摘要
本课题主要研究新型疫苗佐剂---硫酸乙酰肝素(Heparan sulfate, HS)刺激人体重要的抗原提呈细胞---树突状细胞(Dendrtic Cells, DCs)后,DCs差异蛋白质组学的研究。
实验设计如下：(1)采用免疫磁珠分选法分离人外周血来源的CD14+单核细胞,经细胞因子rhGM-CSF与rhIL-4刺激5天,诱导成为未成熟的树突状细胞(immature DCs, imDCs),分别设置不同的实验组,利用流式细胞仪检测HS在体外对DCs的刺激作用；(2)“5天培养法”获得的imDCs分为A与B两组,分别加入不同物质刺激。A组：①空白对照组、②佐剂组(HS)；B组：①抗原组(HBsAg)、②抗原(HBsAg)+佐剂组(HS)。分别于刺激48h后提取DCs的总蛋白,经蛋白质沉淀、蛋白质定量、双向电泳、Image Scanner Ⅲ扫描、Image Master2D Platinum7.0软件分析凝胶差异蛋白点(Ratio>1.5倍)、MALDI-TOF/TOF串联质谱鉴定、生物信息学分析一系列的实验操作,鉴定差异表达的蛋白质并分析其生物学功能；(3)Western Blot实验鉴定差异表达蛋白质中几种重要的蛋白质分子的相对表达差异。
实验结果如下：(1)在体外,HS能够促进DCs的成熟,但促成熟程度作用不显著,推测其发挥的更大作用可能是维持DCs处于一种未成熟状态,从而加强DCs对抗原的摄取与加工过程；(2)A组共发现28种差异表达的蛋白质(表达均上调),按功能分为7类：细胞骨架蛋白、生物大分子合成及代谢相关蛋白、细胞器相关蛋白、分子伴侣、组织蛋白酶、蛋白酶体及通道蛋白;B组共发现29种差异表达的蛋白质(除SERPINB1蛋白表达下调外,其余蛋白质表达均上调),按功能分为5类：细胞骨架蛋白、生物大分子合成及代谢相关蛋白、信号转导相关蛋白、组织蛋白酶及通道蛋白。两组共发现57种差异表达的蛋白质,通过对这些蛋白质功能的分析研究,证实大部分蛋白质在免疫反应系统中均发挥一定的作用,从而为硫酸乙酰肝素作为佐剂,在细胞内发挥作用的分子机制提供了一个很好的研究平台；(3)对差异表达蛋白质中的6种重要的蛋白质分子,分别为：CTSB、PSME1、LTA4H, LSP1、CTSD、SERPINB1进行Western Blot鉴定。其作用机制可能为：抗原的处理及提呈、促进DCs的成熟与稳定、相关细胞因子的分泌、启动细胞免疫应答等。通过Western Blot实验,既对Image Master2D Platinum7.0软件分析双向电泳凝胶点的结果进行了验证,也对实验中6种重要蛋白质的相对表达量的改变进行了鉴定。
本实验利用差异蛋白质组学技术分析新型疫苗佐剂---硫酸乙酰肝素可能的佐剂作用机制,通过对57种差异表达的蛋白质的功能进行分析,对佐剂的作用机制研究提供了很好的后续研究的靶分子范围。之后可以从这些靶分子中挑选某种或多种蛋白质分子进行佐剂刺激DCs后,细胞内蛋白质相互作用及亚细胞定位的深入研究,不但可以进一步完善佐剂作用机制的理论基础,还可以为新型佐剂的开发提供新的靶点。
Objective:The subject mainly studies Heparan sulfate (HS) stimulate dendritic cells (DCs), which are the important antigen presenting cells (APCs) in the body, and then analysis the differential proteomics of DCs.
Methods:(1) CD14+monocytes obtained from peripheral blood mononuclear cell (PBMC) with magnetic activated cell sorting (MACS), and cultured with rhGM-CSF and rhIL-4for5days to acquire the immature dendritic cells (imDCs). imDCs were divided into two groups according to whether treated by HS adjuvant and/or HBV antigen. They are A group:①blank control group;②adjuvant (HS) group and B group:①antigen (HBsAg) group;②antigen (HBsAg)+adjuvant (HS) group.(2) Extract the total proteins of DCs which were stimulated, and then a series of experiments had been performed to detect and analyse protein expression differences in DCs, such as protein precipitation and quantification, two-dimensional electrophoresis (2-DE), scanning, Image Master2D Platinum7.0analysis (Ratio>1.5), MALDI-TOF/TOF detection, and bio informatics analysis.(3) Relative expression differences of six key proteins were identified by Western Blot.
Results:(1) In vitro, HS plays a little role in promoting DCs maturation, but probably plays a greater role in keeping immaturation of DCs to enhance those cells uptake and process antigen.(2)28differentially expressed proteins were found in A group (all of these proteins'expression are up-regulated), which were divided into7different function groups:Cytoskeleton proteins, Macromolecular Biosynthesis and Metabolism associate proteins, Organelle associate proteins, Molecular Chaperones, Cathepsins, Proteasome and Channel proteins.29differentially expressed proteins were found in B group (SERPINB1's expression was down-regulated while others expression were all up-regulated), which were divided into5different function groups:Cytoskeleton proteins, Macromolecular Biosynthesis and Metabolism associate proteins, Signaling Transduction associate proteins, Cathepsins and Channel proteins. Functions of those57differentially expressed proteins were analyzed, and approved that most of these proteins are playing a role in immune response system. So the study provides a good research platform for researching the molecular mechanism of HS in cells.(3) CTSB, PSME1, LTA4H, LSP1, CTSD and SERPINB1were selected to identify the relative expression differences by Western Blot. Western Blot verified the validity of2-DE spots analysis by Image Master2D Platinum7.0and the6important proteins'relative expression differences. From our studies, we suggest that the6proteins play key roles in the adjuvant molecular mechanism of HS. They may play a role in uptaking and procesing antigen, promoting the maturation of DCs, inducing the cellular immune response.
Conclusions:The study found the probably molecular mechanism of HS by differential proteomics, and provided many target molecule for adjuvant mechanism intensive study. We also can select several proteins to study intracellular protein interactions and subcellular localization when adjuvant stimulate DCs, then it can not only further improve the adjuvant mechanism research, but also can provide new targets for adjuvant development.
引文
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