Blimp-1在浆细胞中的作用机制研究
发布时间：2019-04-26 14:46
【摘要】： B淋巴细胞向产生抗体的浆细胞的发育过程大致可以分为几个阶段,包括原始B细胞、前B细胞、不成熟B细胞、成熟B细胞和浆细胞(或记忆细胞)。在由原始B细胞向浆细胞发育的过程中,转录因子起着非常重要的作用。近年研究结果证明,转录因子E2A、EBF和Pax5在由干细胞向早期B淋巴细胞发育中起着决定性的作用。在转录因子Bcl-6缺陷的小鼠不能形成生发中心。Pax-5可以阻断生发中心的B淋巴细胞向浆细胞的分化。浆细胞的发育则需要转录因子XBP-1和IRF4。 浆细胞是B淋巴细胞发育的最终阶段,它能分泌大量的抗体,从而发挥抗感染等重要的体液免疫功能。在抗体产生过程中,成熟的被激活的B细胞向分泌抗体的浆细胞过渡是一个关键步骤,但目前对浆细胞发育阶段基因调控的了解还很有限。成熟B淋巴细胞分化为浆细胞需要XBP-1、IRF4等多个转录因子协同作用。转录因子Blimp-1(B lymphocyte induced maturation protein 1)是具有5个锌指结构的98KD蛋白,它可以诱导成熟B淋巴细胞发育为浆细胞并分泌抗体,被称为“B淋巴细胞终极分化的主调控子”。近年的研究结果提示,在向浆细胞发育的过程中,Blimp-1的表达抑制了B淋巴细胞中高度表达的Pax-5和Bcl-6的表达,而转录因子XBP-1受Pax-5的抑制,Pax-5的下降使XBP-1表达升高。Blimp-1和XBP-1的表达促使成熟B淋巴细胞向浆细胞发育,而Bcl-6和Pax-5表达的抑制为激活B淋巴细胞的进一步发育提供了基础。基因芯片技术表明,Blimp-1可抑制220多个基因的表达,上调30多个基因表达。由于Blimp-1基因敲除导致小鼠胚胎死亡,长期以来对于Blimp-1是否为浆细胞发育所必需一直不清楚。Shapiro-selef等采用条件基因敲除技术特异地在成熟B淋巴细胞敲除Blimp-1,用于研究Blimp-1的功能,研究发现Blimp-1基因缺失的小鼠中,浆细胞的发育严重受阻,血清免疫球蛋白的基础水平及受抗原刺激后的水平都明显降低。虽然已证实Blimp-1可以诱导成熟B淋巴细胞发育为浆细胞,但Blimp-1在浆细胞中的作用及机制目前还无相关报导。Blimp-1的表达与其它浆细胞所需的因子,如BCMA等的关系还不明确,也尚待进一步研究。研究Blimp-1在已终末分化的浆细胞中的作用及其机制,可为治疗多发性骨髓瘤和自身免疫性疾病提供新思路。 本研究首先采用PCR方法从Blimp-1质粒中扩增出编码Blimp-1前350个氨基酸
[Abstract]:The development of B lymphocytes towards the antibody-producing plasma cells can be divided into several stages, including primordial B cells, pre-B cells, immature B cells, mature B cells and plasmacytes (or memory cells). Transcription factors play an important role in the development from primordial B cells to plasmacytes. Recent studies have shown that transcription factors E 2A, EBF and Pax5 play a decisive role in the development of early B lymphocytes from stem cells. No germinal center could be formed in transcription factor Bcl-6 deficient mice. Pax-5 could block the differentiation of B lymphocytes from germinal center to plasmacyte. Plasma cell development requires transcription factors XBP-1 and IRF4.. Plasma cell is the final stage of B lymphocyte development, it can secrete a large number of antibodies, so as to play an important role in humoral immunity, such as anti-infection. The transition from mature activated B cells to antibody-secreting plasmacytes is a key step in the process of antibody production, but the understanding of gene regulation in the plasma cell development stage is still limited. The differentiation of mature B lymphocytes into plasma cells requires the synergistic action of XBP-1,IRF4 and other transcription factors. Transcription factor-1 (Blimp-1 (B lymphocyte induced maturation protein-1) is a 98KD protein with five zinc finger structures. It can induce mature B lymphocytes to develop into plasma cells and secrete antibodies. It is called "the master regulator of the ultimate differentiation of B lymphocytes". The results of recent studies suggest that the expression of Blimp-1 inhibits the expression of Pax-5 and Bcl-6 in B lymphocytes, while the transcription factor XBP-1 is inhibited by Pax-5 in the process of plasma cell development. The decrease of Pax-5 increased the expression of XBP-1. The expression of Blimp-1 and XBP-1 promoted the development of mature B lymphocytes to plasmacytes, while the inhibition of Bcl-6 and Pax-5 expression provided a basis for activating the further development of B lymphocytes. Gene chip technique showed that Blimp-1 could inhibit the expression of more than 220 genes and up-regulate the expression of more than 30 genes. As Blimp-1 knockout results in mouse embryo death, it has long been unclear whether Blimp-1 is necessary for plasma cell development. Shapiro-selef and others used conditional knockout techniques to specifically knock out Blimp-1, on mature B lymphocytes. In order to study the function of Blimp-1, it was found that in the mice with Blimp-1 gene deletion, the development of plasma cells was seriously hindered, and the basic level of serum immunoglobulin and the level of serum immunoglobulin stimulated by antigen were significantly decreased. Although it has been proved that Blimp-1 can induce mature B lymphocytes to develop into plasma cells, the role and mechanism of Blimp-1 in plasma cells have not been reported. The expression of Blimp-1 and other factors required by plasma cells have not been reported. Such as BCMA et al., the relationship is not clear, but also needs to be further studied. To study the role and mechanism of Blimp-1 in terminal differentiated plasma cells may provide a new idea for the treatment of multiple myeloma and autoimmune diseases. In this study, the first 350 amino acids encoding Blimp-1 were amplified from Blimp-1 plasmid by PCR method.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R392
本文编号：2466158
[Abstract]:The development of B lymphocytes towards the antibody-producing plasma cells can be divided into several stages, including primordial B cells, pre-B cells, immature B cells, mature B cells and plasmacytes (or memory cells). Transcription factors play an important role in the development from primordial B cells to plasmacytes. Recent studies have shown that transcription factors E 2A, EBF and Pax5 play a decisive role in the development of early B lymphocytes from stem cells. No germinal center could be formed in transcription factor Bcl-6 deficient mice. Pax-5 could block the differentiation of B lymphocytes from germinal center to plasmacyte. Plasma cell development requires transcription factors XBP-1 and IRF4.. Plasma cell is the final stage of B lymphocyte development, it can secrete a large number of antibodies, so as to play an important role in humoral immunity, such as anti-infection. The transition from mature activated B cells to antibody-secreting plasmacytes is a key step in the process of antibody production, but the understanding of gene regulation in the plasma cell development stage is still limited. The differentiation of mature B lymphocytes into plasma cells requires the synergistic action of XBP-1,IRF4 and other transcription factors. Transcription factor-1 (Blimp-1 (B lymphocyte induced maturation protein-1) is a 98KD protein with five zinc finger structures. It can induce mature B lymphocytes to develop into plasma cells and secrete antibodies. It is called "the master regulator of the ultimate differentiation of B lymphocytes". The results of recent studies suggest that the expression of Blimp-1 inhibits the expression of Pax-5 and Bcl-6 in B lymphocytes, while the transcription factor XBP-1 is inhibited by Pax-5 in the process of plasma cell development. The decrease of Pax-5 increased the expression of XBP-1. The expression of Blimp-1 and XBP-1 promoted the development of mature B lymphocytes to plasmacytes, while the inhibition of Bcl-6 and Pax-5 expression provided a basis for activating the further development of B lymphocytes. Gene chip technique showed that Blimp-1 could inhibit the expression of more than 220 genes and up-regulate the expression of more than 30 genes. As Blimp-1 knockout results in mouse embryo death, it has long been unclear whether Blimp-1 is necessary for plasma cell development. Shapiro-selef and others used conditional knockout techniques to specifically knock out Blimp-1, on mature B lymphocytes. In order to study the function of Blimp-1, it was found that in the mice with Blimp-1 gene deletion, the development of plasma cells was seriously hindered, and the basic level of serum immunoglobulin and the level of serum immunoglobulin stimulated by antigen were significantly decreased. Although it has been proved that Blimp-1 can induce mature B lymphocytes to develop into plasma cells, the role and mechanism of Blimp-1 in plasma cells have not been reported. The expression of Blimp-1 and other factors required by plasma cells have not been reported. Such as BCMA et al., the relationship is not clear, but also needs to be further studied. To study the role and mechanism of Blimp-1 in terminal differentiated plasma cells may provide a new idea for the treatment of multiple myeloma and autoimmune diseases. In this study, the first 350 amino acids encoding Blimp-1 were amplified from Blimp-1 plasmid by PCR method.
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R392
【引证文献】
相关硕士学位论文 前1条
1 叶青;基于免疫机理的化工园区安全生产应急研究[D];华南理工大学;2012年
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