炎性因子活化星形胶质细胞对T细胞调节机制研究

发布时间：2018-01-01 11:17

本文关键词：炎性因子活化星形胶质细胞对T细胞调节机制研究　出处：《第三军医大学》2006年博士论文　论文类型：学位论文

【摘要】： 紧密的血脑屏障(blood-brain barrier,BBB)和免疫抑制微环境的存在使中枢神经系统(central nervous system, CNS)一直被认为是免疫特赦区。但在脑外伤、炎症等情况下,白细胞可通过破坏的BBB进入脑内。大量研究显示,CNS内存在特异性的T细胞免疫应答,在抗微生物感染、多发性硬化症、自身免疫性脑炎以及脑血管病等多种疾病中发挥重要作用。然而,由于脑实质内缺乏淋巴管引流和对启动免疫应答起重要作用的专职抗原提呈细胞(antigen-presenting cell,APC),初始T细胞被抗原活化的启动过程可能主要在外周淋巴器官中完成,而活化的T细胞或致敏的T细胞穿过BBB后,被CNS内的APC再次激活,从而发挥免疫效应。此外,在CNS内的特殊微环境中,由于T细胞活化后存活期短、增殖能力弱以及接受再刺激时的快速凋亡,使得活化后T细胞的效应维持机制显得尤为重要。目前,CNS内的胶质细胞如何参与T细胞免疫应答过程及其作用地位已成为神经免疫领域倍受关注的问题之一。星形胶质细胞(Astrocytes,Ast)作为大脑内最多的细胞群,发挥着维持大脑微环境稳态的重要生理功能,而其神经免疫功能往往被忽视,一般认为小胶质细胞才是脑内行使免疫呈递和免疫调控功能的细胞。但是最近的研究证实,星形胶质细胞可以表达免疫膜分子,分泌炎性因子和释放补体等,参与脑内炎性疾病的发生发展,从而逐渐受到神经免疫学者的关注和重视。星形胶质细胞能够维持大脑的免疫稳态,除通过血脑屏障中丰富的足突结构形成机械屏障以外,可能还存在有生物学屏障,如免疫抑制性分子的存在和分泌抑制性细胞介质发挥免疫保护效应。提示星形胶质细胞有可能成为CNS内免疫效应细胞,参与脑内炎性调控作用。研究证实,星形胶质细胞对内环境改变如炎性刺激、缺血、缺氧以及脑外伤等有高度敏感性,将出现反应性的改变,通常称为“活化”或“胶质化”,即星形胶质细胞在炎性病变中的可塑性变化。已有研究报道证实星形胶质细胞在受到炎性介质的刺激后,血脑屏障的通透性增加,易于T细胞浸润,参与疾病进程。在体通过EAE模型证实活化后的星形胶质细胞具有抗原处理、提呈功能,可以再次活化T淋巴细胞,加剧疾病的发展。因此,星形胶质细胞在CNS内T细胞活化后效应以及对T细胞功能的调控显得极为重要,但这一过程中涉及到CNS内的细胞和T淋巴细胞作用的分子机制目前尚不确切。
[Abstract]:Tight blood-brain barrier (BBS) and blood-brain barrier. BBB) and immunosuppressive microenvironment make the central nervous system central nervous system (CNSs) have been considered as immune amnesty area, but in brain trauma. In cases such as inflammation, leukocytes can enter the brain through damaged BBB. A large number of studies have shown that there is a specific T cell immune response in anti-microbial infections, multiple sclerosis. Autoimmune encephalitis and cerebrovascular diseases play an important role. Because of the lack of lymphatic drainage in the brain parenchyma and the specialized antigen-presenting cell (APC) which plays an important role in initiating the immune response. The priming process of initial T cell activation by antigen may be mainly completed in peripheral lymphoid organs, while activated T cells or sensitized T cells pass through BBB and are reactivated by APC in CNS. In addition, in the special microenvironment of CNS, the survival time of T cells after activation is short, the ability of proliferation is weak, and the rapid apoptosis after re-stimulation. It is very important to maintain the effect of activated T cells. How glial cells in CNS participate in T cell immune response and its role has become one of the most concerned issues in the field of neuroimmunity. As the largest cell group in the brain, astrocytes play an important role in maintaining the homeostasis of microenvironment, but its neuroimmune function is often neglected. It is generally believed that microglia are the cells in the brain that perform immunological presentation and immunomodulation. However, recent studies have confirmed that astrocytes can express immune membrane molecules, secrete inflammatory factors and release complement, etc. Participate in the development of inflammatory diseases in the brain, and gradually attracted the attention of neuroimmunologists. Astrocytes can maintain the immune homeostasis of the brain. In addition to the mechanical barrier formed by the abundant podocyte structure in the blood-brain barrier, there may also be a biological barrier. For example, the existence of immunosuppressive molecules and secretion of inhibitory cell mediators play an immunoprotective effect. It is suggested that astrocytes may become immune effector cells in CNS and participate in the regulation of inflammation in brain. Astrocytes are highly sensitive to changes in the internal environment, such as inflammatory stimulation, ischemia, hypoxia, and brain trauma, and will present reactive changes, commonly known as "activation" or "glialization". That is the plasticity of astrocytes in inflammatory lesions. It has been reported that astrocytes stimulated by inflammatory mediators increase the permeability of blood-brain barrier and are easy to infiltrate T cells. Participate in the disease process. In vivo through the EAE model confirmed that activated astrocytes have antigen processing, presenting function, can reactivate T lymphocytes, aggravate the development of the disease. The effect of astrocytes on T cell activation and the regulation of T cell function in CNS are very important. However, the molecular mechanism involved in the action of cells and T lymphocytes in CNS is uncertain.
【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

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