Section for Translational Epilepsy Research, Department of Neuropathology, University Hospital Bonn, Bonn, Germany.
Department of Epileptology, University Hospital Bonn, Bonn, Germany.
Ann Neurol. 2020 Jun;87(6):869-884. doi: 10.1002/ana.25720. Epub 2020 Apr 10.
Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms.
Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure.
In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ∼70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability.
Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. ANN NEUROL 2020;87:869-884.
评估树突棘支架蛋白 Drebrin 作为复发性癫痫和以疑似脑炎为主要症状的患者的病理生理相关自身抗体靶标的发生情况。
对 4 名成年起病癫痫和疑似病因不明脑炎且自身抗体筛查结果相同的患者的血清进行表位鉴定。我们结合了一系列广泛的方法，包括免疫印迹、免疫沉淀、质谱、原代神经元培养中的亚细胞结合模式分析以及野生型和 Drebrin 敲除小鼠脑中的免疫组织化学，以进行体外分析抗体暴露对突触形成、形态和异常神经元兴奋性的影响。
在一名成年起病癫痫和疑似脑炎患者的血清中，免疫印迹检测到约 70kDa 处的强信号，质谱显示 Drebrin 为潜在抗原。另外 3 名血清也在 Western blot 上约 70kDa 处显示强烈免疫反应的患者也为抗 Drebrin 阳性。抗 Drebrin 血清阳性患者出现癫痫发作、记忆障碍和脑脊液蛋白含量增加。磁共振成像改变包括杏仁核-海马 T2 信号增加和海马硬化。抗 Drebrin 血清阳性患者的诊断性活检显示 T 淋巴细胞性脑炎。将原代海马神经元暴露于抗 Drebrin 自身抗体中，导致异常的突触组成和 Drebrin 分布，以及尖峰率增加和爆发放电的出现，反映了网络过度兴奋。
抗 Drebrin 自身抗体定义了一种复发性癫痫和神经精神损伤以及边缘和偶尔皮质结构炎症的慢性综合征。在这种疾病中应考虑免疫抑制剂治疗。
