Induction mechanisms of B cell self-toleranace

B细胞自我耐受的诱导机制

• 批准号: 11470082
• 负责人: TOKUHISA Takeshi
• 金额: $ 9.54万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470082/
• 关键词: Apoptosis; Memory B cells; BCL6; Germinal center; Autoantibody; Transgenic mice; Lymphoma; Deficient mice; リンパ種; c-Fos; ノックアウトマウス; 血球系幹細胞; 転写抑制

We investigated the induction mechanisms of apoptosisi of self-reactive B cells developed in germinal centers using transgenic system. We show that1. The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B cell lymphomas, encodes a sequence-specific transcriptional repressor, and is strongly expressed in germinal center B and T cells. Adoptive transfer experiments with bone marrow cells from Bcl6-deficient (Bcl6-/-) mice revealed that Bcl6 is essential for the differentiation of germinal center B cells. Bcl6 was also detected in testicular germ cells, mainly spermatocytes, of normal mice. We found numerous apoptotic spermatocytes at the metaphase I stage with induction of Bax protein in adult Bcl6-/-testes. The incidence of apoptosis in heterozygous Bcl6+/-mice was also higher than that of Bcl6+/+mice. Since the activated form of p38 MAP kinase was detected in spermatocytes of adult Bcl6-/-mice, Bcl6 may play a role as a stabilizer in protecting spermatocytes from apoptosis induced by stresses.2. Bcl6-/-mice displayed massive eosinophilic inflammation. We have recently established transgenic mice carrying the Ig-Bcl6 or the lck-Bcl6 gene, and analyzed functions of lymphocytes of these Bcl6 transgenic mice. The germinal center fromation and memory responses were augmented in transgenic mice, suggesting that Bcl6 may play a role in survival of germinal center B cells.3. we describe a newly defined murine inhibitor of apoptosis (LAP), designated TIAP.TIAP interacted with the processed form of Caspase-3 and inhibited caspase-induced cell death. The expression of TIAP was upregulated in synchronized NIH3T3 cells at S to G2/M phase of the cell cycle. We propose that during cell proliferation, cellular protective activity may be augmented with inducible IAPs such as TIAP.We are investigating the role of TIAP in germinal center B cells.

我们研究了使用转基因系统在生发中心发育的自身反应性 B 细胞的凋亡诱导机制。我们表明1。 Bcl6 基因已从 B 细胞淋巴瘤的染色体易位断点中鉴定出来，编码序列特异性转录抑制因子，并在生发中心 B 和 T 细胞中强烈表达。对 Bcl6 缺陷 (Bcl6-/-) 小鼠骨髓细胞的过继转移实验表明，Bcl6 对于生发中心 B 细胞的分化至关重要。在正常小鼠的睾丸生殖细胞（主要是精母细胞）中也检测到了 Bcl6。我们在成年 Bcl6-/-睾丸中发现大量处于中期 I 阶段的精母细胞凋亡，并诱导 Bax 蛋白。杂合子Bcl6+/-小鼠的细胞凋亡发生率也高于Bcl6+/+小鼠。由于在成年Bcl6-/-小鼠精母细胞中检测到激活形式的p38 MAP激酶，Bcl6可能作为稳定剂发挥作用，保护精母细胞免受应激诱导的凋亡。 2． Bcl6-/-小鼠表现出大量嗜酸性粒细胞炎症。我们最近建立了携带Ig-Bcl6或lck-Bcl6基因的转基因小鼠，并分析了这些Bcl6转基因小鼠的淋巴细胞功能。转基因小鼠生发中心的形成和记忆反应增强，提示Bcl6可能在生发中心B细胞的存活中发挥作用。 3．我们描述了一种新定义的小鼠细胞凋亡抑制剂 (LAP)，命名为 TIAP。TIAP 与 Caspase-3 的加工形式相互作用，并抑制 caspase 诱导的细胞死亡。 TIAP 的表达在细胞周期 S 期至 G2/M 期的同步 NIH3T3 细胞中上调。我们提出，在细胞增殖过程中，可诱导的 IAP（例如 TIAP）可能会增强细胞保护活性。我们正在研究 TIAP 在生发中心 B 细胞中的作用。

项目成果

Kojima,S., et al.: "Disruption of the Bcl6 gene increases testicular germ cell apoptosis in mice."Development. 128. 57-65 (2001)

Kojima,S. 等人：“Bcl6 基因的破坏会增加小鼠睾丸生殖细胞的凋亡。”开发。

Kojima,S., et al.: "Disruption of the Bc16 gene increases testicular germ cell apoptosis in mice."Development. 128. 57-65 (2001)

Kojima,S. 等人：“Bc16 基因的破坏会增加小鼠睾丸生殖细胞的凋亡。”开发。

Okada, S.: "Overexpression of c-fos suppresses cell cycle entry of dormant hematopoietic stem cells"Blood. 93. 816-825 (1999)

Okada, S.：“c-fos 的过度表达抑制休眠造血干细胞的细胞周期进入”血液。

Tagaya,H., et al.: "Intramedullary and extramedullary B Iymphopoiesis in osteopetrotic mic"Blood. 95. 3363-3370 (2000)

Tagaya, H. 等人：“骨石症麦克风中的髓内和髓外 B 淋巴细胞”血液。

Okada S et al.: "Prolonged expression of c-fos suppresses cell cycle entry of dormant hematopoietic stem cells"Blood. 93. 816-825 (1999)

Okada S 等人：“c-fos 的延长表达抑制休眠造血干细胞的细胞周期进入”血液。