Induction mechanisms of B cell self-toleranace

我们利用转基因系统研究了生发中心培养的自反应性B细胞凋亡的诱导机制。我们展示了1。Bcl6基因从B细胞淋巴瘤的染色体易位断点被鉴定，编码序列特异性转录抑制因子，并在生发中心B细胞和T细胞中强烈表达。Bcl6缺失（Bcl6-/-）小鼠骨髓细胞过继移植实验表明，Bcl6对生发中心B细胞的分化至关重要。在正常小鼠睾丸生殖细胞，主要是精母细胞中也检测到Bcl6。在成年Bcl6-/-睾丸中，我们发现在Bax蛋白的诱导下，在I中期出现了大量凋亡的精母细胞。杂合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p38 MAP激酶的活化形式，Bcl6可能在保护精母细胞免受应激诱导的凋亡中发挥稳定剂的作用。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。转基因小鼠的生发中心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。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，抑制caspase诱导的细胞死亡。同步NIH3T3细胞在细胞周期的S ~ G2/M期TIAP表达上调。我们提出，在细胞增殖过程中，细胞保护活性可能通过诱导IAPs（如TIAP）增强。我们正在研究TIAP在生发中心B细胞中的作用。

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.