【摘要】： B淋巴細(xì)胞向產(chǎn)生抗體的漿細(xì)胞的發(fā)育過程大致可以分為幾個(gè)階段,包括原始B細(xì)胞、前B細(xì)胞、不成熟B細(xì)胞、成熟B細(xì)胞和漿細(xì)胞(或記憶細(xì)胞)。在由原始B細(xì)胞向漿細(xì)胞發(fā)育的過程中,轉(zhuǎn)錄因子起著非常重要的作用。近年研究結(jié)果證明,轉(zhuǎn)錄因子E2A、EBF和Pax5在由干細(xì)胞向早期B淋巴細(xì)胞發(fā)育中起著決定性的作用。在轉(zhuǎn)錄因子Bcl-6缺陷的小鼠不能形成生發(fā)中心。Pax-5可以阻斷生發(fā)中心的B淋巴細(xì)胞向漿細(xì)胞的分化。漿細(xì)胞的發(fā)育則需要轉(zhuǎn)錄因子XBP-1和IRF4。 漿細(xì)胞是B淋巴細(xì)胞發(fā)育的最終階段,它能分泌大量的抗體,從而發(fā)揮抗感染等重要的體液免疫功能。在抗體產(chǎn)生過程中,成熟的被激活的B細(xì)胞向分泌抗體的漿細(xì)胞過渡是一個(gè)關(guān)鍵步驟,但目前對(duì)漿細(xì)胞發(fā)育階段基因調(diào)控的了解還很有限。成熟B淋巴細(xì)胞分化為漿細(xì)胞需要XBP-1、IRF4等多個(gè)轉(zhuǎn)錄因子協(xié)同作用。轉(zhuǎn)錄因子Blimp-1(B lymphocyte induced maturation protein 1)是具有5個(gè)鋅指結(jié)構(gòu)的98KD蛋白,它可以誘導(dǎo)成熟B淋巴細(xì)胞發(fā)育為漿細(xì)胞并分泌抗體,被稱為“B淋巴細(xì)胞終極分化的主調(diào)控子”。近年的研究結(jié)果提示,在向漿細(xì)胞發(fā)育的過程中,Blimp-1的表達(dá)抑制了B淋巴細(xì)胞中高度表達(dá)的Pax-5和Bcl-6的表達(dá),而轉(zhuǎn)錄因子XBP-1受Pax-5的抑制,Pax-5的下降使XBP-1表達(dá)升高。Blimp-1和XBP-1的表達(dá)促使成熟B淋巴細(xì)胞向漿細(xì)胞發(fā)育,而Bcl-6和Pax-5表達(dá)的抑制為激活B淋巴細(xì)胞的進(jìn)一步發(fā)育提供了基礎(chǔ)�；蛐酒夹g(shù)表明,Blimp-1可抑制220多個(gè)基因的表達(dá),上調(diào)30多個(gè)基因表達(dá)。由于Blimp-1基因敲除導(dǎo)致小鼠胚胎死亡,長(zhǎng)期以來對(duì)于Blimp-1是否為漿細(xì)胞發(fā)育所必需一直不清楚。Shapiro-selef等采用條件基因敲除技術(shù)特異地在成熟B淋巴細(xì)胞敲除Blimp-1,用于研究Blimp-1的功能,研究發(fā)現(xiàn)Blimp-1基因缺失的小鼠中,漿細(xì)胞的發(fā)育嚴(yán)重受阻,血清免疫球蛋白的基礎(chǔ)水平及受抗原刺激后的水平都明顯降低。雖然已證實(shí)Blimp-1可以誘導(dǎo)成熟B淋巴細(xì)胞發(fā)育為漿細(xì)胞,但Blimp-1在漿細(xì)胞中的作用及機(jī)制目前還無相關(guān)報(bào)導(dǎo)。Blimp-1的表達(dá)與其它漿細(xì)胞所需的因子,如BCMA等的關(guān)系還不明確,也尚待進(jìn)一步研究。研究Blimp-1在已終末分化的漿細(xì)胞中的作用及其機(jī)制,可為治療多發(fā)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方法從Blimp-1質(zhì)粒中擴(kuò)增出編碼Blimp-1前350個(gè)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.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類號(hào)】：R392

【引證文獻(xiàn)】

相關(guān)碩士學(xué)位論文 前1條

1 葉青;基于免疫機(jī)理的化工園區(qū)安全生產(chǎn)應(yīng)急研究[D];華南理工大學(xué);2012年

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本文編號(hào)：2466158