白细胞介素23与多发性硬化

发布时间：2018-01-09 18:11

本文关键词：白细胞介素23与多发性硬化　出处：《河北医科大学》2009年硕士论文　论文类型：学位论文

【摘要】： 多发性硬化(multiple sclerosis,MS)是一种中枢神经系统自身免疫性疾病,以时间和空间上反复发作的白质脱髓鞘为主要病理特点。MS的临床表现包括视力、运动、感觉、植物神经和认知功能的缺损,由于病程迁延、缺乏根治措施,常常对患者生活造成严重影响。该病的发病机制尚未阐明,较公认的观点是遗传易患个体与环境因素相互作用而致病。实验性自身反应性脑脊髓炎(experimental autoimmune encephalomyelitis, EAE)是MS的动物模型,可以利用髓鞘抗原在敏感的动物品系上诱导建立。由于它和MS在病理表现及机制等方面有很多相似之处,因此被广泛应用于MS的研究当中。髓鞘抗原特异性CD4+效应T细胞与白细胞介素23(Interleukin-23,IL-23)等多种细胞因子与MS的发生发展密切相关。IL-23是新近发现的促炎性细胞因子,隶属于IL-12家族,由两种亚单位(p40和p19)通过二硫键形成异二聚体分子,主要来源于巨噬细胞和树突状细胞,能够诱导初始T细胞活化并分泌IFNγ、IL-17等细胞因子,在维护机体内环境的稳定以及病理条件下免疫系统的激活等方面发挥着独特的生物学作用。既往认为IL-12在MS的发生、发展过程中居于关键地位,但是,以前关于IL-12的研究,大多是建立在对p40亚单位的研究之上的,并且借助了p40或IL-12Rβ1链基因敲除的动物来进行。而新近发现的细胞因子IL-23,不仅在结构上和IL-12相似,而且和IL-12共用p40亚单位以及IL-12Rβ1链。所以,敲除或阻断p40或IL-12Rβ1链导致的效应,应该是IL-12和IL-23共同缺失引起的。现在看来,以前关于IL-12在MS和EAE中的认识存在着误区,即由于不了解IL-23的存在,将本属于IL-23或IL-23、IL-12共有的功能错误的归于IL-12。 EAE的发生实际由IL-12和IL-23共同完成——IL-12启动初始T细胞向Th1方向分化,促进炎症细胞侵入CNS; IL-23发挥关键作用,诱导T细胞分泌IL-17,促进炎症细胞进一步募集、激活,维持后续Th17炎症反应。MS病灶中IL-23主要来源于巨噬细胞和树突状细胞,成熟树突状细胞在颅内血管周围聚集可能与疾病复发有关。MS患者CD46相关变异造成其树突状细胞过度分泌IL-23,Th17反应失控,发生自身免疫反应。
[Abstract]:Multiple sclerosis (MS) is an autoimmune disease of central nervous system. The clinical manifestations of MS include visual acuity, movement, sensation, vegetative nerve and cognitive function defect. Due to the prolongation of the course of disease, there is a lack of radical cure. The pathogenesis of the disease has not been elucidated. It is generally accepted that the genetic predisposition individuals interact with environmental factors and cause the disease. Experimental autoimmune encephalomytis (EAE) is an animal model of MS. Myelin sheath antigen can be used to induce the establishment of sensitive animal strains. It is widely used in the study of MS because of its many similarities with MS in pathological manifestations and mechanisms. Myelin antigen specific CD4 effector T cells and interleukin-23. IL-23 and other cytokines are closely related to the occurrence and development of MS. IL-23 is a newly discovered pro-inflammatory cytokine belonging to the IL-12 family. The heterodimer molecules, mainly derived from macrophages and dendritic cells, are formed by disulfide bonds from two subunits, p40 and p19. They can induce the activation and secretion of IFN 纬 from the initial T cells. Cytokines such as IL-17 play a unique biological role in maintaining the stability of the body's environment and activating the immune system under pathological conditions. It has been thought that IL-12 plays a key role in the development of MS, but most of the previous studies on IL-12 were based on the study of p40 subunit. And it was done by using p40 or IL-12R 尾 1 knockout animals, and the newly discovered cytokine IL-23 was not only structurally similar to IL-12. The p40 subunit and IL-12R 尾 1 chain are shared with IL-12. Therefore, knockout or blocking the effect of p40 or IL-12R 尾 1 chain. It should be caused by the absence of both IL-12 and IL-23. Now it seems that there were some misunderstandings about IL-12 in MS and EAE, that is, because of not knowing the existence of IL-23. Attribute functional errors that are common to IL-23 or IL-23 IL-12 to IL 12. The occurrence of EAE was actually accomplished by IL-12 and IL-23. IL-12 initiated the initial T cell differentiation to Th1 direction and promoted inflammatory cells to invade CNS. IL-23 plays a key role in inducing T cells to secrete IL-17 and promote the further recruitment and activation of inflammatory cells. The main sources of IL-23 were macrophages and dendritic cells. The accumulation of mature dendritic cells around intracranial blood vessels may be related to the recurrence of disease. The CD46 related variation in patients with MS may cause the excessive secretion of IL-23 and Th17 by dendritic cells and the reaction is out of control. An autoimmune response occurs.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2009
【分类号】：R392;R744.51

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