水通道蛋白4抗体检测的方法学比较及其临床意义

目的 比较经典分析法和水通道蛋白4(AQP4)抗体分析法对AQP4抗体检测率的异同,并探讨该抗体对区分中国视神经脊髓炎(NMO)和多发性硬化(MS)患者的诊断准确度.方法 选择44例NMO和46例MS患者的血清,采用经典分析法检测血清中的NMO-IgG(AQP4),AQP4抗体分析法检测血清中AQP4抗体.结果 90份血清中,两种方法检测结果均为阳性的36份,两种方法检测结果均为阴性的45份,经典分析法阳性但AQP4抗体分析法阴性血清4份,AQP4抗体分析法阳性但经典分析法阴性血清5份,2种方法的阳性率、阴性率差异无统计学意义(P=1.000).2种方法一致性检验Kappa=0.798,P=0.000.经典分析法检测NMO患者NMO-IgG的灵敏度为77.3%,阳性预测值85.0%,特异度87.0%,阴性预测值87.0%,诊断正确率为82.2%,Youden指数74.3%.AQP4抗体分析法检测NMO患者AQP4抗体的灵敏度为88.6%,阳性预测值95.1%,特异度95.7%,阴性预测值89.8%,诊断正确率为92.2%,Youden指数84.3%.结论 两种AQP4抗体检测方法对区分MS与NMO都具有高灵敏度与特异度,但是抗AQP4抗体分析法对NMO诊断具有更高的诊断准确性,值得推广.     

水通道蛋白4抗体检测的方法学比较及其临床意义

目的 比较经典分析法和水通道蛋白4(AQP4)抗体分析法对AQP4抗体检测率的异同,并探讨该抗体对区分中国视神经脊髓炎(NMO)和多发性硬化(MS)患者的诊断准确度.方法 选择44例NMO和46例MS患者的血清,采用经典分析法检测血清中的NMO-IgG(AQP4),AQP4抗体分析法检测血清中AQP4抗体.结果 90份血清中,两种方法检测结果均为阳性的36份,两种方法检测结果均为阴性的45份,经典分析法阳性但AQP4抗体分析法阴性血清4份,AQP4抗体分析法阳性但经典分析法阴性血清5份,2种方法的阳性率、阴性率差异无统计学意义(P=1.000).2种方法一致性检验Kappa=0.798,P=0.000.经典分析法检测NMO患者NMO-IgG的灵敏度为77.3%,阳性预测值85.0%,特异度87.0%,阴性预测值87.0%,诊断正确率为82.2%,Youden指数74.3%.AQP4抗体分析法检测NMO患者AQP4抗体的灵敏度为88.6%,阳性预测值95.1%,特异度95.7%,阴性预测值89.8%,诊断正确率为92.2%,Youden指数84.3%.结论 两种AQP4抗体检测方法对区分MS与NMO都具有高灵敏度与特异度,但是抗AQP4抗体分析法对NMO诊断具有更高的诊断准确性,值得推广.     

水通道蛋白4抗体检测的方法学比较及其临床意义

目的 比较经典分析法和水通道蛋白4(AQP4)抗体分析法对AQP4抗体检测率的异同,并探讨该抗体对区分中国视神经脊髓炎(NMO)和多发性硬化(MS)患者的诊断准确度.方法 选择44例NMO和46例MS患者的血清,采用经典分析法检测血清中的NMO-IgG(AQP4),AQP4抗体分析法检测血清中AQP4抗体.结果 90份血清中,两种方法检测结果均为阳性的36份,两种方法检测结果均为阴性的45份,经典分析法阳性但AQP4抗体分析法阴性血清4份,AQP4抗体分析法阳性但经典分析法阴性血清5份,2种方法的阳性率、阴性率差异无统计学意义(P=1.000).2种方法一致性检验Kappa=0.798,P=0.000.经典分析法检测NMO患者NMO-IgG的灵敏度为77.3%,阳性预测值85.0%,特异度87.0%,阴性预测值87.0%,诊断正确率为82.2%,Youden指数74.3%.AQP4抗体分析法检测NMO患者AQP4抗体的灵敏度为88.6%,阳性预测值95.1%,特异度95.7%,阴性预测值89.8%,诊断正确率为92.2%,Youden指数84.3%.结论 两种AQP4抗体检测方法对区分MS与NMO都具有高灵敏度与特异度,但是抗AQP4抗体分析法对NMO诊断具有更高的诊断准确性,值得推广.     

构建M23-AQP4稳定表达的HEK293细胞应用于血清抗AQP4抗体检测的研究

目的构建M23-AQP4稳定表达HEK293细胞(HEK293-M23-AQP4)并用于抗AQP4抗体检测,以探索临床可行的抗AQP4抗体检测方法。方法用磷酸钙转染试剂将pEGFP-N1-M23-AQP4质粒转入HEK293细胞,通过G418筛选HEK293-M23-AQP4,以细胞间接免疫荧光法(CBA)检测M23-AQP4表达及分布。以HEK293-M23-AQP4为底物的CBA法检测视神经脊髓炎(NMO)6例、多发性硬化(MS)16例、其他脱髓鞘疾病(视神经炎、脊髓炎、吉兰-巴雷综合征、急性播散性脑脊髓炎)30例、非脱髓鞘性疾病患者10例血清抗AQP4抗体及其滴度,并比较4组抗体阳性率,计算抗AQP4抗体诊断NMO的敏感性,分别以非NMO的脱髓鞘疾病和非脱髓鞘疾病作对照计算抗AQP4抗体诊断NMO的特异性。将HEK293-M23-AQP4细胞于室温、4℃、-20℃保存4周,分别作为底物检测经首次检测所得抗AQP4抗体阳性标本并随机选取5例抗体阴性标本的抗AQP4抗体及滴度,比较其阳性率及滴度变化;将上述首次检测所得抗AQP4抗体阳性标本及5例抗体阴性标本反复冻融3次后分别于室温、4℃、-20℃保存1周后,检测其抗AQP4抗体及滴度,比较阳性率和滴度变化。结果 HEK293-M23-AQP4构建成功,M23-AQP4主要表达在细胞膜上。NMO患者抗AQP4抗体阳性率达83.3%(5/6),显著高于MS患者〔6.3%(1/16)〕、其他脱髓鞘疾病〔3.3%(1/30)〕和非脱髓鞘性疾病〔0.0%(0/10)〕(均P0.01);抗AQP4抗体诊断NMO的敏感性为83.3%(5/6),以非NMO的脱髓鞘疾病作对照时,其诊断NMO特异性为95.6%(44/46),以非脱髓鞘疾病作对照时,其诊断NMO特异性为100%(10/10)。HEK293-M23-AQP4于不同温度保存后所检测抗AQP4抗体阳性率和滴度与首次检测比较均无统计学意义(均P=1.0)。血清标本4℃及-20℃保存1周后所检测抗AQP4抗体阳性率和滴度与首次检测比较差异均无统计学意义(均P=1.0);室温保存1周后抗体滴度(1∶400、1∶400、1∶3200、1∶6400、1∶6400、1∶12800、1∶51200)与首次检测(1∶800、1∶1600、1∶12800、1∶25600、1∶25600、1∶51200、1∶120400)比较均显著下降(均P0.01),但阳性率差异无统计学意义(P=1.0)。结论成功构建HEK293-M23-AQP4细胞。以此细胞为底物的CBA法检测血清抗AQP4抗体对诊断NMO的敏感性和特异性较高,且对标本存储条件要求较低。     

血清MOG抗体阳性炎性脱髓鞘疾病患者临床特征分析

目的探讨MOG抗体阳性炎性脱髓鞘疾病患者的临床特征。方法回顾性分析36例血清MOG抗体阳性炎性脱髓鞘疾病患者(MOG抗体阳性组)与87例血清AQP4抗体阳性NMOSD患者(AQP4抗体阳性组)的临床信息,分析比较两组患者的临床特征。结果 MOG抗体阳性组与AQP4抗体阳性组患者相比,患病男女比例(1︰1.77 vs.1︰6.25,P=0.005)及发病年龄[(23.17±14.37)岁vs.(35.91±12.91)岁,P=0.000]差异存在统计学意义,两组患者均以女性为多,MOG抗体阳性组患者以儿童和青年为主。MOG抗体阳性组首发脱髓鞘事件中ADEM患者比例高于AQP4抗体阳性组[7例(19.4%)vs.0例(0%),P=0.000],脊髓炎[11例(30.6%)vs.47例(50.4%),P=0.018)]和脑干综合征[5例(13.9%)vs.25例(28.7%),P=0.049)]患者比例低于AQP4抗体阳性组。MOG抗体阳性组患者出现肢体抽搐症状患者比例高于AQP4抗体阳性组[5例(13.9%)vs.0(0%),P=0.002]。影像学表现上,MOG抗体阳性组头部总病灶[27例(75.0%)vs.33例(37.9%)]及NMO非典型病灶[23例(85.2%)vs.4例(12.1%)]患者比例高于AQP4抗体阳性组,头部NMO典型病灶[4例(14.8%)vs.29例(87.9%)]患者比例低于AQP4抗体阳性组(均P=0.000),仅14.8%MOG抗体阳性炎性脱髓鞘疾病患者存在典型NMO头部病灶。MOG抗体阳性组患者截访时EDSS评分低于AQP4抗体阳性组[(2.36±1.66)分vs.(3.83±1.66)分,P=0.000]。结论 MOG抗体阳性炎性脱髓鞘疾病患者男女比例差异较小,与AQP4抗体阳性NMOSD患者相比发病年龄小,首次发作以ADEM、视神经炎及脊髓炎为主,易出现肢体抽搐症状,少见NMO典型头部病灶,倾向于累及下段脊髓,预后较好。     

临床孤立综合征转归为视神经脊髓炎的相关因素分析

目的探讨临床孤立综合征(CIS)转归为视神经脊髓炎(NMO)的影响因素。方法收集2004-09-2011-09就诊于作者医院神经内科CIS患者109例。回顾性分析所有患者首次发病时头颅和脊髓MRI特点及临床表现。采用酶联免疫吸附法(ELISA)检测血清水通道蛋白4抗体(AQP4-Ab)水平,另备30份健康者血清作为健康对照组,以高于健康对照组血清AQP4-Ab浓度的均值+3倍标准差者为阳性。结果 (1)随访0.5～7年,中位数为3.0年,四分位数间距为4.6年,转归为NMO 46例,转归为多发性硬化(MS)29例,其余仍是CIS,包括24例脊髓炎,10例视神经炎(ON)。(2)转归为NMO组血清AQP4-Ab水平明显高于MS组、脊髓炎组、ON组和健康对照组(P<0.05)。(3)转归为NMO组AQP4-Ab阳性率为63.03%(29/46),高于转归为MS组的13.79%(4/29)、脊髓炎组的29.17%(7/24)、ON组的20.00%(2/10),差异均有统计学意义(P<0.05)。(4)多因素分析结果提示:AQP4-Ab阳性、NMO颅内典型病灶、脊髓损伤>3个节段、扩展残疾状态量表(EDSS)与CIS转归为NMO有关。结论 AQP4-Ab阳性、NMO颅内典型病灶或者脊髓损伤>3个节段、EDSS评分对预测CIS转归为NMO有临床价值。     

视神经脊髓炎患者血清 NMO-IgG 检测及其诊断价值

目的 检测神经脊髓炎(neuromyelitis optica,NMO)患者血清NMO-IgG的表达,并探讨其在NMO诊断中的价值.方法 收集北京、辽宁丹东、山西大同三家医疗机构临床诊断为NMO患者26例、多发性硬化(multiple sclerosis,MS)患者32例、神经科其他疾病患者77例;以稳定表达人源水通道蛋白-4(aquaporin-4,AQP4)的人胚肾293(HEK293)细胞株为底物,应用间接免疫荧光法检测患者血清NMO-IgG水平.结果 16例(61.5%)NMO患者血清NMO-IgG阳性,其阳性检出率显著高于MS患者(9.4 %)和MS+神经科其他疾病患者(4.6 %)(P<0.01).NMO-IgG对NMO诊断的灵敏度为61.5%,以MS作为对照时,该抗体对NMO诊断特异度为90.6%,以MS+神经科其他疾病作对照时,其特异度为95.4%.结论 NMO患者血清中普遍存在NMO-IgG,其可作为国内NMO诊断的重要生物学指标.     

AQP4抗体测定对中国人群NMO及HR-NMO临床意义的系统分析

目的系统评价中国NMO与HR-NMO患者AQP4抗体检测对其诊断及鉴别诊断的意义,明确进一步的治疗和预后评估。方法检索中国学术期刊全文数据库(CNKI)、万方数据库、中国生物医学文献数据库(CBM disc)、Pubmed、e BASE等。严格按照纳入和排除标准进行筛选文献。采用Stata.12进行数据处理。结果纳入11篇13组研究资料其中包含AQP4抗体阳性NMO患者350例,HR-NMO患者168例。Meta分析结果:NMO组AQP4抗体阳性率高于HR-NMO组,差异具有统计学意义,合并效应量为RR=0.66,95%Cl(0.53,0.83)。分层后CBA(细胞分析法)RR=0.636,95%Cl(0.461,0.878)显示NMO组AQP4抗体阳性率高于RH-NMO组;IIFA(间接荧光免疫法)RR=0.681,95%Cl(0.460,1.009)显示两组阳性率差异无统计学意义。结论 AQP4抗体检测对NMO疾病谱疾病诊断、治疗及预后评估具有重要的临床意义。     

视神经脊髓炎脊髓损害的磁共振研究

目的分析视神经脊髓炎(NMO)和多发性硬化(MS)患者脊髓MRI特点,以及血清抗水通道蛋白4(AQP4)IgG抗体阳性与阴性NMO患者脊髓MRI特点。方法回顾分析贵州省中枢神经系统脱髓鞘疾病数据库中42例NMO和32例有脊髓损害的MS患者的脊髓MRI资料。结果与MS组比较,NMO患者脊髓病灶累及更长的椎体节段(P0.05),在脊髓MRI矢状位上表现为线样征和纵向延展的脊髓损害(LESCL)(P0.05)。轴位T2WI上亮斑状损害(BSLs)以及中心性、横贯性脊髓损害更常见(P0.05);在病灶部位及强化病灶上,NMO和MS组间比较差异无统计学意义。与血清抗AQP4-IgG抗体阴性NMO患者比较,阳性患者线样征、BSLs、中心性损害更常见(P0.05),在脊髓病灶部位、受累椎体节段数、LESCL、横贯性损害及强化病灶方面,抗AQP4-IgG抗体阳性组和阴性组间比较差异无统计学意义。结论除LESCL、线样征、横贯性损害和中心性损害特点外,BSLs可能是另一个有助于鉴别NMO与MS的脊髓病灶MRI特征。BSLs、线样征、中心性损害特点可能与NMO患者抗AQP4-IgG抗体的血清学状态有关。     

水通道蛋白4启动子基因多态性与多发性硬化、视神经脊髓炎遗传易患性的关系

目的 探讨水通道蛋白4(AQP4)启动子区基因多态性与我国南方多发性硬化(MS)、视神经脊髓炎(NMO)患者血清抗AQP4抗体水平及遗传易患性的关系.方法 收集18例NMO、38例MS、13例复发性脊髓炎(RM)、6例复发性视神经炎(RON)患者及39名对照,PCR扩增AQP4外显子0及外显子1启动子基因(即AQP4-promoter0和AQP4-promoter 1),并行DNA测序.结果 共发现14个AQP4-promoter0及6个AQP4-promoter 1基因多态性位点.血清抗AQP4抗体阳性患者AQP4-promoter 0中-1003 bp多态性位点(A突变为G)发生率比血清抗AQP4抗体阴性患者(13/18与20/45,P=0.046)及对照组(13/18与10/39,P=0.001)高,差异有统计学意义.血清抗AQP4抗体阳性患者及血清抗AQP4抗体阴性患者AQP4-promoter 1中- 401 bp与-400 bp之间多态性位点(插入1个C)发生率均比对照组高(5/16与0/28,P=0.008; 8/38与0/28,P=0.027),差异有统计学意义.NMO及MS患者-1003bp多态性位点及-401 bp与-400 bp之间多态性位点发生率均比对照组高,差异有统计学意义(NMO:11/18与10/39,P=0.010;4/15与0/28,P=0.020;MS:19/38与10/39,P=0.027;8/34与0/28,P=0.018).结论 AQP4启动子区基因存在多态性位点,且与NMO、MS易患性有一定的关系;AQP4外显子0启动子中- 1003 bp多态性位点可能与血清抗AQP4抗体的出现有关.     

脑脊液BAFF、VEGF水平在视神经 脊髓炎患者中的变化及其意义

目的 探讨脑脊液B淋巴细胞活化因子(BAFF)、血管内皮生长因子(VEGF)水平在视神经脊髓炎(NMO)患者中的变化及其意义。方法 选取2015年1月-2018年1月本院收治的NMO患者50例作为NMO组,选取同期多发性硬化症(MS)患者50例作为MS组及非炎性神经系统疾病患者50例作为对照组,所有患者均检测脑脊液BAFF、VEGF水平、急性期扩展残疾状态量表(EDSS)评分、水通道蛋白4抗体(AQP4-Ab)滴度,分析BAFF、VEGF与EDSS评分、AQP4-Ab滴度的关系。结果 NMO组和MS组脑脊液BAFF、VEGF水平明显高于对照组,NMO组脑脊液BAFF、VEGF水平和EDSS评分、AQP4-Ab滴度阳性率明显高于对照组(P<0.05); Pearson相关性分析显示,脑脊液BAFF、VEGF水平均与EDSS评分呈正相关(r=0.695,0.668,P<0.05),但均与AQP4-Ab滴度无关(r=0.121,0.116,P>0.05)。结论 脑脊液BAFF、VEGF水平与NMO的发生发展有关,检测二者水平可作为鉴别NMO、MS及评估NMO病情的重要参考指标。     

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.     

视神经脊髓炎患者血清神经丝重链SMI-35临床意义初探

目的探讨视神经脊髓炎(NMO)患者血液神经丝重链(NfH)的水平及其临床意义。方法选取27例NMO患者、20例多发性硬化(MS)患者以及健康志愿者26名,采用ELISA法检测各组血清NfHSMI-35水平及NMO患者血清水通道蛋白抗体(AQP4-IgG)水平,观察NfH在NMO、MS和健康人群间以及在NMO患者AQP4-IgG阳性和阴性组间的差异,同时分析NMO患者NfH水平同NMO受累脊髓节段和临床神经功能缺损程度的相关性。结果NMO组、MS组和健康对照组血清NfHSMI-35水平分别为(0.100±0.024)、(0.082±0.012)和(0.064±0.021)ng/mL,NMO组和MS组血清NfHSMI-35水平均高于健康对照组(P0.05),且NMO组NfHSMI-35水平高于MS组(P0.05);NMO患者AQP4-IgG阳性和阴性者间NfHSMI-35水平比较无统计学差异〔(0.106±0.029)ng/mνs.(0.091±0.013)ng/mL,P0.05〕;NMO组NfHSMI-35水平与脊髓受累节段长度呈正相关(r=0.556,P0.01),与临床扩展致残量表评分(EDSS)无相关性(r=0.214,P0.05)。结论 NMO患者外周血NfHSMI-35明显升高,有可能成为NMO的生物标志物,并有可能成为与MS相鉴别的临床监测指标,但仍需要进一步观察和研究。     

Neuromyelitis optica and astrocytic damage in its pathogenesis

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extended, transverse myelitis. There have been long controversial whether NMO is a variant of multiple sclerosis (MS) or a different disease. However, since the discovery of an NMO-specific autoantibody to aquaporin 4 (AQP4), a dominant water channel in the central nervous system densely expressed on foot processes of astrocytes, the clinical distinction between NMO and MS has become clear, and now AQP4 antibody status is critically important for neurologists in deciding on treatment strategy. Moreover, pathological studies demonstrated an extensive loss of immunoreactivities to AQP4 and glial fibrillary acidic protein (GFAP) with relative preservation of the staining of myelin basic protein in acute NMO lesions, which is not seen in MS. In fact, the GFAP levels in the cerebrospinal fluid during acute exacerbation of NMO are remarkably elevated, while the values in MS are not different from those in controls. In addition, recent experimental studies conducted in vitro and in vivo have shown that AQP4 antibody is pathogenic. These findings strongly suggest that AQP4 antibody has diagnostic, therapeutic and pathogenetic implications, and that severe astrocytic damage mediated by AQP4 antibody distinguishes NMO from MS.     

The role of aquaporin-4 antibodies in Chinese patients with neuromyelitis optica

We determined the presence of aquaporin-4 (AQP4) antibodies by indirect immunofluorescence in human AQP4-transfected cells, and evaluated the diagnostic and prognostic relevance of AQP4 antibodies in 210 Chinese patients with neuromyelitis optica (NMO), high-risk NMO (HR-NMO), classic multiple sclerosis (MS), and other neurologic diseases. Patients were enrolled from The General Hospital of the Chinese People’s Liberation Army and followed-up for a median of 2 years. The patients with HR-NMO had optico-spinal MS (OSMS; n = 3), longitudinally extensive transverse myelitis (TM) (n = 35), recurrent optic neuritis (ON) (n = 2), ON with Sjögren’s syndrome (n = 1) and TM positive for Sjögren-A(SSA) antibody (n = 1). The sensitivity and specificity of AQP4 antibodies in NMO were 70.9% and 91%, respectively. The median AQP4 antibody titer was significantly higher in patients with NMO (1:320) than in those with HR-NMO (1:100) and MS (1:50). Relapse of ON or TM was more likely in patients with AQP4 seropositive, than AQP4 seronegative, HR-NMO. Among AQP4 seropositive patients, 66.7% (36/55) had severe ON, 75.9% (41/55) had TM, and 55.6% (30/55) had spinal cord lesions longer than three segments, and there were relapses in eight of 55 patients with ON (14.8%) and 19 of 55 patients with TM (35.2%) during the 2-year follow-up. In conclusion, our study reveals that AQP4 antibody is a sensitive and specific biomarker for discrimination of NMO, classic MS, and other neurological diseases, and is particularly useful for the diagnosis of HR-NMO. AQP4 antibody-positive patients showed higher frequencies of relapse of ON or TM compared with AQP4 antibody-negative patients.     

Anti-aquaporin 4 antibody in Japanese multiple sclerosis with long spinal cord lesions]

Multiple sclerosis (MS) in Asian populations is often characterized by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum, or brainstem, as well as in the ON and SP. In Western countries, inflammatory demyelinating disease preferentially involves the ON and SP is called neuromyelitis optica (NMO). Recently, Lennon et al. have reported that NMO-immunoglobulin G (NMO-IgG), which has been shown to bind to aquaporin 4 (AQP4), could be a specific marker of the NMO. To examine the epidemiological and clinical spectra of Japanese MS with this antibody, we established an immunohistochemical detection system for the AQP4-Ab using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese MS patients with long spinal cord lesions extending over three vertebral segments (LCL (+) MS). Patients with OSMS without LCL and those with classic MS were negative for this antibody. AQP4 is totally lost in the OSMS lesions. The AQP4-Ab titer correlates with the activity of the disease and the symptom improves after plasma exchange. These results suggested the close relation to the pathogenesis of AQP4-Ab to NMO/OSMS.     

Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions

Multiple sclerosis (MS) in Asian populations is often characterized by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum or brainstem. In Western countries, inflammatory demyelinating disease preferentially involving the ON and SP is called neuromyelitis optica (NMO). Recently, Lennon et al. discovered that NMO-IgG, shown to bind to aquaporin 4 (AQP4), could be a specific marker of NMO and also of Japanese OSMS whose clinical features were identical to NMO having long spinal cord lesions extending over three vertebral segments (LCL). To examine this antibody in larger populations of Japanese OSMS patients in order to know its epidemiological and clinical spectra, we established an immunohistochemical detection system for the anti-AQP4 antibody (AQP4-Ab) using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese OSMS patients with LCL. Patients with OSMS without LCL and those with CMS were negative for this antibody. Our results accorded with those of Lennon et al. suggest that Japanese OSMS with LCL may have an underlying pathogenesis in common with NMO.     

Early disruption of glial communication via connexin gap junction in multiple sclerosis,Baló's disease and neuromyelitis optica

Multiple sclerosis (MS), neuromyelitis optica (NMO), and Baló's disease (BD) are inflammatory demyelinating diseases of the CNS. We previously reported anti‐aquaporin‐4 (anti‐AQP4) antibody‐dependent AQP4 loss occurs in some NMO patients, while antibody‐independent AQP4 astrocytopathy can occur in heterogeneous demyelinating conditions, including MS, NMO and BD. To investigate the relationship between astrocytopathy and demyelination, we focused on connexins (Cxs), which form gap junctions (GJs) between astrocytes and oligodendrocytes and maintain homeostasis in the CNS. We evaluated expression of astrocytic Cx43/Cx30 and oligodendrocytic Cx47/Cx32 in autopsied materials from MS, NMO and BD patients. Astrocytic Cx43 and oligodendrocytic Cx32/Cx47 expressions were significantly diminished in both demyelinated and preserved myelin layers in all BD samples. In the leading edge of BD lesions, Cx43 and AQP4 loss preceded Cx32/Cx47 loss. Half of the NMO and MS samples showed preferential loss of astrocytic Cx43 expression in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte‐oligodendrocyte GJs were lost. Cases with Cx43 loss were significantly associated with rapid disease progression, regardless of the disease phenotype. Pathologically, Cx43 loss was frequently accompanied by distal oligodendrogliopathy. Our findings suggest that Cx43 astrocytopathy can occur in MS, BD and NMO. Moreover, astrocytic Cx43 loss may be associated with disease aggressiveness and distal oligodendrogliopathy in demyelinating conditions. Early disruption of glial communications via GJs may cause loss of glia syncytium, thereby inducing oligodendroglial damage and myelin loss. Inhibition of Cx hemichannels and restoration of GJs may be a possible therapeutic target for demyelinating disorders.     

Neuromyelitis optica: Diagnosis,pathogenesis, and treatment

Although the co-occurrence of myelitis and optic neuritis that characterizes neuromyelitis optica (NMO) was recognized over a century ago, distinguishing NMO from multiple sclerosis relied solely on clinical criteria until recently. The identification of a biomarker that has high specificity for NMO is clinically useful for distinguishing NMO from multiple sclerosis and identifying patients at high risk for recurrent myelitis and optic neuritis. That fact that the biomarker is an autoantibody that recognizes aquaporin 4 (AQP4), a water channel expressed on astrocyte podocytes, has substantially contributed to the hypothesis that NMO is a humorally mediated autoimmune disease. This review discusses the discovery of the NMO-IgG biomarker, the identification of AQP4 as its target, the clinical applications of these advances, the pathologic implications for the anti-AQP4 antibody, and advances in NMO treatment.