: "Role of IgE in Th2 cell-mediated alllergic airway inflammation."International Archives of Allergy and Immunology. 131. 2-6 (2003)

Maezawa, Y.、Nakajima, H.、Kumano, K.、Kubo, S.、Karasuyama, H.、Iwamoto, I.：“IgE 在 Th2 细胞介导的过敏性气道炎症中的作用。”国际过敏与免疫学档案馆

Tsuchiya, K., Kawano, Y., Kojima, T., Nagata, K., Takao, T., Okada, M., Shinohara, H., Maki, K., Toyama-Sorimachi, N., MIyasaka, N., Watanabe, M., Karasuyama, H.: "Molecular cloning and characterization of TPP36 and its isoform TPP32, novel substrates of

土屋，K.，河野，Y.，小岛，T.，永田，K.，高尾，T.，冈田，M.，筱原，H.，真木，K.，富山反町，N.，宫坂，N