Memory B cell commitment, maintenance and terminal differentiation

记忆 B 细胞定型、维持和终末分化

• 批准号: 16043261
• 负责人: TAKEMORI Toshitada
• 金额: $ 25.34万
• 依托单位: RIKEN (2006)National Institute of Infectious Diseases (2004-2005)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 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/en/grant/KAKENHI-PROJECT-16043261/
• 关键词: memory B cell; memory B cell genes; survival; secondary response; SMN; AIF; committment; AID; Somatic mutations; 記憶B細胞系列決定; 抗体産生細胞; 抗酸化ストレス; 抗アポトーシス活性; 生存維持; ミトコンドリア; 呼吸鎖複合体; 抗アポトーシス; Ras; 抗原受容体

Memory B cells acquire several intrinsic properties that differ from na・e B cells, suggesting that memory B cells may have a unique gene expression that differs quantitatively and/or qualitatively from other stages of B cells. Therefore, to clarify the mechanism responsible for memory B cell commitment, survival and terminal differentiation upon antigen reexposure, we identified changes in gene expression that occur in the transition from a naive B cell to either GC B cells, memory B cells or plasma cells upon antigen stimulation. We have cloned several genes which are highly expressed in memory B cells, including E52 and 4010. E52 was turned out to be a human homologue of the survival of motor neuron gene (SMN)1, which is a causative gene for spinal muscular atrophy (SMA). Over expression of SMN in B cell lymphoma cell lines prolonged cell survival in proapoptotic culture conditions, raising the idea that the gene could be responsible for memory B cell survival. Therefore, we characte … More rized the role of SMN in cell survival by biochemical analysis and concluded that SMN prolonged cell survival upon oxidant stress and enhanced the activity of the mitochondrial respiratory chain complex I.The 4010 gene encodes an adopter molecule and its overexpression in splenic B cells results in an augmentation of IgG1 response upon stimulation with anti-Igs and anti-CD40 mAbs in vitro. Thus, 4010 could be involved in the signaling cascade responsible for either memory B cell terminal differentiation or antibody secretion. To examine this possibility we are now establishing conditional knock out mice.To know the regulatory network responsible for memory B cell commitment, we utilized Affymetrix GeneChip analysis and characterize the changes in gene expression in the transition from naive B cells to GC B cells, memory B cells or plasma cells upon antigen stimulation. Q-PCR confirmation revealed that memory B cell population expressed a group of transcripts selectively enriched in this population, with similar time-dependent changes in their expression patterns. To utilize such genetic markers for the memory B cell lineage, we analyzed the early events in antigen-specific B cell response and suggested that activated B cells progress to memory B cells, at least, from day 5 to day 6 after immunization, accompanied by class-switch recombination and efficient proliferation. Less

记忆B细胞获得了与na·e B细胞不同的几种内在特性，这表明记忆B细胞可能具有独特的基因表达，与其他阶段的B细胞在数量上和/或质量上不同。因此，为了阐明抗原再暴露后记忆B细胞定型、存活和终末分化的机制，我们鉴定了抗原刺激后从幼稚B细胞向GC B细胞、记忆B细胞或浆细胞转变中发生的基因表达变化。我们已经克隆了几个在记忆B细胞中高表达的基因，包括E52和4010。E52是运动神经元存活基因（SMN）1的同源基因，SMN 1是脊髓性肌萎缩症（SMA）的致病基因。在B细胞淋巴瘤细胞系中，SMN的过度表达延长了细胞在促凋亡培养条件下的存活时间，提出了该基因可能负责记忆B细胞存活的观点。因此，我们将 ...更多信息 通过生化分析提高了SMN在细胞存活中的作用，并得出结论，SMN延长了氧化应激后的细胞存活，并增强了线粒体呼吸链复合物I的活性。4010基因编码一种过继分子，其在脾B细胞中的过表达导致体外抗Ig和抗CD 40 mAb刺激后IgG 1应答增强。因此，4010可能参与负责记忆B细胞终末分化或抗体分泌的信号级联。为了研究这种可能性，我们现在正在建立条件性基因敲除小鼠。为了了解负责记忆B细胞定型的调控网络，我们利用Affyssin基因芯片分析并表征抗原刺激后从幼稚B细胞向GC B细胞、记忆B细胞或浆细胞转变中基因表达的变化。Q-PCR证实，记忆B细胞群体表达一组选择性富集在该群体中的转录本，其表达模式具有相似的时间依赖性变化。为了利用记忆B细胞谱系的遗传标记，我们分析了抗原特异性B细胞应答的早期事件，并表明活化的B细胞至少在免疫后第5天至第6天进展为记忆B细胞，伴随着类别转换重组和有效增殖。少

项目成果

A unique role of Ras in memoryB cell response.

Ras 在记忆 B 细胞反应中的独特作用。

• 发表时间: 2005
• 期刊: Immunity 23
• 作者: Takahashi;Y;Inamine A;Hashimoto;S.-I;Yoshioka;E;Kojima;N;Abe;R;Takemroi T.
• 通讯作者: Takemroi T.

An essentialrole for the RNA-pr b GANP for somatic hypermu tation of immunoglobulin gene in germinal center B cells.

RNA-pr b GANP 在生发中心 B 细胞免疫球蛋白基因体细胞超突变中发挥重要作用。

• 发表时间: 2004
• 期刊: Pric, Natl. Acad. Sci. USA 101
• 作者: Kuwahara;K;Fujita;S;Takahashi;Y;Xing;Y;Nakagata;N;Takemori;T;Aizawa;S;Sakaguchi;N.
• 通讯作者: N.

B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts

• DOI: 10.4049/jimmunol.177.9.5928
• 发表时间: 2006-11-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Hori, Junko;Wang, Mingcong;Azuma, Miyuki
• 通讯作者: Azuma, Miyuki

Interferon regulatory factor-4 negatively regulates the product of proinfalmmatory cytokines by macrophages in response to LPS.

干扰素调节因子 4 负向调节巨噬细胞响应 LPS 产生的促炎症细胞因子的产物。

• 发表时间: 2005
• 期刊: Proc. Natl. Acad. Sci. USA 102
• 作者: Honnma;K;Udono;H;Ohkusu-Tsukada;K;Khono;T;Yamamoto;K;Ogawa;A;Takemori;T;Kumatori;A;Suzuki;S;Matsuyama;T;Yui;K.
• 通讯作者: K.

Analysis of anti-SRAS corona virus response in mice inoculated with UV-irradiated virus.

接种紫外线照射病毒的小鼠的抗 SRAS 冠状病毒反应分析。

• 发表时间: 2004
• 期刊: Int.Immnol. 16
• 作者: Takasuka;N.;et al.
• 通讯作者: et al.