Mechanism of B cell proliferation and diffentiation in peripheral lymphoid organs

外周淋巴器官B细胞增殖和分化的机制

基本信息

批准号：
10670313
负责人：
KAISHO Tsuneyasu
金额：
$ 2.3万
依托单位：
Research Institue for Microbial Diseases, Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670313/
关键词：
peripheral lymphoid organ B cell follicular dendritic cell gene targeting 末梢リンパ器官

项目摘要

B cell development in peripheral lymphoid organs requires an intimate interaction with follicular dendritic cells (FDC). FDC provides antigens, chemokines, and cyokines, which support B cell growth and differentiation. Then, transcriptional machinery including NF-kappaB is activated. This study aims to clarify these steps in vivo mainly by using gene targeting approach.1. FDC produces a chemokine, BLC, which is known to act on mature B cells in vitro. In order to clarify its in vivo roles, we have established BLC-deficient mice. BLC-deficient mice were born healthy. We plan to analyze B cell distribution in peripheral lymphoid organs, FDC differentiation, and immune responses in BLC-deficient mice.2. Both IkappaB kinase (IKK) alpha and beta activate NF-kappaB activities, which are critical for B cell growth and differentiation. Although these two kinases shows similar molecular structures and functions, they are differentially required for various tissues. IKKalpha-deficient mice die soon after birth because of limb and epidermis malformation. In order to analyze how IKKalpha plays critical roles in B cells, we have established IKKalpha-deficient chimeric mice by transferring IKKalpha-deficient fetal liver cells into irradiated mice. IKKalpha-deficient chimeras showed decrease of mature B cell population mainly through enhanced apoptosis. They also showed severe impairment of immunoglobulin production and immune response. The results suggest that IKKalpha is essential for B cell growth and differentiation in peripheral lymphoid organs and that IKKbeta alone cannot properly activate NF-kappaB in mature B cells.3. We have established the mutant mice lacking a transcription factor, C/EBPgamma. C/EBPgamma-deficient natural killer (NK) cells showed impairment of NK activity and interferon-gamma production. Novel gene(s) were assumed to be involved in C/EBPgamma-mediated NK activity. Identification of the target gene of C/EBPgamma is now in progress.

外周淋巴器官中的 B 细胞发育需要与滤泡树突状细胞 (FDC) 密切相互作用。 FDC 提供抗原、趋化因子和细胞因子，支持 B 细胞生长和分化。然后，包括 NF-kappaB 在内的转录机制被激活。本研究的目的主要是通过基因打靶的方法在体内阐明这些步骤。 1． FDC 产生一种趋化因子 BLC，已知其在体外作用于成熟 B 细胞。为了阐明其体内作用，我们建立了 BLC 缺陷小鼠。 BLC 缺陷小鼠出生时健康。我们计划分析BLC缺陷小鼠外周淋巴器官中B细胞的分布、FDC分化和免疫反应。2． IkappaB 激酶 (IKK) α 和 β 均可激活 NF-kappaB 活性，这对于 B 细胞生长和分化至关重要。尽管这两种激酶显示出相似的分子结构和功能，但不同组织对它们的需求不同。 IKKα缺陷的小鼠在出生后不久就会因四肢和表皮畸形而死亡。为了分析IKKalpha如何在B细胞中发挥关键作用，我们通过将IKKalpha缺陷的胎儿肝细胞转移到辐射小鼠体内，建立了IKKalpha缺陷的嵌合小鼠。 IKKalpha 缺陷嵌合体主要通过增强细胞凋亡来减少成熟 B 细胞群。他们还表现出免疫球蛋白产生和免疫反应的严重受损。结果表明，IKKα对于外周淋巴器官中B细胞的生长和分化至关重要，单独的IKKβ不能正确激活成熟B细胞中的NF-κB。3．我们已经建立了缺乏转录因子 C/EBPgamma 的突变小鼠。 C/EBPgamma 缺陷的自然杀伤 (NK) 细胞显示 NK 活性和干扰素-γ 产生受损。假定新基因参与 C/EBPgamma 介导的 NK 活性。 C/EBPgamma 靶基因的鉴定正在进行中。