AIRE通过TLR4及Notch1对Treg影响的研究

发布时间：2018-06-19 07:16

本文选题：AIRE + 外周耐受　；参考：《吉林大学》2009年硕士论文

【摘要】： 自身免疫调节因子(Autoimmune regulator,AIRE)单一基因突变将导致由自身免疫应答介导的、以多器官损伤为特征的自身免疫性多腺体综合症I。由于这一基因的异常可导致多腺体的自身免疫疾病的发生,因此推测在正常条件下AIRE很可能在维持自身耐受中发挥重要作用。以往研究表明,AIRE在维持中枢耐受方面发挥着重要的功能,而AIRE在中枢及外周免疫器官及细胞上均有表达。提示AIRE除参与中枢耐受机制外,在外周耐受机制中可能也同样发挥着重要作用。但其确切的作用及作用机制仍不清楚。本课题组前期研究表明,AIRE可调控APC上TLRs、MHC-II类分子和CD86表达,从而可能影响APC的抗原识别、提呈和活化T细胞的能力,在外周免疫应答中发挥重要作用。本研究将在课题组前期工作的基础上深入探讨表达在外周的AIRE通过何种机制发挥其在外周免疫耐受中的作用。本研究以探讨AIRE通过TLR4对CD4+CD25+Treg的影响及其机制为目的,从以下三方面进行研究: 1、通过将AIRE基因转入APC细胞中,建立细胞模型,进行对CD4+CD25+Treg细胞的数量及其功能的研究,初步探讨AIRE在外周耐受中的作用机制。研究结果发现转染AIRE的RAW264.7细胞可以促进CD4+CD25+Treg细胞的产生及Foxp3的表达。结果表明AIRE很可能在维持外周耐受方面发挥着重要的作用。 2、进一步研究了TLR4在AIRE对CD4+CD25+Treg细胞影响中的作用,研究结果发现当阻断TLR4后,CD4+CD25+Treg细胞的数量减少及功能降低。结果表明AIRE可能通过调节TLR4来影响CD4+CD25+Treg细胞的数量及功能,进而在维持外周耐受方面发挥着重要的功能。 3、最后研究了AIRE是否是通过TLR4影响Notch1进而对CD4+CD25+Treg细胞产生影响,研究结果发现AIRE能够促进Notch1的表达,当阻断Notch1后,CD4+CD25+Treg细胞的数量减少及功能降低。结果表明Notch1可能在AIRE对CD4+CD25+Treg细胞影响的过程中发挥一定的作用,进而在维持外周耐受方面发挥着重要的功能。但由于时间的原因,AIRE是否是通过TLR4影响Notch1的变化进而对CD4+CD25+Treg细胞产生影响这一推测没有得到证实,在今后的实验中将会继续研究。本研究意义在于:进一步揭示了AIRE在维持外周耐受方面发挥着重要的作用。为全面理解AIRE突变在APECED发病中的作用机制提供了新的实验依据,并为应用AIRE基因诱导耐受,干预治疗自身免疫病、移植排斥等开辟了新的思路。
[Abstract]:Autoimmune regulatory factor autoimmune regulatory agent AIREA single gene mutation will lead to autoimmune polyglandular syndrome, which is mediated by autoimmune response and characterized by multiple organ damage. Since the abnormality of this gene can lead to autoimmune disease in polyglandular body, it is assumed that air may play an important role in maintaining self tolerance in normal conditions. Previous studies have shown that air plays an important role in maintaining central tolerance, and air is expressed in both central and peripheral immune organs and cells. These results suggest that air may also play an important role in peripheral tolerance in addition to its central tolerance mechanism. However, its exact role and mechanism are still unclear. Our previous studies have shown that Aire can regulate the expression of TLRsSU MHC-II molecules and CD86 on APC, which may affect the ability of antigen recognition, presentation and activation of T cells, and play an important role in peripheral immune response. Based on the previous work of the research group, this study will explore the mechanism by which the peripheral air expression plays its role in peripheral immune tolerance. The purpose of this study was to investigate the effect of aire on CD4 CD25 Treg by TLR4 and its mechanism. The following three aspects were studied: 1. The cell model was established by transferring air gene into APC cells. To study the number and function of CD4 CD25 Treg cells and to explore the mechanism of air in peripheral tolerance. The results showed that RAW264.7 cells transfected with aire could promote the production of CD4 CD25 Treg cells and the expression of Foxp3. The results suggest that air may play an important role in maintaining peripheral tolerance. 2. The role of TLR4 in the effect of air on CD4 CD25 Treg cells was further studied. The results showed that when TLR4 was blocked, the number and function of CD4 CD25 Treg cells decreased. These results suggest that air may affect the number and function of CD4 CD25 Treg cells by regulating TLR4. It also plays an important role in the maintenance of peripheral tolerance. 3. Finally, it is studied whether air affects Notch1 and CD25 Treg cells through TLR4. The results show that air can promote the expression of Notch1. When Notch1 was blocked, the number and function of CD4 CD25 Treg cells decreased. The results suggest that Notch1 may play a role in the effect of aire on CD4 CD25 Treg cells, and thus play an important role in maintaining peripheral tolerance. However, the hypothesis of whether air affected Notch1 by TLR4 and then on CD4 CD25 Treg cells has not been confirmed due to time, and will continue to be studied in future experiments. The significance of this study is that air plays an important role in maintaining peripheral tolerance. It provides a new experimental basis for understanding the role of aire mutation in the pathogenesis of APECED, and provides a new idea for the application of aire gene to induce tolerance, to intervene in the treatment of autoimmune diseases and to transplant rejection.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2009
【分类号】：R392

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