权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular events in the generation of memory B cells.

记忆 B 细胞生成中的分子事件。

基本信息

批准号：
13470076
负责人：
TAKEMORI Toshitada
金额：
$ 4.61万
依托单位：
NATIONAL INSTITUTE OF INFECTIOUS DISEASES
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

We have previously observed that a Fas-mediated signal regulated the generation of memory B cells which heavily accumulated somatic mutations in the V_H gene at the late immune response. To examine the role of Fas in the persistence of memory B cells, memory B cells were purified from NP-primed C57BL/6 or C57BL/6-lpr/lpr mice and transferred into carrier-primed mice, followed by a challenge using a soluble NP-carrier protein administered at different intervals after cell-transfer. The result shows that NP-primed memory cells did not elicit a secondary response when transferred cells were left in the recipient for 3wks, however, NP-primed lpr memory cells responded to the secondary challenge at the same condition. Administration of anti-Fas mAbs into the recipient immediately after the transfer of normal NP-primed B cells resulted in the generation of a secondary response by challenge 3wks after the transfer. These results suggest that the Fas mediated signal negatively regulates memory persistence.Although it is known that a deficiency in several molecules responsible for GC-formation reduces the generation of high-affinity memory B cells, the mechanism for the generation of memory B cells at the post GC-formation remains largely unknown. To examine the role of ras in memory B cell development, we have analyzed the B cell response in C57BL/6 mice who express dominant-negative ras at high levels in their B-lineage cells. Inhibition of ras activity reduced the frequency of high affinity memory cells in the spleen and impaired memory B cell activity for the secondary response. However, inhibition of Ras activity did not affect the primary response by serum antibodies, GC-formation, somatic mutations and selection of high-affinity GC and antibody-forming cells. These results suggest that ras is selectively involved in the establishment of memory B cells.

我们以前观察到，Fas介导的信号调节记忆B细胞的产生，在免疫反应后期，记忆B细胞大量积累V_H基因的体细胞突变。为了研究Fas在记忆B细胞持续存在中的作用，从NP免疫的C57BL/6或C57BL/6-LPR/LPR小鼠中纯化了记忆B细胞，并将其转移到载体免疫的小鼠中，然后在细胞转移后的不同时间段用可溶性NP载体蛋白进行攻击。结果表明，当移植细胞在受体体内停留3wk时，NP诱导的记忆细胞没有引起二次反应，而在相同条件下，NP诱导的LPR记忆细胞对二次刺激有反应。在移植正常的NP免疫的B细胞后，立即给受体注射抗Fas单抗，可在移植后3周激发产生二次反应。这些结果表明，Fas介导的信号负向调节记忆的持续性。尽管已知参与GC形成的几个分子的缺陷会减少高亲和力记忆B细胞的产生，但在GC形成后产生记忆B细胞的机制仍然很大程度上仍不清楚。为了研究ras在记忆B细胞发育中的作用，我们分析了在其B系细胞中高水平表达显性-负性ras的C57BL/6小鼠的B细胞反应。抑制ras活性减少了高亲和力记忆细胞在脾中的频率，并损害了次级反应的记忆B细胞的活性。然而，抑制RAS活性不影响血清抗体、GC形成、体细胞突变以及高亲和力GC和抗体形成细胞的选择。这些结果表明，ras选择性地参与了记忆B细胞的建立。