急性出血性白质脑病的临床病理研究

为了探讨急性出血性白质脑病（ＡＨＬＥ）的临床病理特征，采用免疫组化染色的方法，对１例ＡＨＬＥ患者进行临床病理研究并复习我国以往报道的６例。结果显示，ＡＨＬＥ临床表现超急性特征，多数于短期内死亡；中枢神经病损部位为大脑（７／７）、脊髓（５／７，为全部经病检脊髓）、小脑（４／７）、脑干（４／７）；组化染色显示病灶内存有大量ＩｇＧ、ＩｇＡ、Ｃ３补体，并有Ｔ淋巴细胞浸润。结论：ＡＨＬＥ与免疫反应尤其是体液免疫密切相关；脊髓也是常见病损部位之一，这与以往特别是国外的报道有所不同     

多发性硬化免疫组织化学观察及病理机制探讨

目的 探讨免疫球蛋白在ＭＳ病理过程中的作用机制与变化规律。方法 本文应用免疫组化法对７例ＭＳ患者的脑组织进行了ＩｇＡ、ＩｇＧ、ＩｇＭ及ＧＦＡＰ染色观察。结果 远隔病灶的白质区可见胞浆ＩｇＡ、ＩｇＧ、ＩｇＭ及ＧＦＡＰ阳性表达的星形胶质细胞;急性炎症坏死病灶内吞噬细胞胞浆ＩｇＡ、ＩｇＧ、ＩｇＭ呈较强阳性表达;并且神经细胞（主要为锥体细胞）ＩｇＡ、ＩｇＧ、ＩｇＭ也有较强的阳性表达。结论 ＭＳ是一种涉及中枢神经系统多种细胞的复杂免疫性疾病,可能与病毒感染有关。     

体液细胞免疫在进行性肌营养不良症发病过程中的作用

探讨体液免疫和细胞免疫在进行性肌营养不良症（ＰＭＤ）发病过程中的作用。方法应用免疫组化ＳＰ法及免疫荧光一步法。结果ＰＭＤ肌组织中免疫球蛋白ＩｇＭ、ＩｇＧ和补体Ｃ３的阳性表达率分别为５０．０％、３１．１％和１１．１％，ＩｇＭ与对照组相比，差异有显著性意义（Ｐ＜０．０５），主要定位于肌膜和间质小血管壁上，与肌纤维萎缩性病变有关；ＰＭＤ肌组织中有巨噬细胞和Ｔ淋巴细胞浸润，阳性反应率分别为１００．０％和５５．５％，巨噬细胞聚集在坏死灶中，Ｔ细胞分布于退变肌纤维和血管周围，以ＣＤ８＋Ｔ细胞为主，多数表达ＨＬＡ－ＤＲ。结论提示免疫因素可能参与ＰＭＤ的病变过程。     

多发性肌炎患者周围神经中免疫球蛋白及补体的沉积

用免疫化学技术，对６例多发性肌炎患者的周围神经中免疫球蛋白（Ｉｇ）及补体（Ｃ３）的沉积进行研究。结果表明，这些神经除了有一般的脱髓鞘及轴索变性病理改变外，还有ＩｇＧ、ＩｇＭ、ＩｇＡ及Ｃ３呈阳性，它们主要沉积于神经外膜、神经束膜及神经纤维间的毛细血管壁上，个别着色颗粒还可见于神经纤维上。由此表明免疫球蛋白及补体沉积在多发性肌炎伴随的周围神经病理损害中起着一定重要的作用。     

急性脑梗死和Alzheimer病脑脊液高水平髓鞘素抗原B细胞免疫应答

目的确认急性脑梗死（ＡＣＩ）和Ａｌｚｈｅｉｍｅｒ病（ＡＤ）对髓鞘素碱性蛋白（ＭＢＰ）、髓鞘素结合糖蛋白（ＭＡＧ）和含脂质蛋白（ＰＬＰ）的Ｂ细胞免疫应答。方法采用酶联免疫斑点技术检测了ＡＣＩ、临床可能ＡＤ和其它神经疾病（ＯＮＤ）对照组患者外周血和脑脊液（ＣＳＦ）中ＭＢＰ、ＭＡＧ和ＰＬＰ抗体分泌细胞。结果ＡＣＩ、ＡＤ和ＯＮＤ患者外周血中均可检出ＩｇＧ、ＩｇＡ、ＩｇＭ三种表型ＭＢＰ、ＭＡＧ、ＰＬＰ抗体分泌细胞，无显著差异。但ＡＣＩ和ＡＤ患者ＣＳＦ中ＩｇＧ型ＭＢＰ、ＭＡＧ和ＰＬＰ抗体分泌细胞均呈显著性增高。结论ＡＣＩ急性脑缺血损伤和ＡＤ神经变性可能导致体内Ｂ细胞激活及ＣＮＳ内髓鞘素反应性Ｂ细胞免疫应答，其病理意义有待探讨。     

实验性过敏性脑脊髓炎豚鼠中枢神经系统一氧化氮合酶的表达

目的探讨诱导型一氧化氮合酶（ｉＮＯＳ）在中枢神经系统脱髓鞘疾病中的作用。方法采用硫辛胺脱氢酶染色和抗诱导型一氧化氮合酶（抗ｉＮＯＳ）抗体的免疫组化方法，对髓鞘碱性蛋白诱导豚鼠产生的实验性过敏性脑脊髓炎（ＥＡＥ）病程中，脑和脊髓的一氧化氮合酶（ＮＯＳ）和ｉＮＯＳ表达情况进行研究。结果在ＥＡＥ的急性期主要为血管、血管周围细胞、浸润细胞和小胶质细胞显示ｉＮＯＳ免疫反应阳性，在恢复期星形细胞则出现免疫反应阳性。结论提示一氧化氮是ＥＡＥ早期血脑屏障破坏以及进展期髓鞘和少突胶质细胞破坏的重要介导物质。     

重症肌无力患者若干临床问题探讨（附10例分析）

报告１０例ＭＧ病人均检测了周围血淋巴细胞计数、血清免疫球蛋白（ＩｇＧ、ＩｇＡ、ＩｇＭ）、补体Ｃ３、ＣＨ５０、Ｅ－玫瑰花结试验（ＥＲＦＴ）和淋巴细胞转换试验（ＬＴＴ），同时还测定血丙酮酸及酶谱（ＧＯＴ、ＬＤＨ、ＣＰＫ），并设３０例正常对照。ＭＧ组与对照组比较，除ＥＲＦＴ（Ｐ＜０．００１）、ＧＯＴ（Ｐ＜０．０１）、ＣＰＫ（Ｐ＜０．０１）、及ＬＤＨ（Ｐ＜０．０５）有差异外，余诸项均无统计学意义、提示一般血清免疫学或补体测定对ＭＧ诊断无特异性意义，结合文献复习对ＭＧ患者若干临床问题分别进行讨论。     

多发性硬化症脑脱髓鞘病灶TGF—β1和bFGF的表达

目的进一步认识细胞的转化生长因子（ＴＧＦ）β１和碱性成纤维细胞生长因子（ｂＦＧＦ）在中枢神经系统脱髓鞘病中的作用。方法采用ＨＥ染色以及抗蓖麻凝集素１标记小胶质细胞和巨噬细胞、抗胶质细胞原纤维酸性蛋白标记星形胶质细胞、抗人ＴＧＦβ１和抗人ｂＦＧＦ的免疫组织化学方法对３例多发性硬化症尸检病人脑组织中的脱髓鞘病灶进行研究。结果在急性期病灶中主要为巨噬细胞、小胶质细胞和血管内皮细胞呈ＴＧＦβ１免疫反应阳性，而慢性静止病灶中则主要为星型胶质细胞。ｂＦＧＦ主要在慢性病灶中的星型胶质细胞中表达。结论ＭＳ脑脱髓鞘病灶星形胶质细胞中表达ＴＧＦβ１和ｂＦＧＦ可能与脱髓鞘病灶的恢复有关，而脑血管内皮细胞表达ＴＧＦβ１可能与急性期炎性细胞浸润有关。     

左旋咪唑迟发性脑病免疫功能的研究

用间接免疫荧光法测定４８例左旋咪唑迟发性脑病（ＬＩＤＥ）患才外周血淋巴细胞亚群，同时用ＩＣＳ－Ⅱ分析仪以速率散射比浊法检测患者血清和脑脊液（ＣＳＦ）配对标本的部分体液免疫指标。结果表明：ＬＩＤＥ组ＣＤ３、ＣＤ４、ＣＤ２５、ＣＤ４／ＣＤ８比值均显著高于对照组，ＣＤ８低于对照组（Ｐ〈０．００１）。血清和ＣＳＦＩｇＧ、ＩｇＡ、ＩｇＭ及ＩｇＧ鞘内合成率（ＩｇＧ－Ｓｙｎ）亦均明显高于对照组（Ｐ〈０．００１）     

实验性自身免疫性脑脊髓炎的小胶质细胞和星形胶质细胞反应

目的确定小胶质细胞和星形胶质细胞在实验性自身免疫性脑脊髓炎（ＥＡＥ）发病及病变发展中的作用。方法用牛脊髓髓鞘碱性蛋白（ＭＢＰ）免疫豚鼠发生ＥＡＥ,用免疫组化法观察ＥＡＥ不同病期小胶质细胞和星形胶质细胞对炎性脱髓鞘病灶的反应。结果发生ＥＡＥ的前３天,小胶质细胞即开始激活,在临床症状出现时其数量及激活程度达高峰,并持续至高峰期。恢复期数量逐渐减少,激活程度逐渐减弱。星形胶质细胞在症状高峰期开始激活并围绕在浸润细胞和病变血管周围,似有隔离小胶质细胞与病灶接触的作用,至恢复期激活明显。结论小胶质细胞激活在ＥＡＥ的发病及进展中起重要作用,而星形胶质细胞主要与疾病的恢复有关。     

Biphasic and regionally-restricted chemokine expression in the central nervous system in the Theiler's virus model of multiple sclerosis

Intracerebral infection of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) induces a biphasic disease characterized by acute polioencephalitis followed by chronic demyelination and viral persistence in the spinal cord white matter. There has been limited study of soluble mediators responsible for the initial recruitment of inflammatory cells into the gray matter, and the secondary influx into the white matter during infection with TMEV. We used sensitive and specific RT - PCR/dot blot hybridization assays to quantitate the relative levels of chemokine mRNA in the brains and spinal cords during the acute and chronic phases of TMEV infection in mice susceptible (B10.M, H-2f) and resistant (B10, H-2b) to virus-induced demyelination. TMEV infection resulted in robust expression of mRNA for IP-10, RANTES, and MCP-1, but not GRO-alpha, in brains and spinal cords in both strains of mice within 5 days. By day 21, virus was cleared, inflammation reduced, and expression of all three chemokines subsided to baseline levels in the brains and spinal cords of resistant mice, and the brains of susceptible mice. Chemokine expression was also reduced in the spinal cords of susceptible mice, corresponding to a shift in TMEV replication from the gray to the white matter. During the chronic, demyelinating phase of infection, there was a resurgence in IP-10, RANTES, and MCP-1 mRNA in spinal cords of susceptible B10.M mice. This study demonstrates the coordinated regulation and regionally restricted expression of chemokines in a biphasic disease of the central nervous system and provides greater understanding of the mechanism by which inflammation is established and maintained in the CNS.     

多发性硬化28例磁共振分析

目的 探讨临床确诊和实验室检查支持确诊的MS患者特异性磁共振表现。方法 回顾性分析28例临床确诊或实。验室检查支持确诊的MS患者脑和脊髓磁共振矢、冠、轴平扫与增强扫描结果。结果 所有患者脑或脊髓MRI平扫均发现病灶，病灶多发于侧脑室体部及三角区周围白质，多呈桃仁状，尖指向侧脑室，不与室管膜相连；脑干与脊髓亦常受累；部分病灶有增强。结论 MS的确诊除了临床表现和脑脊液检查外，MRI也可做为另一敏感、特异的指标。     

Quantitation of multiple sclerosis specific central nervous system antigens in various regions of MS brains

We have estimated the levels of partially purified multiple sclerosis (MS) specific glycoproteins (MSG2) in gray matter, white matter, spinal cord and brain stem of MS autopsy brains by an enzyme immunoassay in which antisera to a pooled MSG2 was employed. Similarly, the levels of KG2 (non-MS brain isolate corresponding to MSG2) were assayed in various topographic areas of non-MS autopsy brains. Comparison of data on MS and non-MS groups revealed that the MS specific antigens may be preferentially located in the normal appearing white matter of MS brains. The concentration of MS antigens was found to be highest in the normal appearing white matter of MS brains, followed by periplaque and finally plaque. These results indicate that the MS specific antigens are not the degraded products of MS brains. They further support the view that normal appearing white matter of MS brains should be the target tissue for the isolation of MS specific antigens.     

Immunoregulation of experimental autoimmune encephalomyelitis by the selective CB1 receptor antagonist

During immune-mediated demyelinating lesions, the endocannabinoid system is involved in the pathogenesis of both neuroinflammation and neurodegeneration through different mechanisms. Here we explored the cellular distribution of the CB1 receptor (CB1R) in the central nervous system (CNS) and detected the level of CB1R expression during experimental autoimmune encephalomyelitis (EAE) by RT-qPCR, Western blotting, and immunostaining. Expression of CB1R was observed in neurons and microglia/macrophages but was barely detected in astrocytes. During EAE, the expression of CB1R in spinal cords was reduced at days 9, 17, and 28 postimmunization (p.i.), but the level of CB1R expression in spleens did not show a significant difference compared with complete Freund's adjuvant (CFA)-immunized mice. A selective CB1R antagonist (SR141716A) increased EAE clinical score, accompanied by weight loss. Unexpectedly, SR141716A inhibited the expression of CB1R but increased the expression of CB2R in brains, spinal cords, and spleens simultaneously. The administration of SR141716A increased interferon-γ, interleukin-17 (IL-17), and inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-α in brains and/or spinal cords. A similar increase was observed in spontaneous and specific antigen-stimulated splenic mononuclear cells compared with vehicle controls. Interestingly, the expression of CX3CL1 was increased in brains and spinal cords but declined in spleens of EAE mice treated with SR141716A. These results indicate that manipulation of the CB1R may have therapeutic value in MS, but its complexity remains to be carefully considered and studied in further clinical application.     

Evidence of axonal damage in human acute demyelinating diseases

Substantial axon damage, detected by immunostaining for beta amyloid precursor protein (betaAPP) has been demonstrated in acute demyelinating lesions in multiple sclerosis. AIMS: The present study aimed to determine if this was also the case in the other human acute demyelinating diseases, acute hemorrhagic leucoencephalitis (AHLE), acute disseminated encephalomyelitis (ADEM) and central pontine myelinolysis (CPM). METHODS: BetaAPP immunostaining was used as a marker of axonal damage in autopsy material from these conditions. RESULTS: Axonal damage was detected in all these conditions. Its extent varied within and between them. Axonal damage was largely confined to tissue adjacent to veins and venules in AHLE and ADEM but was unrelated to proximity to these vessels in CPM. CONCLUSION: Substantial axon damage occurs in fatal cases of AHLE, ADEM and CPM.     

Calcium channel blockers ameliorate disease in a mouse model of multiple sclerosis

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, are inflammatory demyelinating diseases of the central nervous system. The inflammatory attacks lead to glial dysfunction and death, axonal damage, and neurological deficits. Numerous studies in rat suggest that extracellular calcium influx, via voltage-gated calcium channels (VGCC), contributes to white matter damage in acute spinal cord injury and stroke. Our immunohistochemical finding that mouse spinal cord axons display subunits of L-type VGCC also supports this hypothesis. Furthermore, we hypothesized that VGCC also play a role in EAE, and possibly, MS. In our study, administration of the calcium channel blockers (CCB) bepridil and nitrendipine significantly ameliorated EAE in mice, compared with vehicle-treated controls. Spinal cord samples showed reduced inflammation and axonal pathology in bepridil-treated animals. Our data support the hypothesis that calcium influx via VGCC plays a significant role in the development of neurological disability and white matter damage in EAE and MS.     

Non-MS autoimmune demyelination

Connective tissue diseases can be characterised by central nervous system (CNS) involvement, in some patients manifested by demyelination areas in the white matter of the brain and spinal cord, which are difficult to differentiate from multiple sclerosis (MS) and other demyelinating processes, such as transverse myelitis and optic neuritis. Demyelinating process may be the feature of nervous impairment in systemic lupus erythematosus, Behcet's disease (BD), Sjoegren's syndrome (SS), systemic sclerosis (SSc) or very rarely other systemic autoimmune diseases. An acute isolated neurological syndrome, as the most common symptom of MS can sometimes be the only feature or even first manifestation of nervous impairment in connective tissue disease, hence presenting the diagnostic problem. Although the white matter abnormalities seen by magnetic resonance imaging may be similar in non-MS autoimmune demyelination and MS, it is the most important diagnostic tool in the differential diagnosis of the mentioned conditions. Investigating the presence of various autoantibodies potentially involved in the pathogenesis of demyelinating lesions as well as cerebrospinal fluid (CSF) analysis can be helpful.     

Major histocompatibility complex Class I expression in oligodendrocytes induces hypomyelination in transgenic mice

Increased expression of MHC Class I occurs in the central nervous system in association with demyelinating diseases such as multiple sclerosis and experimental allergic encephalomyelitis. To determine if MHC Class I expression by oligodendrocytes induces white matter pathology, the MHC Class I gene was expressed in transgenic mice under the control of the myelin basic protein (MBP) promoter. These mice display a neurological phenotype at 21 days-of-age. We examined these mice at 1, 3, and 12 weeks-of-age. MHC Class I was detected in the brains and spinal cords of transgenic mice but not in control mice. Class I was located in oligodendrocyte perikarya but not in myelin sheaths. The central nervous system of these transgenic mice was hypomyelinated and contained hypertrophic microglia and astrocytes. These observations establish that Class I expression by oligodendrocytes delays normal myelination but does not cause inflammatory demyelination. This hypomyelinating animal model is of potential use in studying the interactions between immunologically active molecules and remyelination in disorders of myelin. © 1996 Wiley-Liss, Inc.     

Improved detectability of experimental allergic encephalomyelitis in excised swine spinal cords by high b-value q-space DWI

Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple sclerosis (MS), which involves both inflammation and demyelination and is known to be species-dependent. Spinal cord abnormalities were found in more than 80% of postmortem specimens of MS patients. In the present study, T1, T2 and high b-value q-space diffusion-weighted magnetic resonance imaging (MRI) were used, for the first time, to characterize the EAE model in excised swine spinal cords. The MR images were compared with histological staining and clinical scoring. Although all spinal cords were excised from swine with severe or very severe (clinical score between 3 to 5 on a scale of 5) motor impairments, T1- and T2-weighted MRI revealed white matter (WM) abnormalities in only five of the ten EAE diseased spinal cords studied, while high b-value q-space diffusion weighted MRI (q-space DWI) detected WM abnormalities in all diseased spinal cords studied. Interestingly, high b-value q-space DWI was able to detect abnormalities in the normal appearing white matter (NAWM) even in spinal cords where no plaques were identified by the T1- and T2-weighted MR images. Good anatomical correlation was observed between the high b-value q-space MR images and histology. The extent of DWI abnormalities paralleled the clinical scoring and correlated with histology. In addition, areas classified as NAWM by the T1- and T2-weighted MR images that showed abnormalities in the q-space DWI were also found to have abnormal histology. This improved detection level of the EAE model by high b-value q-space DWI over conventional T1-, and T2-weighted MRI is briefly discussed.     

Topography of remyelinated chronic spinal cord lesions in herpes simplex virus type 2 infections of mice

Six-week-old outbred mice were infected intracerebrally with a low dose of the MS strain of herpes simplex virus type 2. About 1% of neurologically abnormal survivors developed paralysis or severe leg weakness during the first three weeks of infection. Weakness persisted with little subsequent improvement. Five to 8 months later, 4 such mice were killed, and each spinal cord was examined in Epon sections in a series of transverse sections along their lengths. All cords had 2 or more major white matter lesions which were typically greatly elongated in the rostrocaudal dimension, as seen in multiple sequential sections. While a lesion's appearance frequently suggested some degree of tract association, its size, contour and position frequently varied from level to level in a manner which is not characteristic of tract degeneration. Further, axons were preserved in these lesions, and had been remyelinated. This was accomplished by a combination of oligodendrocytes and Schwann cells. The only evidence of Wallerian degeneration in these spinal cords was a modest reduction in the cross-sectional area of a white matter column associated with the most severe lesions. These pathological findings are consistent with previous ones in this model. Rostrocaudal elongation of spinal cord lesions may be seen in other animal models of virus-induced demyelination; this and other features reported here have been described in multiple sclerosis.