慢性实验性变应性猴脑脊髓炎的轴突病变及其意义

目的 探讨自身免疫性中枢神经系统脱髓鞘疾病慢性型的病理点及其临床意义。方法 建立猴实验性变态反应性脑脊髓炎（EAE）模型,于首次发病后4年进行病理取材和电镜观察。结果　①活动性病灶内轴突病变十分突出,其形式包括有空泡样变性、皱缩或消失,此外也可见到成片的髓鞘松解、断裂或融合,以及少突胶质细胞变性,见散在巨噬细胞;②可疑活动性病灶内轴突病变程度稍轻,以空泡样变为主,轴突完全消失及皱缩则少见,部分髓鞘内板松解,亦有少突胶质细胞变性,散在巨噬细胞。结论 慢性EAE的病理改变同时存在髓鞘与轴突的变性,多发性硬化后期不可逆的功能障碍可能与后者有着更大的相关。     

进行性多灶性白质脑病

正进行性多灶性白质脑病是一种中枢神经系统脱髓鞘性疾病,由JC病毒机会性感染所致。病变常位于灰白质交界处,髓鞘染色可见髓鞘脱失,病灶内特别是活动性病灶内有大量泡沫细胞,仅可见散在淋巴细胞浸润。受感染的少突胶质细胞胞核较大、深染,"毛玻璃"样改变的少突胶质细胞多见于病灶周边(图1a),病灶内及周围脑组织可见体积增大、深染、异形性或多核、     

实验性变应性猴脑脊髓炎的超微结构改变

目的探讨自身免疫性中枢神经系统（ＣＮＳ）脱髓鞘的病理特点和发病过程。方法建立猴实验性变态反应性脑脊髓炎（ＥＡＥ）的模型，并从病情不同阶段进行病理取材和电镜观察。结果（１）ＥＡＥ脱髓鞘最早的靶是少突胶质细胞（ＯＤＣ），而不是髓鞘本身；（２）无论急性期还是慢性期，脱髓鞘病灶内只有极少的炎细胞浸入；（３）急性期髓鞘改变轻微，以变性为主，ＯＤＣ肿胀显著，轴突相对完整。远离髓鞘变性区有大量炎细胞浸入；（４）慢性期病变区髓鞘脱失明显，ＯＤＣ严重变性或部分丢失，继发性轴突变性，边缘可见少量薄的髓鞘再生，血脑屏障破坏。结论ＥＡＥ的ＣＮＳ脱髓鞘过程首先累及ＯＤＣ。     

少突胶质细胞包涵体对多系统萎缩的诊断意义

目的 观察多系统萎缩脑和脊髓内少突胶质细胞包涵体并评估其诊断意义。方法 应用Gallyas-Braak银染色法研究4例经临床和传统病理方法诊断的多系统萎缩的脑和脊髓标本，以8例运动神经元病的脑和脊髓，6例无神经系统症状和病理改变的同龄人脑标本作对照。结果 4例病例中3例的脑和脊髓白质发现少突胶质细胞包涵体，该包涵体位于少突胶质细胞胞质内，呈半月形、镰刀形、火焰形。主要分布于脑桥、小脑、苍白球－壳核、延髓白质纤维束，脊髓外侧束，且与髓鞘变性脱失的分布一致。另有1例临床缺乏植物神经症状，黑质和脊髓中间外侧柱细胞无明显病变者，其脑和脊髓白质未观察到这种包涵体。所有对照病例的脑和脊髓白质内也未发现少突胶质细胞包涵体。结论 少突胶质细胞包涵体是散发性多系统萎缩特异性较高的病理标志，提示少突胶质细胞变性可能与多系统萎缩的髓鞘脱失有关。     

经颅磁刺激调控中枢神经系统髓鞘形成的研究进展

<正>中枢神经系统(central nervous system, CNS)髓鞘形成涉及多种细胞、信号通路和细胞因子的调控。少突胶质细胞(oligodendrocyte, OL)是CNS的髓鞘形成细胞,提供营养支持轴突和产生髓鞘包裹轴突;少突胶质前体细胞(oligodendrocyte progenitor cell, OPC),可增殖分化补充OL;小胶质细胞可以释放炎症分子影响OL的发育和髓鞘修复,也可以吞噬髓鞘碎片;     

钾通道阻滞剂可以有效修复受伤轴突的冲动传导

在脊椎中枢神经系统中,少突胶质细胞能形成轴突的髓鞘.髓鞘对轴突具有保护作用,使轴突具有电绝缘的特性,其独特的节段状结构使髓鞘化的神经轴突能快速、跳跃式地传导神经冲动.髓鞘损伤常见于脊髓损伤和一些慢性神经退行性疾病,由其引起的轴突传导阻滞被认为是引起损伤相关的神经并发症的主要原因.钾离子通道在发生于脊髓损伤和多发性硬化征...     

多种神经营养因子联合诱导培养骨髓间充质干细胞向少突胶质样细胞的定向分化

背景：轴突再生后髓鞘化是影响脊髓损伤后恢复的一个关键性因素,而少突胶质细胞存活的多少直接影响轴突再生后髓鞘化。 目的：探讨骨髓间充质干细胞经神经营养因子诱导培养后,向少突胶质样细胞定向分化的可行性。 设计、时间及地点：细胞分子生物学的体外实验,于2006-09/2007-06在同济医院骨科实验室完成。 材料：选用2~4周龄SD大鼠5只,雌雄不拘,取其双侧股骨、胫骨骨髓,分离培养骨髓间充质干细胞。培养用诱导因子表皮生长因子、碱性成纤维细胞生长因子、胰岛素样生长因子为美国Invitrogen公司产品。 方法：取培养至第4代的骨髓间充质干细胞,加入含有20 ng/mL碱性成纤维细胞生长因子、20 ng/mL表皮生长因子、N2添加剂的无血清培养基的诱导液诱导48 h后,加含500 ng/mL胰岛素样生长因子1、N2添加剂的分化培养液培养3 d。 主要观察指标：相差显微镜观察诱导过程中骨髓间充质干细胞的形态学变化。半定量RT-PCR检测少突胶质细胞特异性标志物mRNA的表达。应用神经元细胞标志物抗微管相关蛋白,星形胶质细胞标志物抗神经纤维酸性蛋白,少突胶质细胞标志物抗半乳糖脑苷脂、抗磷脂碱性蛋白抗体进行免疫细胞化学染色,检测骨髓间充质干细胞定向分化为少突胶质样细胞的阳性率。 结果：①骨髓间充质干细胞向少突胶质样细胞诱导分化过程中的形态学变化：经诱导分化后,大部分骨髓间充质干细胞表现出少突胶质细胞的形态学特征,胞质向细胞核回缩,细胞突起向外延伸,折光性增强,随时间延长多个细胞突起相互连接形成典型的网状结构。②少突胶质细胞特异性标志物mRNA的表达：细胞诱导分化后可检测到磷脂碱性蛋白mRNA、半乳糖脑苷脂mRNA的特异性条带。③少突胶质细胞阳性率：在诱导分化条件下,半乳糖脑苷脂阳性率为65%,磷脂碱性蛋白阳性率为45%,微管相关蛋白2阳性率为10%。 结论：碱性成纤维细胞生长因子、表皮生长因子与胰岛素样生长因子联合应用能够有效促进骨髓间充质干细胞向少突胶质样细胞定向分化。     

NF155及其在脑白质损伤疾病中的研究

在中枢神经系统（central nervous system,CNS）,髓鞘由少突胶质细胞（oligodendrocyte,OL）形成,神经元轴突髓鞘化完成预示着神经发育成熟。髓鞘具有重要的生理功能,它不仅能对神经元轴突起保护作用,而且使轴突绝缘,以确保神经冲动通过跳跃式传导而高速传递。然而在脑白质损伤中,由于神经细胞脱髓鞘,髓鞘生理功能部分或完全丧失,导致一系列病理生理改变。脑白质损伤引起的神经纤维脱髓鞘包括了原发性脱髓鞘和继发性脱髓鞘。     

小鼠实验性自身免疫性脑脊髓炎的病理变化

目的用髓鞘少突胶质细胞糖蛋白多肽(MOG35-55)诱发实验性自身免疫性脑脊髓炎(experi-m ental autoimmune encephalomyelitis,EAE)小鼠模型。方法应用MOG35-55抗原加完全弗氏佐剂免疫C57BL/6小鼠,利用光镜、电镜观察小鼠组织学改变。结果光镜下可见小血管周围炎细胞浸润,呈袖套状改变、血管周围明显脱髓鞘及神经元变性,B ieschowsky银染显示大量轴索肿胀和轴索卵形体的形成,电镜下可见髓鞘结构松散、断裂或融合,包括不同程度的髓鞘重建,脊髓病变广泛,程度重于脑部。结论EAE的病理改变为血管周围炎性细胞浸润、白质脱髓鞘及髓鞘重建。     

NgR1复合物的实验研究进展与干扰策略

成年哺乳动物周围神经系统损伤后可有效再生,但中枢神经系统损伤后却很难再生。在分子途径促进损伤中枢神经系统轴突再生的研究中,发现了3种髓磷脂相关抑制性蛋白：Nogo、髓鞘相关糖蛋白（myelinassociatedglycoprotein,MAG）、少突胶质细胞髓鞘糖蛋白（oligodendroeytemyelinglycoprotein,OMgp）在中枢神经系统损伤后发挥着抑制轴突生长的作用,并发现Nogo—A、MAG、OMgp存在于中枢白质的髓鞘内外环和少突胶质细胞的表面,通过与共同受体NgR1特异性结合诱导生长锥塌陷并抑制轴突生长。进而提出了通过阻断NgR1复合物及其下游的信号转导途径来促进神经元轴突再生的设想。本文拟对近年来关于NgR1复合物的研究加以综述。     

多病程Wistar大鼠实验性变态反应性脑脊髓炎的病理研究

目的:在建立wistar大鼠多病程实验性变态反应性脑脊髓炎(EAE)的动物模型的基础上,进行病理学研究,探讨不同发病类型EAE的基本病理改变如炎细胞浸润、脱髓鞘和轴索损伤等方面的差别,为多发性硬化(MS)的研究提供实验依据。方法:以豚鼠全脊髓匀浆(GPSCH)为抗原免疫Wistar大鼠建立EAE的动物模型,进行常规HE染色、Weil髓鞘染色和改良的Bielschowsky,并行GFAP免疫组化染色,观察不同发病类型EAE的病理政变。结果:根据病理和临床表现可将Wistar大鼠EAE模型分为5种发病形式:急性型、缓解-复发型、持续进展型、良性型和隐匿型。光镜下可见不同发病时期的EAE的病理改变有所不同,急性型EAE炎症浸润明显,尤脱髓鞘改变,缓解-复发型和持续进展型EAE髓鞘脱失和轴索损伤更明显,且有陈旧病灶周围的星型胶质细胞增生,而新发病灶无此表现,良性型EAE则改变接近正常。结论:首次建立了Wistar大鼠多病程EAE,且病理证实不同类型EAE的炎细胞分布、髓鞘脱失及轴索损伤等基本病理改变是不同的,它具有人类MS的许多发病特点,其中多病程的发病形式和主要病理特点与MS极其相似,是理想的MS动物模型。     

Survival of oligodendrocytes in chronic relapsing experimental autoimmune encephalomyelitis

Demyelinated plaques of chronic relapsing experimental autoimmune encephalomyelitis (EAE) have been examined in Strain 13 guinea pigs. Oligodendrocytes could be identified within these lesions adjacent to naked axons and astrocytic processes. Oligodendrocytes were identified both ultrastructurally and immunocytochemically. Many of these cells showed bizarre shapes and myelin within their cytoplasm. The survival of oligodendrocytes within these lesions suggests that the myelin sheath, not the oligodendrocyte, is the primary target in autoimmune demyelination. A similar sequence of events has been proposed in multiple sclerosis, for which chronic relapsing EAE serves as a laboratory model. The persistence of myelinating cells in areas of chronic demyelination and gliosis might have significant reparatory implications.     

Large subpial plaques of demyelination in a new form of chronic experimental allergic encephalomyelitis in the guinea pig

The current report describes a new technique for producing chronic experimental allergic encephalomyelitis (EAE) accompanied by demyelination in adult strain 13 guinea pigs. The disease is induced by a combination of passive transfer of lymph node cells sensitized to myelin basic protein (BP) and active challenge of the recipients with homologous spinal cord in Freund’s complete adjuvants. The clinical-pathologic spectrum ranges from a progressively fatal form of chronic EAE leading to death in 4–7 wk, through a remitting-relapsing form, to a chronic-stable form lasting many months. In all of these forms large subpial plaques of demyelination occur in the spinal cord with active phagocytosis of myelin debris, especially at the edges. The axons are swollen, but remain intact throughout. The histologic appearances of the lesions suggest that lysis of myelin occurs before phagocytosis, one of the hypotheses proposed for the pathogenesis of lesions occurring in humans with multiple sclerosis.     

实验性自身免疫性脑脊髓炎大鼠听神经损害研究

目的建立实验性自身免疫性脑脊髓炎(experimental autoimmune encephalomyelitis,EAE)大鼠模型,研究其脑干听觉诱发电位(brainstem auditory evoked potential,BAEP)Ⅰ波和听神经组织学改变。方法40只Wistar大鼠分为实验组和对照组,实验组(EAE组)用含卡介苗的豚鼠全脊髓匀浆为抗原免疫Wistar大鼠建立EAE动物模型,对照组用生理盐水混合完全福氏佐剂注射,采用诱发电位仪检测EAE组急性发病的大鼠和对照组大鼠的BAEP,通过透射电镜观察发病大鼠听神经外周段组织学改变。结果急性发病实验组大鼠BAEP的Ⅰ波潜伏期较对照组显著延长(P<0.01)。透射电镜下观察听神经外周段髓鞘松散,板层分离,局部变薄,呈不完全性脱髓鞘改变,轴突完整。对照组大鼠未见组织学改变。结论急性发病EAE大鼠听神经外周段脱髓鞘可能引起脑干听觉诱发电位Ⅰ波的改变。     

实验性自身免疫性脑脊髓炎的视神经病理改变

目的 研究实验性自身免疫性脑脊髓炎(EAE)的视神经病理改变.方法 足垫皮下注射豚鼠脊髓匀浆和完全弗氏佐剂(CFA)混合物制作Wismr大鼠EAE模型,于发病后第6d将大鼠处死,取视神经、脑和脊髓,行HE和LFB染色,光镜和电镜下观察其病理改变.结果 病理检查发现EAE模型组大鼠脑、脊髓有不同程度的炎症反应和脱髓鞘改变;均有视神经病变,光镜主要表现为炎症反应和脱髓鞘,视神经髓鞘脱失重于炎症反应;电镜主要表现为髓鞘稀疏,少突胶质细胞数量减少、胞核固缩,其周围包裹的髓鞘板层松解,轴突髓鞘分离.结论 EAE大鼠存在明显的视神经病变,主要为视神经炎症反应和脱髓鞘改变.     

Immunocytochemical study of Myelin-associated Glycoprotein (MAG) and Basic Protein (BP) in acute Experimental Allergic Encephalomyelitis (EAE)

To compare distributions of oligodendroglial myelin-associated glycoprotein (MAG) and myelin basic protein (BP) during demyelination in acute experimental allergic encephalomyelitis (EAE). Lewis rats were sensitized with an emulsion containing guinea pig spinal cord and complete Freund's adjuvant. The rats were examined clinically and groups were perfused with fixative before symptoms appeared (7d), within 48 h of symptom onset (10d) and during more severe illness (14d, 21d). Paraffin sections of cerebrum, brainstem, and spinal cord were immunostained with antisera to MAG and BP. Other sections in each serially mounted series were stained with luxol fast blue, hematoxylin and eosin or with the Bodian method to correlate MAG and BP results with histological changes. No abnormalities were detected 7d after sensitization. After 10d, small perivenular inflammatory cell infiltrates were present in white matter, displaced myelinated fibers, but their MAG stained periaxonal regions and BP-stained myelin sheaths appeared normal. In pontine grey matter lesions, there were focal abnormalities in a few myelin sheaths. After 21d, demyelinating lesions were present that were largest in pontine grey matter. Decreased MAG staining was present in areas of myelin sheath loss. MAG-stained fragments were found in zones of active myelin breakdown but no decrease or other change in MAG staining extended beyond the margins of demyelinating lesions into areas with normally stained myelin sheaths. Thus, in contrast to multiple sclerosis (Itoyama et al. 1980), changes in periaxonal oligodendroglial MAG are not present in acute EAE before inflammatory cell infiltrates or myelin sheath changes appear. Our findings suggest that myelin sheaths are the primary targets in EAE-induced demyelination. Oligodendroglia appear to be relatively unaffected and are available to remyelinate axons.     

Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: a case for antigen-specific antibody mediation.

Neuropathological and ultrastructural features of central nervous system demyelination were compared in marmoset experimental autoimmune encephalomyelitis (EAE) induced with myelin/oligodendrocyte glycoprotein (MOG), and in 3 cases of multiple sclerosis (MS) displaying recent lesions. At the edges of EAE and MS lesions, a zone of myelin vacuolation was common, whereas in the lesion proper, myelin sheaths were consistently transformed into vesiculated membranous networks. These networks became dissociated from axons by cell processes from macrophages. Oligodendrocytes were remarkably spared and evidence of myelin repair was present but not prominent. Axonal pathology was more common in the MS material than in marmoset EAE. Immunocytochemistry, using gold-labeled encephalitogenic peptides of MOG and silver enhancement to detect MOG autoantibodies, revealed the presence of MOG-specific autoantibodies over vesiculated myelin networks. Gold-labeled antibody to IgG also gave a positive reaction. Gold-labeled peptide of myelin basic protein did not react with MOG/EAE tissue, but the same conjugate gave positive staining in MS (and in marmoset EAE induced by whole white matter), perhaps indicating broader spectrum immunoreactivity or sensitization to myelin antigens. Thus, vesicular disruption of myelin was a constant feature in these evolving, highly active lesions in primate EAE and MS and appeared causally related to the deposition of antigen-specific autoantibodies.     

Chronic relapsing experimental allergic encephalomyelitis: CNS plaque development in unsuppressed and suppressed animals

Summary Central nervous system (CNS) lesion morphology has been studied in inbred Strain 13 guinea pigs sensitized for chronic relapsing EAE in which the disease was either left to develop (unsuppressed) or was suppressed with injections containing myelin basic protein (MBP). Pathologic changes correlated well with clinical activity. In unsuppressed chronic EAE animals, active clinical disease was invariably matched by acute inflammation in the CNS. In more chronic states, the CNS displayed fibrosis and remyelination while response showed the CNS to contain recent changes superimposed upon old lesions. In animals in which the disease was suppressed by injections of MBP, clinical signs did not develop. However, some early subclinical changes were seen morphologically. These lesions were able to remyelinate early on and there was no progression in lesion formation. Apparently, therefore, MBP had a beneficial effect upon the course of the disease and had promoted structural repair. It thus appears that MBP therapy might be one effective approach for the prevention of chronic relapsing EAE. The findings should prove relevant to future MBP trials in multiple sclerosis.     

The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion

Advances in the neuropathology of multiple sclerosis (MS) have contributed greatly to our understanding of the mechanisms of tissue injury in the condition. Particular interest has focussed on the active MS lesion, defined by macrophage activity in the presence of partially demyelinated axons. This has led to the prevailing consensus that a T-cell dependent, macrophage-mediated, autoimmune attack on constituents in the normal myelin sheath underlies the disease. This hypothesis, which has been largely supported by comparisons with the animal model, experimental allergic encephalomyelitis, has recently been questioned by an analysis of the pathological events preceding myelin phagocytosis in nascent MS lesions. The prephagocytic changes in evolving lesions examined shortly after the onset of an MS relapse raise the possibility that oligodendrocyte cell death and associated changes within the myelin sheath initiate local macrophage scavenger activity, with subsequent amplification of the inflammatory response. The presence of such lesions in patients with a spectrum of pathological changes in nearby or distant active phagocytic plaques suggests that pathological heterogeneity in MS is largely due to evolution of lesional pathology, rather than pathogenic heterogeneity.