抗髓鞘碱性蛋白抗体及抗髓鞘少突胶质细胞糖蛋白抗体在中枢神经系统炎性脱髓鞘疾病诊断中的价值

目的探讨抗髓鞘碱性蛋白抗体(抗MBP抗体)及抗髓鞘少突胶质细胞糖蛋白抗体(抗MOG抗体)在中枢神经系统炎性脱髓鞘疾病中的表达率,并研究两种抗体对该病的临床诊断价值。方法选取我院于2012-03—2013-09收治的中枢神经系统炎性脱髓鞘疾病患者90例为实验组(MS组30例,AM组30例,NMO组30例);同时选取45例非中枢神经系统炎性疾病患者为对照组。应用ELISA方法对各组患者血清和脑脊液中抗MBP抗体、抗MOG抗体进行检测,并对比分析各组及各亚组之间表达水平差异。结果实验组在血清及CSF中的抗MOG抗体和抗MBP抗体水平均明显高于对照组(P0.05)。而各组的血清抗体阳性率与CSF差异无统计学意义(P0.05)。MS组与AM组血清及CSF中抗MOG抗体阳性率均显著低于NMO组(P0.05)。MS组血清中抗MBP抗体阳性率明显高于AM组(χ2=4.356,P0.05),其余各亚组及CSF中的抗MBP抗体水平均无显著差异(P0.05)。而MS组血清中的抗MBP抗体阳性率显著高于CSF组(χ2=5.963,P0.05)。结论中枢神经系统炎性脱髓鞘疾病患者中抗MBP抗体、抗MOG抗体高表达,对疾病诊断具有临床意义;同时血清中的抗MOG抗体和抗MBP抗体含量差异可辅助疾病各亚型的鉴别诊断。     

MOG抗体相关自身免疫性脱髓鞘疾病三例报道及文献复习

髓鞘少突胶质细胞糖蛋白(myelin oligodendrocyte glycoprotein,MOG)是中枢神经系统少突胶质细胞和髓鞘表面特异表达的蛋白 ^{[ 1]} 。MOG抗体相关自身免疫性脱髓鞘疾病(MOG antibodies-associated autoimmune demyelination diseases,MOG-AD)是一种主要与MOG抗体相关,可能不同于多发性硬化(multiple sclerosis,MS)和视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)的独立疾病实体 ^{[ 1, 2]} 。虽然近年来有一些针对MOG-AD的研究报道,但目前对此病的认识仍然很少,初步的研究认为MOG-AD与MS、NMOSD在影像学特点、实验室检查及病理机制、治疗方法及预后等方面均有明显不同 ^{[ 3]} 。笔者现将南京医科大学附属脑科医院神经内科近期收治的3例抗MOG抗体阳性、诊断为MOG-AD的患者的临床诊治经过报道如下,并结合相关文献对其特点进行阐述。     

儿童MOG抗体阳性的中枢神经系统脱髓鞘病变12例临床特点分析

目的探讨髓鞘少突胶质细胞糖蛋白(MOG)抗体阳性的儿童中枢神经系统脱髓鞘病变的临床特点。方法回顾性分析2016年1月至2018年12月广东三九脑科医院神经内科收治的12例儿童MOG抗体阳性的中枢神经系统脱髓鞘病患者的临床症状、影像学特点、实验室检查、预后及随诊情况。结果 12例患者中男4例,女8例,起病年龄5~10岁,平均(8.0±3.1)岁。首发症状以意识水平下降、癫痫大发作等急性播散性脑脊髓膜炎(ADEM)样症状最多见(8例,8/12),其次为视力下降(5例,5/12),其中1例以ADEM样症状和视力下降同时起病。另有3例以ADEM样症状首发,起病后1周左右出现视力下降。12例患者行头颅MRI检查,11例(11/12)可见颅内异常病灶,以皮层下白质(10例,10/11)、脑干(7例,7/11)、丘脑(6例,6/11)、视神经(5例,5/11)受累为主,小脑(4例,4/11)、胼胝体(1例,1/11)亦可受累。9例患者行全脊髓MRI检查,5例(5/9)有异常病灶,均累及颈髓(5例,5/5),3例(3/5)累及胸髓,累及胸髓的病灶均为>3个椎体节段的长节段脊髓受累。12例患者行血清MOG抗体检测,11例(11/12)阳性,另1例(1/12)血清抗体阴性而脑脊液抗体阳性;8例患者行脑脊液MOG抗体检测,3例(3/8)阳性。所有患者经糖皮质激素及免疫球蛋白治疗,预后均良好,3例患者出现复发。结论MOG抗体相关的儿童中枢神经系统脱髓鞘病变以ADEM、视神经脊髓炎谱系疾病(NMOSD)最常见,往往以意识水平下降、癫痫大发作或视力下降起病,其预后相对较好,糖皮质激素治疗对缓解临床症状及预防复发有重要作用。     

光学相干断层成像术在中枢神经系统脱髓鞘疾病中的应用价值

光学相干断层成像术(optical coherence tomography,OCT)可客观清楚地显示视网膜结构变化,在眼科疾病诊疗中被广泛应用.视神经炎(optic neuritis,ON)是中枢神经系统脱髓鞘疾病的主要临床表现,可引起不同程度的视觉功能障碍.在临床工作中对视觉功能的评估方法 多样,各有利弊.现就OC...     

髓鞘少突胶质细胞糖蛋白抗体在多发性硬化中的意义

目的探讨髓鞘少突胶质细胞糖蛋白(MOG)抗体与多发性硬化(MS)临床表现及复发缓解型MS(RRMS)复发的关系。方法采用酶联免疫吸附法(ELISA)对60例MS、23例其他炎性神经疾病(OIND)、29例非炎性神经疾病(NIND)以及50例神经系统正常的对照(NC)患者血清及脑脊液(CSF)MOG抗体进行检测。结果MS患者CSFMOG抗体阳性率为28.3%(17/60),明显高于NC组[2%(1/50)]和NIND组[0%(0/29)],但与OIND组[21.7%(5/23)]比较差异无统计学意义。各组血清MOG抗体均为阴性。抗体阳性率急性活动期为31.8%(14/44),与稳定期[18.75%(3/16)]比较差异无统计学意义。CSFMOG抗体阳性的RRMS患者复发时间早于阴性患者,且其第1、2年复发率均高于阴性患者。结论在部分MS患者中枢神经系统内存在异常的MOG特异性B细胞免疫应答,且CSFMOG抗体对RRMS的复发有一定预测作用。     

髓鞘少突胶质细胞糖蛋白抗体相关疾病

髓鞘少突胶质细胞糖蛋白抗体相关疾病（MOGAD）为近年来确立的一类自身免疫性中枢神经系统脱髓鞘疾病,以血清可检测出抗全长髓鞘少突胶质细胞糖蛋白IgG1为关键诊断标准。该疾病尽管与多发性硬化、水通道蛋白4抗体相关视神经脊髓炎谱系疾病在临床表现上有些类似,但其具有相对特殊的病程、病理学以及影像学特征,应作为独立的病种去探讨和研究。文中拟对MOGAD的致病机制、诊断与治疗进展作一概述,为临床实践提供指导。     

MOG抗体介导的特发性炎性脱髓鞘疾病

正近年来有关髓鞘少突胶质细胞糖蛋白(myelin oligodendrocyte glycoprotein,MOG)抗体的特发性炎性脱髓鞘疾病(idiopathic inflammatory demyelinating disease,IIDDs)的研究增多,该抗体介导的炎性脱髓鞘疾病可能成为一类IIDDs的新类型,有学者称之为MOG抗体介导的IIDDs(简称为"MOG抗体病")。此类疾病临床表现与其他类型IIDDs有一定的重叠,这些表现在AQP4抗体     

MOG抗体和AQP4抗体相关脱髓鞘疾病的临床鉴别诊断

1 总论中枢神经系统炎症性脱髓鞘疾病(inflammatory demyelinating diseases,IDDs)是一组与自身免疫相关的,以中枢神经系统炎症脱髓鞘病变为主要表现的一类疾病的总称,病程可呈单相性或复发性,临床常见有视神经脊髓炎谱系疾病(neuromyelitis optica spectrum d...     

多发性硬化患者抗髓鞘少突胶质细胞糖蛋白抗体的检测及其意义

目的　检测多发性硬化 (MS)患者抗髓鞘少突胶质细胞糖蛋白抗体并探讨其意义。方法　采用EL ISA方法测定 5 6例多发性硬化患者急性期血清和脑脊液配对标本的抗髓鞘少突胶质细胞糖蛋白 (MOG)抗体 ,30例其它神经疾病 (OND)患者为对照。结果　 MS患者血清和脑脊液均可测到抗 MOG抗体 ,血清抗 MOG抗体阳性率为 35 .7% ,脑脊液抗 MOG抗体阳性率为 4 2 .8% ,OND组血清和脑脊液抗 MOG抗体阳性率均为 6 .7% ,与 OND组比较均有显著性意义 (P<0 .0 5 ) ,但血清和脑脊液比较无显著性意义 (P>0 .0 5 )。结论　多发性硬化患者血清和脑脊液中均可检测到抗 MOG抗体 ,可为临床诊断和治疗提供指导。     

视神经脊髓炎水通道蛋白4抗体分布特征及其与脑脊液寡克隆区带间关系的临床研究

目的观察视神经脊髓炎患者水通道蛋白4(AQP4)抗体在血清和脑脊液的分布特征,探讨血清AQP4抗体与脑脊液寡克隆区带之间的关系。方法采用酶联免疫吸附试验和间接免疫荧光法检测视神经脊髓炎和多发性硬化患者血清和脑脊液AQP4抗体,动态定时散射比浊法检测白蛋白和IgG,等电聚焦电泳联合免疫固定法检测脑脊液寡克隆区带,免疫印迹法检测寡克隆区带阳性视神经脊髓炎患者脑脊液电泳条带中AQP4抗体。结果视神经脊髓炎组患者血清AQP4抗体滴度[8.94(5.41,11.93)ng/ml]与多发性硬化组[7.34(4.76,12.00)ng/ml]相近(Z=-0.510,P=0.610),脑脊液AQP4抗体滴度[0.45(0.42,0.47)ng/ml]高于多发性硬化组[0.41(0.40,0.41)ng/ml;Z=-2.359,P=0.018],而且血清水平高于脑脊液(Z=-3.702,P=0.000)。视神经脊髓炎组患者脑脊液AQP4抗体阳性检出率高于多发性硬化组(5/7对1/5),但差异未达到统计学意义(Fisher确切概率法:P=0.242);复发期血清AQP4抗体滴度[8.54(5.32,11.42)ng/ml]与缓解期[9.97(5.41,13.28)ng/ml]相近(Z=-0.347,P=0.728);寡克隆区带阳性检出率低于多发性硬化组(3/13对10/14)且差异有统计学意义(Fisher确切概率法:P=0.021)。未在寡克隆区带阳性视神经脊髓炎患者的IgG电泳条带中检出AQP4抗体。结论视神经脊髓炎患者血清AQP4抗体滴度高于脑脊液,行脑脊液AQP4抗体检测具有一定临床意义。视神经脊髓炎患者鞘内合成IgG能力低于多发性硬化患者,且无针对AQP4抗原的成分。     

Neuromyelitis optica spectrum disorders: Features of aquaporin-4, myelin oligodendrocyte glycoprotein and double-seronegative-mediated subtypes

The new diagnostic classification of neuromyelitis optica spectrum disorder (NMOSD) in 2015 highlights the central role of biomarkers, such as antibodies against aquaporin-4 (AQP4-Ab), in diagnosis. Also, in approximately 20–25% of patients without AQP4-Ab (NMOSD^AQP4?) the presence of an antibody directed against myelin oligodendrocyte glycoprotein (MOG) characterizes a specific population of NMOSD patients (NMOSD^MOG+), according to their demographic and clinical data and prognoses. While double-seronegative cases (NMOSD^NEG) have not been fully described, they may correspond to the very first patients with opticospinal demyelination reported by Devic and Gault in 1894. The present report reviews the current knowledge of the pathophysiology and clinical features of NMOSD^AQP4+, NMOSD^MOG+ and NMOSD^NEG patients, and also discusses the relationship between the extended spectrum of MOG disease and NMOSD^MOG+. Finally, the current treatments for acute relapses and relapse prevention are described, with a focus on serological-based therapeutic responses and the promising new therapeutic targets.     

等电聚焦电泳联合免疫印迹法检测寡克隆区带诊断神经系统炎性脱髓鞘疾病

目的 探讨等电聚焦电泳(IEF)联合免疫印迹法检测寡克隆区带(OB)在神经系统炎性脱髓鞘疾病(IDD)中的应用.方法 IEF联合免疫印迹法检测112例IDD及24例神经系统非炎性疾病(NIND)患者血清和脑脊液中OB,并进行对比分析.结果 与视神经脊髓炎(5/21,23.8%,x2=32.679)、急性播散性脑脊髓炎(1/4,Fisher精确检验)、系统性自身免疫病继发中枢神经系统IDD(3/19,15.8%,x2=37.425)、周围神经系统IDD(0,x2=51.944)和NIND(0,x2=51.944)患者比较,多发性硬化(MS)患者脑脊液OB阳性率(44/46,91.7%)显著升高(P＜0.01).IEF联合免疫印迹法检测OB诊断MS的敏感度为91.7%,特异度为89.8%,高于其他检测方法.2例急性播散性脑脊髓炎患者和1例MS患者血清和脑脊液OB有相同条带,呈"镜像分布".结论 IEF联合免疫印迹法检测OB在MS诊断中具有一定的临床价值.

Abstract：

Objective To explore the diagnostic value of oligoclonal band (OB) detected by isoelectric focusing (IEF) with immunoblotting in inflammatory demyelinating diseases (IDD) in nervous system.Methods Serum and cerebrospinal fluid (CSF) OB was detected by IEF with immunoblotting in 112 patients with IDD ( multiple sclerosis ( MS):n = 48;neuromyelitis optica ( NMO):n = 21:acute disseminated encephalomyelitis ( ADEM):n = 4;secondary IDD from systemic autoimmune diseases:n = 19;peripheral nervous system IDD:n =20) and 24 patients with non-inflammatory neurological disease (NIND).Results CSF-restricted OB was detected in 91.7% (44/48) of MS patients,23.8% (5/21) of NMO patients(x2nmO vs MS= 32.679),1/4 of ADEM patients (Fisher' s excact test),15.8% (3/19) of secondary IDD patients (x2secondary IDD vs MS = 37.425 ),0 of peripheral nervous system IDD patients (x2peripheral nervous system IDD vs MS =37.425) and 0 of NIND patients (x2NIND vs MS =37.425).MS patients had significantly higher percentage of patients with CSF-restricted OB ( all P ＜0.01),compared with NIND and other IDD patients.The sensitivity and specificity of OB detected by IEF with immunoblotting for MS were 91.7% and 89.8%,which were higher than that of OB detected by other methods.Identical serum and CSF OB ( "mirror pattern" ) was detected in 2 of 4 ADEM patients and 1 of 48 MS patients.Conclusion IEF with immunoblotting to detect OB is a reliable method of diagnosis for MS.     

Anti-aquaporin-4 antibody in Chinese patients with central nervous system inflammatory demyelinating disorders

Objective

To determine seroprevalence of aquaporin-4 (AQP4) antibody in Chinese patients with central nervous system (CNS) inflammatory demyelinating disorders.

Methods

AQP4 antibody was detected by anti-AQP4 antibody assay. We measured seroprevalence in 200 patients with neuromyelitis optica (NMO, n = 44), multiple sclerosis (MS, n = 46), transverse myelitis (TM, n = 44), optic neuritis (ON, n = 13), acute disseminated encephalomyelitis (ADEM, n = 2), and other neurological diseases (OND, n = 51).

Results

AQP4 antibody seropositivity was 88.6% in patients with NMO, 4.3% in patients with MS, 30.8% in patients with ON and 51.7% in patients with LETM (longitudinally extensive TM). No patients with acute partial TM, ADEM, OND were positive for AQP4 antibody. Sensitivity of the test was 88.6% (95% CI 80–95) in patients with NMO. Specificity is 97.9% (95% CI 95.1–100) in 46 MS patients, with 51 OND patients as the control group. If the patients with recurrent ON, LETM were considered high risk for NMO (n = 37) and the remaining patients (n = 119) were considered controls, the sensitivity of this assay would be 48.6% (95% CI 33.4–64.1) and the specificity 97.5% (95% CI 94.7–100).

Conclusion

This study confirms that AQP4 antibody is a sensitive and specific biomarker for discrimination between NMO and other CNS autoimmune diseases.     

The distribution of myelin-associated glycoprotein and myelin basic protein in actively demyelinating multiple sclerosis lesions

Active plaques from 4 patients with multiple sclerosis were examined for myelin-associated glycoprotein (MAG) and myelin basic protein (MBP) using the peroxidase-antiperoxidase (PAP) immunocytochemical procedure applied to paraffin sections. MBP loss was intimately related to the presence of infiltrating macrophages which appeared to remove MBP-positive fragments directly off intact myelin sheaths. Phagocytosis of MAG-positive myelin sheaths was also observed. These findings support previous morphological studies that suggest that phagocytosis by macrophages of myelin attached to axons is an important mechanism of demyelination in multiple sclerosis.     

NMO-IgG在中枢神经系统脱髓鞘疾病中的诊断价值

水通道蛋白4是维持中枢神经系统正常跨膜水转运、血-脑屏障完整性和中枢神经系统内环境稳定的水通道蛋白,其特异性自身抗体NMO-IgG是视神经脊髓炎的特异性生物学标志物,但其在视神经脊髓炎中的阳性率并非100%,甚至在某些其他中枢神经系统脱髓鞘疾病中也可检测到。本文拟对NMO-IgG在中枢神经系统脱髓鞘疾病中的意义进行概述,以加深对该抗体的认识并指导中枢神经系统脱髓鞘疾病的诊断与鉴别诊断。     

Oligoclonal IgG bands synthesized in the central nervous system are present in rats with experimental autoimmune encephalomyelitis

OBJECTIVE: Oligoclonal bands (OBs) in electrophoresis of cerebrospinal fluid (CSF) are present in multiple sclerosis and here is investigated whether these also occur in experimental autoimmune encephalomyelitis (EAE). MATERIAL AND METHODS: Experimental autoimmune encephalomyelitis was induced in 42 DA rats after immunization with rat spinal chord homogenate and the occurrence of OBs were detected by electrophoresis of both sera and CSF. The relationship between disease symptoms, antibody response against myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and appearance of OBs was studied. RESULTS: Development of CSF-specific OB was found to occur, 6 weeks after immunization, in seven of 42 rats. OB was detected in rats with an antibody response against MBP, whereas as a role no such bands were present in rats with an antibody response against MOG. Initially severe disease symptoms were correlated to a concomitant intense oligoclonal antibody response. CONCLUSION: Cerebrospinal fluid-specific OB occurs in EAE. It is present in rats with an anti-MBP, but not in rats with an anti-MOG antibody response. A severe disease results in an intense oligoclonal antibody response, which might have an anti-inflammatory effect.     

Inflammatory demyelinating diseases of the central nervous system in Niger

Background

In sub-Saharan Africa (SSA), few studies have been reported on inflammatory demyelinating diseases of the central nervous system (CNS). Neuromyelitis optica spectrum disorders (NMOSD) seems to be the most frequent inflammatory demyelinating disease of CNS in sub-Saharan Africans or people of sub-Saharan African descent.

An immunohistochemical study of myelin proteins during remyelination in the central nervous system

Summary The process of remyelination in the superior cerebellar peduncles of mice following demyelination with Cuprizone was studied immunohistochemically using antisera to myelin basic protein (MBP) and myelin-associated glycoprotein (MAG). Demyelination occurred after formation of myelinic vacuoles and resulted in almost complete loss of demonstrable MBP and MAG from the peduncle. Prior to the onset of remyelination, oligodendrocytes with cytoplasmic staining for both proteins appeared in the peduncle. These cells were then associated with remyelinating axons. The axons were remyelinated in clusters until the MBP and the MAG in the whole peduncle were reconstituted, although the axon sheaths were thinner than those in normal animals. The results show that the immunohistochemical distribution of MBP and MAG in remyelinating axons resembles that in normal axons, and that the expression of myelin proteins in oligodendrocytes during remyelination reverts to that seen during normal development.Supported by MRC grant no. MT 5818Presented in part at the 59th Meeting of the American Association of Neurologists, St. Louis, MO, USA, June 1983     

Preparation of a novel monoclonal antibody specific for myelin basic protein phosphorylated on Thr

Phosphorylation is one of a number of post-translational modifications resulting in charge microheterogeneity of myelin basic protein (MBP). This phosphorylation is claimed to destabilise the compact myelin sheath by decreasing the interaction of membrane bilayers, thereby creating or maintaining pockets of cytoplasm. To further investigate and localise MBP phosphorylation to discrete regions of the myelin sheath we raised a monoclonal antibody with specificity for a known phosphorylation site in MBP. A synthetic peptide was made by Fmoc peptide chemistry and phosphorylation of Thr⁹⁸ was achieved on the resin by the global phosphorylation methodology, utilising dibenzyl-N,N-diethylphosphoramidite phosphitylation and t-butylhydroperoxideoxidation. The peptide coupled to tuberculin was used to immunise mice for monoclonal antibody production. The selected hybridoma (Clone P12) secreted an IgG2a antibody which reacted strongly with the phosphorylated immunogen and with phosphorylated fractions of bovine MBP obtained by ion exchange chromatography. The antibody had minimal reactivity with the unphosphorylated peptide; the same peptide phosphorylated at another site Ser¹⁰²; a preparation of unphosphorylated MBP obtained by ion exchange chromatography; and with an irrelevant phosphorylated protein (histone). Similar phosphorylation state-specific monoclonal antibodies could be made to recognise other specific phosphorylation sites in MBP or other proteins. It is planned to use these antibodies to quantify and locate the extent of MBP phosphorylation in normal and multiple sclerosis myelin.