Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica.
Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica.
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DOI：
10.1371/journal.pone.0072919
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kira J
中科院分区：
文献类型：
--
作者：
Masaki K;Suzuki SO;Matsushita T;Matsuoka T;Imamura S;Yamasaki R;Suzuki M;Suenaga T;Iwaki T;Kira J
多发性硬化（MS）和视神经脊髓炎（NMO）偶尔会有极具侵袭性且使人衰弱的病程；然而，其分子基础尚不清楚。本研究旨在确定亚洲多发性硬化和视神经脊髓炎患者中连接蛋白（Cx）病理与疾病侵袭性之间的关系。
样本包括11例视神经脊髓炎和视神经脊髓炎谱系疾病（NMOSD）尸检病例、6例多发性硬化病例以及20例其他神经系统疾病（OND）病例。分析方法包括星形胶质细胞Cx43/Cx30、少突胶质细胞Cx47/Cx32相对于水通道蛋白4（AQP4）及其他星形胶质细胞和少突胶质细胞蛋白的免疫组织化学表达，脱髓鞘程度，补体和免疫球蛋白的血管中心沉积，以及通过对巨噬细胞进行CD68染色进行病变分期。病变分为活动期脱髓鞘（n = 59）、慢性活动期（n = 58）和慢性非活动期（n = 23）。通过基于细胞的检测方法对120名受试者（包括30例多发性硬化、30例视神经脊髓炎、40例其他神经系统疾病和20例健康对照）的血清进行抗Cx43抗体检测。6例视神经脊髓炎/视神经脊髓炎谱系疾病和3例多发性硬化病例在活动期脱髓鞘和慢性活动期病变的脱髓鞘区域之外显示出星形胶质细胞Cx43优先缺失，其中异型Cx43/Cx47星形胶质细胞 - 少突胶质细胞间隙连接大量缺失。Cx43缺失与快速进展的病程显著相关，因为9例Cx43缺失的病例中有6例在疾病发作后两年内死亡，而8例无Cx43缺失的病例无论疾病表型如何均无死亡（66.7%对0%，P = 0.0090）。总体而言，9例Cx43缺失的病例中有5例出现以选择性髓鞘相关糖蛋白缺失为特征的远端少突胶质细胞病，而8例无Cx43缺失的病例中无此情况（55.6%对0.0%，P = 0.0296）。在所有多发性硬化和视神经脊髓炎/视神经脊髓炎谱系疾病病例的大多数活动期和慢性期病变中均观察到少突胶质细胞Cx32和Cx47表达缺失。视神经脊髓炎/视神经脊髓炎谱系疾病和多发性硬化患者中不存在Cx43特异性抗体。
这些发现表明，不依赖自身抗体的星形胶质细胞Cx43缺失可能与多发性硬化和视神经脊髓炎的疾病侵袭性以及远端少突胶质细胞病有关。
Multiple sclerosis (MS) and neuromyelitis optica (NMO) occasionally have an extremely aggressive and debilitating disease course; however, its molecular basis is unknown. This study aimed to determine a relationship between connexin (Cx) pathology and disease aggressiveness in Asian patients with MS and NMO. Samples included 11 autopsied cases with NMO and NMO spectrum disorder (NMOSD), six with MS, and 20 with other neurological diseases (OND). Methods of analysis included immunohistochemical expression of astrocytic Cx43/Cx30, oligodendrocytic Cx47/Cx32 relative to AQP4 and other astrocytic and oligodendrocytic proteins, extent of demyelination, the vasculocentric deposition of complement and immunoglobulin, and lesion staging by CD68 staining for macrophages. Lesions were classified as actively demyelinating (n=59), chronic active (n=58) and chronic inactive (n=23). Sera from 120 subjects including 30 MS, 30 NMO, 40 OND and 20 healthy controls were examined for anti-Cx43 antibody by cell-based assay. Six NMO/NMOSD and three MS cases showed preferential loss of astrocytic Cx43 beyond the demyelinated areas in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte oligodendrocyte gap junctions were extensively lost. Cx43 loss was significantly associated with a rapidly progressive disease course as six of nine cases with Cx43 loss, but none of eight cases without Cx43 loss regardless of disease phenotype, died within two years after disease onset (66.7% vs. 0%, P=0.0090). Overall, five of nine cases with Cx43 loss and none of eight cases without Cx43 loss had distal oligodendrogliopathy characterized by selective myelin associated glycoprotein loss (55.6% vs. 0.0%, P=0.0296). Loss of oligodendrocytic Cx32 and Cx47 expression was observed in most active and chronic lesions from all MS and NMO/NMOSD cases. Cx43-specific antibodies were absent in NMO/NMOSD and MS patients. These findings suggest that autoantibody-independent astrocytic Cx43 loss may relate to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO.
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影响因子：
11.2
作者：
Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
通讯作者：
Hemmer, Bernhard
影响因子：
5.8
作者：
Kowajiri, M.;Mogi, M.;Kira, J. I.
通讯作者：
Kira, J. I.
影响因子：
5.8
作者：
Kawajiri, M.;Mogi, M.;Kira, J. I.
通讯作者：
Kira, J. I.
影响因子：
4.4
作者：
Kira, Jun-ichi
通讯作者：
Kira, Jun-ichi
影响因子：
11.2
作者：
Brueck, Wolfgang;Popescu, Bogdan;Metz, Imke
通讯作者：
Metz, Imke