Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese
Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese
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DOI：
10.1093/brain/awm027
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发表时间：
2007-05-01
期刊：
影响因子：
14.5
通讯作者：
Kira, Jun-ichi
中科院分区：
文献类型：
--
作者：
Matsuoka, Takeshi;Matsushita, Takuya;Kira, Jun-ichi
亚洲人的视神经脊髓型多发性硬化症（OSMS）与西方人的视神经肌萎缩症（NMO）的复发-缓解型有相似的特征。基于频繁检测到靶向水通道蛋白-4（AQP 4）的特异性IgG（命名为NMO-IgG），OSMS被认为是NMO。本研究旨在阐明抗-AQP 4自身免疫的意义，在整个频谱的MS。血清从113个连续的日本患者临床确诊MS，基于Poser标准，抗-AQP 4抗体进行了测定免疫荧光使用GFP-AQP 4融合蛋白转染的HEK-293 T细胞。使用在马约诊所预先确定的NMO-IgG状态的血清样本计算抗AQP 4抗体测定的灵敏度和特异性，分别为83.3%和100%。OSMS患者抗AQP 4抗体阳性率（13/48，27.1%）显著高于CMS患者（3/54，5.6%）、其他神经系统疾病患者（0/52）和健康对照组（0/35）。没有一个II患者测试与脑干脊髓形式的MS是积极的。在OSMS患者中，抗体阳性率最高的OSMS患者的纵向广泛脊髓病变（LESCL）延伸超过三个椎体节段和脑病变，符合Barkhof标准（5/9，55.6%）。多项逻辑分析显示，抗AQP 4抗体的出现仅与较高的复发率呈正相关，但与视神经脊髓表现或LESCL无关。与抗AQP 4抗体阴性的CMS患者相比，抗AQP 4抗体阳性的MS患者显示出显著更高的严重视神经炎、急性横肌炎和LESCL的频率，而大多数情况也常见于抗AQP 4抗体阴性的OSMS患者。抗AQP 4抗体阳性患者的LESCL位于胸髓中上段，而抗AQP 4抗体阴性的OSMS患者的LESCL则遍布颈胸髓。在轴面上，前者最常表现为中央灰质受累，而后者则以全息索受累为主。相反，抗AQP 4抗体阴性CMS患者的LESCL优先累及颈髓中段，呈现外周白色物质为主的模式，如在短病变中所见。符合明确NMO标准的抗AQP 4抗体阳性MS患者与抗AQP 4抗体阴性OSMS伴LESCL患者相比，女性占优势，复发率较高，脑病变频率较高，对干扰素β-Ib的反应频率较低。这些结果表明，LESCLs在抗AQP 4抗体阳性和临床表型上是不同的。在日本，存在与CMS不同的抗AQP 4抗体阳性MS/NMO和抗AQP 4抗体阴性OSMS伴LESCL的病例。这表明在具有视脊髓呈递的情况下，产生LESCL的机制也是异质的，即AQP 4自身免疫相关和不相关。
Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the II patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-Ib than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.