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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）的密切相互作用。FDC提供支持B细胞生长和分化的抗原、趋化因子和细胞因子。然后，包括NF-κ B的转录机制被激活。本研究主要通过基因打靶的方法在体内阐明这些步骤. FDC产生一种趋化因子BLC，已知其在体外作用于成熟B细胞。为了阐明其在体内的作用，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分化和免疫应答. I κ B激酶（IKK）α和β均激活NF-κ B活性，这对B细胞生长和分化至关重要。虽然这两种激酶显示出相似的分子结构和功能，但它们对各种组织的需求不同。IKKalalpha缺陷小鼠出生后很快死亡，因为肢体和表皮畸形。为了分析IKK α如何在B细胞中发挥关键作用，我们通过将IKK α缺陷型胎肝细胞转移到辐射小鼠中来建立IKK α缺陷型嵌合小鼠。IKKalalpha缺陷型嵌合体显示成熟B细胞群减少，主要通过增强凋亡。他们还表现出严重的免疫球蛋白产生和免疫反应受损。结果表明IKK α对外周淋巴器官中B细胞的生长和分化是必不可少的，IKK β单独不能正确激活成熟B细胞中的NF-κ B.我们已经建立了缺乏转录因子C/EBP γ的突变小鼠。C/EBP γ缺陷型自然杀伤（NK）细胞表现出NK活性和干扰素γ产生的损害。新基因被认为参与C/EBP γ介导的NK活性。C/EBP γ的靶基因鉴定正在进行中。