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1、脱髓鞘疾病,中南大学湘雅医院神经内科 周文斌,神经纤维指轴突而言，分为有髓和无髓神经纤维。Nerve fiber or an axon, Myelinated Nerve Fiber Unmyelinated Nerve Fiber,髓鞘:紧裹在有髓鞘神经轴突外面的脂质细胞膜，由髓鞘形成细胞膜组成。Myelin is a layer that forms around nerves formed by wrapped plasma membrane of myelinization cells.,髓鞘：蛋白质22%，脂类78%Myelin： protein 22and lipids 78 蛋白
2、质: 碱性蛋白、脂蛋白、糖蛋白等。Protein：Basic protein、lipoprotein、glucoprotein 脂类: 胆固醇、神经鞘磷脂、脑苷脂与神经节苷脂。Lipide：lipide、sphingomyelin、galactosyl ceramide、ganglioside,生理作用： Physiological functions 神经冲动的快速传导；Speeding the transmission of impulses 对神经轴突起绝缘、保护作用。Insulation and protection of neuraxon 髓鞘系统： 髓鞘、轴索与完整的血供Myeli
3、n system: myelin、axon and intact blood supply,脱髓鞘疾病： CNS白质对各种有害因素的反应 Demyelinating disease 脱髓鞘脑病 Demyelinating encephalopathy 髓鞘构成缺陷性疾病（白质营养不良症） myelin construction deficiency syndrome Leukodystrophy 周围神经系统脱髓鞘疾病 Peripheral nerveous demyelination,CNS: White matter disease,Demyelinating: mainly acquir
4、ed MS PML Encephalomyelitis(ADEM) Anti-MAG Disease,CNS: White matter disease,Dysmyelinating: mainly inheritedLeukodystrophies: ALD Alexander Canavan disease Krabbe Disease MLD Pelzaeus-Merzbacher Disease Refsum,PNS: Neuropathies,Acquired: mainly autoimmune, demyelinating polyneuropathies. Acute: GBS
5、 Chronic: CIDP Anti-MAG syndrome Multiple Motor Neuropathy (MMN),PNS: Neuropathies,Hereditary: mainly dysmyelinating. HMSN/CMT Cockayne Syndrome, Krabbe Disease MLD Refsum Disease,Conduction in a Demyelinated Nerve Fiber-KH,多发性硬化 Multiple Sclerosis,CNS白质的慢性，炎性，斑块性脱髓鞘，CD 4+ T 细胞介导的自身免疫性疾病。 Chronic, p
6、rogressive immune-mediated CNS diseaseCharacterized by demyelination and axonal loss全世界病人超过200万。 Affecting over 2 million persons worldwide,概述overview,最常损害部位是脑室周围白质、视神经、脊髓、脑干传导束及小脑白质。 white matter bordering the lateral ventricles、opticus、spinal cord、pyramidal tract and Cerebellar white matter引起年轻成人中
7、神经残疾的最常见疾病（美国）。 The most common disabling neurological disease of young people .,概述overview,女性多见 Women outnumber men 2:1缓解复发病程，逐渐加重 Progressive relapsing-remitting course 可能与早期病毒感染有关 no specific causes, viral may be responsible,概述overview,Vit D缺乏与MS,MS具有显著的地理分布特征:,在赤道几内亚区MS的发生率几乎为零，在两半球随着纬度的增加而戏剧性的增
8、加,在瑞士高海拔区MS发生率低，低海拔区发生率高,低纬度区阳光充足，高海拔区紫外光强度高，能够促使大量Vit D合成,Vit D缺乏与MS,VitD能抑制DC分化、Th1细胞增殖，减少IL-12、IFN-产生VitD能促进调节性T细胞增殖，促进IL-10、TGF-分泌,概述overview,第一次肯定了MS临床症状与MS尸检病理之间的关系；第一次提出了“硬化与斑块”的概念； “sclerose en plaques“ 第一个认定MS是一种独立的疾病；第一个提出MS的诊断标准-即“Chacot三联症”； Triad: nystagmus, intention tremor, scanning s
9、peech 他还对MS的病理特征进行了详细的描述，如“髓鞘脱失“ demyelination,“胶质纤维增生“ macrophages等。,病因、发病机制 Etiology：,免疫immunity：EAE Experimental allergic encephalomyelitis ，致敏（活化）的抗原特异性的CD4+T细胞。The activated antigenic specifically CD4+ cell.病毒virus：分 子模拟机制molecule mimicry mechanism激发自身免 疫反应autoimmune etiology 遗传heredity：单卵双生子、H
10、LA,EAE：实验性自身免疫性脑脊髓炎Experimental allergic encephalomyelitis 使用MBP或PLP免疫Lewis 大鼠；Immunizing the Lewis rat by MBP and PLP MBP致敏的T细胞转输给正常大鼠。transfusion the MBP activated Tc to normal rats,病因、发病机制 Etiology ：,初始CD4+T细胞分化,正常,MS,Th1/Th2平衡,Th1细胞：IL-2、IFN-等 Th2细胞：IL-4、IL-6等 Th17细胞：IL-17 巨噬细胞、DC：IL-12、IL-23,Th
11、1/Th2平衡,IL-12主要由树突状细胞、巨噬细胞产生，是由p35及p40 2条多肽链以二硫键的形式结合在一起的异二聚体型（IL-12 p70）。IL-12能刺激Th1细胞增殖, 诱导免疫效应细胞产生IFN-。IFN-可调节细胞因子“级联作用模式”增强免疫应答。,Th1/Th2平衡,IL-12是Th1分化的关键因子，然而 IL-12基因敲除小鼠仍能产生EAE；IFN-是Th1的重要致病因子，然而IFN-基因敲除仍能诱导产生EAE，而且恢复缓慢。,其他致病机制？,Th1/Th2平衡,Thl7细胞是新近发现的辅助性CD4+ 细胞，因其独特的表型特征和分泌IL-17而得名。IL-17具有强大的招募
12、中性粒细胞及促进多种细胞因子释放的作用，处于固有免疫和适应性免疫反应的交接面。,Th17细胞,IL -17 在EAE 模型小鼠急性期的外周血和脑脊液中都有较高水平的表达, IL-17-/-小鼠对EAE不敏感，抗IL-17抗体可以使EAE症状明显减轻 。多发性硬化病人的脑组织、血的单核细胞以及脑脊液中IL-17 的mRNA 及蛋白的表达均明显升高。,Th17细胞,CD4+CD25+ 调节性T 细胞是具有免疫调节功能的T 细胞亚群，具有免疫无能和免疫抑制两大功能特征。MS 患者外周血CD4+CD25+ T 细胞数量变化不明显， 但CD4+CD25+T 细胞抑制活性降低。,调节性T细胞,Th17、T
13、h1、Th2、CD4+CD25+T细胞这4种T细胞亚群及细胞因子相互作用、此消彼长组成的复杂网络在MS/EAE的疾病发展进展中起重要作用 免疫反应背离Th2 、CD4+CD25+T细胞，而向Th1 、 Th17细胞偏移是自身免疫性疾病发生发展的重要机制,Antibodies in MS,OCBs: 90% patients, temporal and clonal invariance Restricted B-cell VH repertoire in MS CSF and MS lesions antigen-driven response List of autoantibodies i
14、n MS ever-expanding High titre antibodies against myelin Ag in MS are inconsistent and unrelated to clinical outcomes. OCBs are not eliminated by RTX,Autoantibody-mediated disorders of the CNS?1. Antibodies directed towards a relevant cell surface epitope 2. Immunotherapy and PLEX result in a reduct
15、ion in antibody titre associated with amelioration of disease 3. Passive transfer of the immunoglobulin (Ig) fraction from an affected patient reproduces the clinical phenotype in an experimental animal. Autoantibodies may be negative regulators of inflammation (lipid antigen: antiphosphatidylcholin
16、e,病理pathology,CNS白质内有多发性脱髓鞘斑块，围绕小静脉分布，血管周围袖套状、淋巴细胞为主的浸润，引起髓鞘的崩解，可伴有轴索的破坏。Peri-venule distribution of Demyelinating Plaques occur anywhere within the white matter of the CNS.cuffs of lymphocytes around small blood vessels,damage of myelin sheath and destruction of axis-cylinder.,脑、脊髓和视神经常有萎缩。The atrophy of brain、spinal cord and optical nerve.晚期星状细胞增生、神经胶质形成硬化斑。Proliferation of astrocytes, sclerosis plaques with glial scar formation in the late phase,
