Wan Dongshan, Zhao Shufang, Zhang Chen, Xu Fang, Wang Huizi, Tao Shaoxin, Qiu Zhandong, Jiang Hao, Li Dawei, Wang Fei, Li Dong, Chen Jiahao, Wang Yan, Yan Yao, Zhao Yan, Gao Xiaohan, Jin Bingxue, Liu Di, Zhang Mengyao, Feng Jingjing, Hou Shiyue, Wang Mingyang, Chen Teng, Lin Ming, Han Jinming, Wen Xinmei, Jiang Wei, Liu Liang, Long Youming, Zhao Yinan, Kira Jun-Ichi, Liu Zheng, Chai Guoliang, Hao Junwei
Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China.
Department of Neurology, PLA Rocket Force Characteristic Medical Center, Beijing, China.
JAMA Neurol. 2025 Mar 1;82(3):247-257. doi: 10.1001/jamaneurol.2024.4763.
Autoantibodies targeting astrocytes, such as those against glial fibrillary acidic protein (GFAP) or aquaporin protein 4, are crucial diagnostic markers for autoimmune astrocytopathy among central nervous system (CNS) autoimmune disorders. However, diagnosis remains challenging for patients lacking specific autoantibodies.
To characterize a syndrome of unknown meningoencephalomyelitis associated with an astrocytic autoantibody.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series study included samples collected from April 2021 to May 2024 at a tertiary referral hospital among patients with uncharacterized CNS autoimmune disorders and similar clinical and radiological features. Single-cell RNA sequencing (scRNA-seq) was performed on cerebrospinal fluid (CSF) cells of 2 index patients to identify the putative target antigen of the clonally expanded B cells. A comprehensive screening for additional patients was conducted using blinded cell-based and tissue-based assay. Candidate patients were followed up for a median (range) duration of 23 (5-31) months.
scRNA-seq, autoantibody characterization, and testing.
Detection of the autoantibody and characterization of the associated autoimmune meningoencephalomyelitis.
Fourteen candidate patients (10 [71%] female; median [IQR] age, 33 [23-41] years) were identified. Initially, CSF from 2 female patients with unknown encephalomyelitis showed astrocytic reactivity on rat tissue but was negative for GFAP IgG. A total of 17 of 37 clonally expanded B cell clonotypes (46%) in their CSF expressed IgG autoantibodies targeting the astrocytic intermediate filament protein vimentin. Subsequent screening identified 12 additional patients. These 14 patients shared a unique clinical profile characterized by relapsing courses and symptoms prominently involving the cerebellum, brainstem, and corticospinal tract (CST). All patients also exhibited elevated CSF protein and cells, intrathecal immunoglobulin synthesis, and magnetic resonance imaging (MRI) showing bilateral lesions on CST. Notably, 8 of 12 patients (67%) who received first-line immunotherapy at their first episode responded well. At the last follow-up, 11 patients (79%) experienced significant disability (modified Rankin Scale ≥3).
In this case series, autoantibodies targeting the astrocytic intermediate filament protein vimentin were identified in patients with previously undifferentiated meningoencephalomyelitis and common radiographic features.
针对星形胶质细胞的自身抗体，如针对胶质纤维酸性蛋白（GFAP）或水通道蛋白4的自身抗体，是中枢神经系统（CNS）自身免疫性疾病中自身免疫性星形胶质细胞病的关键诊断标志物。然而，对于缺乏特异性自身抗体的患者，诊断仍然具有挑战性。
对一种与星形胶质细胞自身抗体相关的不明脑膜脑脊髓炎综合征进行特征描述。
设计、地点和参与者：这项回顾性病例系列研究纳入了2021年4月至2024年5月在一家三级转诊医院收集的样本，研究对象为患有未明确诊断的中枢神经系统自身免疫性疾病且具有相似临床和影像学特征的患者。对2例索引患者的脑脊液（CSF）细胞进行了单细胞RNA测序（scRNA-seq），以确定克隆扩增的B细胞的假定靶抗原。使用基于细胞和组织的盲法检测对其他患者进行了全面筛查。对候选患者进行了中位（范围）为期23（5 - 31）个月的随访。
scRNA-seq、自身抗体特征分析和检测。
自身抗体的检测以及相关自身免疫性脑膜脑脊髓炎的特征描述。
确定了14例候选患者（10例[71%]为女性；中位[四分位间距]年龄，33[23 - 41]岁）。最初，2例患有不明脑脊髓炎的女性患者的脑脊液在大鼠组织上显示出星形胶质细胞反应性，但GFAP IgG检测为阴性。她们脑脊液中37种克隆扩增的B细胞克隆型中有17种（46%）表达了针对星形胶质细胞中间丝蛋白波形蛋白的IgG自身抗体。随后的筛查又确定了12例患者。这14例患者具有独特的临床特征，表现为复发病程，症状主要累及小脑、脑干和皮质脊髓束（CST）。所有患者还表现出脑脊液蛋白和细胞升高、鞘内免疫球蛋白合成增加，以及磁共振成像（MRI）显示CST双侧病变。值得注意的是，12例在首次发作时接受一线免疫治疗的患者中有8例（67%）反应良好。在最后一次随访时，11例患者（79%）出现了严重残疾（改良Rankin量表≥3）。
在本病例系列中，在先前未分化的脑膜脑脊髓炎且具有共同影像学特征的患者中发现了针对星形胶质细胞中间丝蛋白波形蛋白的自身抗体。
