【作者】 熊加祥；

【导师】 白云；

【作者基本信息】 第三军医大学 ， 免疫学， 2006， 博士

【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。更多还原

【Abstract】 The central nervous system (CNS) has been regarded as an‘immunologically privileged’area for a long time, since the blood–brain barrier (BBB) and the immune suppressive microenviroments exist in CNS. This strict regulation of CNS immune reactivity is disrupted in brain injury or inflammation, in which large numbers of leukocytes are recruited to the CNS through the damaged BBB. Several evidences have shown this specific immune response in CNS play a key role in many immune diseases, such as anti-bacterium, multiple sclerosis, autoimmune cerebritis and so on. However, due to the absence of the lymphatic vessels and dendritic cells in CNS where function as antigen-presenting cells (APC) in PNS, na?ve T cells are mainly initiated in peripheral lymphoid organs and then activated T cells enter into CNS across BBB. Once these activated or primed T cells are restimulated upon encounter of the target antigen presented by local APCs, specific immune response will occur in CNS. Moreover, T cells infiltrating the CNS fail to proliferate because of short-lived and rapid apoptosis of effector T cells after restimulation, so it is very important to maintain the activated T cell response in CNS. One of the most debated and controversial issues is how and to what extent glia cells in CNS participate the stimulation and reactivation of CNS-targeted T cells.As the most population cells of brain, Astrocytes have important physiological properties as they relate to CNS homeostasis. Most people think the microglial cells present the antigen and regulate the immune effects in CNS, while the neuro-immunology function of Astrocytes was often ignored. Recently, Astrocytes were shown to express co-stimulatory molecules, produce the inflammatory factor and release the complements to anticipate the brain inflammatory disease. Astrocytes could maintain the immune homeostasis depending on the mechanical barrier of BBB and the biological barrier as well, such as the expression of immune suppressive molecules and releasing the inhibitory mediator. It suggested the Astrocytes could become the immune effector cells to join the modulation of brain inflammation. Study has shown the Astrocytes can sense the change of internal environment更多还原