Anti-NMDA receptor antibodies from patients with limbic encephalitis

项目总结： 抗N-甲基-D-天冬氨酸受体脑炎是一种潜在的致命性脑炎，可归因于抗N-甲基-D-天冬氨酸自身抗体。 甲基-D-天冬氨酸受体(NMDAR)抗NMDAR脑炎患者表现为精神障碍和 认知症状，然后进展为严重的神经功能障碍，包括癫痫，异常 运动、意识受损和自主神经不稳定，经常需要机械通风。在……里面 尽管症状很严重，但接受以下治疗的患者仍有可能基本康复 降低抗NMDAR抗体效价的免疫抑制疗法。尽管有很强的关联性 抗NMDAR抗体与临床证候的关系及抗NMDAR的致病作用 这种疾病中的抗体还没有确定下来。同样，抗NMDAR抗体的作用 对神经元的研究还不完全清楚。 决定性研究的主要障碍是缺乏从患者身上克隆的纯抗NMDAR抗体。之前 研究仅限于从患者血清中获得有限数量的多克隆抗体和 脑脊液。从患者身上获得的抗NMDAR的单克隆抗体将首次允许证明 认为导致抗NMDAR脑炎的病理生理事件可归因于抗-NMDAR脑炎 单独使用NMDAR抗体。这些抗体将有助于研究它们如何影响脑内谷氨酸能信号转导。 大脑，促进抗NMDAR脑炎动物模型的开发，并允许进行结构建模 抗体-NMDAR复合体，然后可以指导靶向治疗的设计。 我们的假设是，在抗NMDAR脑炎中，针对NMDAR胞外区的抗体导致 神经元上受体的内在化，导致NMDAR功能低下。我们的主要目标是测试这一点 克隆抗NMDAR脑炎患者抗体的假说 这种疾病的特点。我们将收集抗NMDAR脑炎患者的B细胞，克隆他们的 抗体，并表征其NMDAR结合特性和对受体功能的影响。这些 实验将确定抗NMDAR单抗是否具有与疾病主要作用一致的特征 发病机制。他们将为动物模型和结构模型的最终实验奠定基础 研究描绘与疾病相关的免疫复合体的分子结构。 1

Project Summary: Anti-NMDA receptor encephalitis is a potentially lethal encephalitis attributed to autoantibodies against the N- methyl-D-aspartate receptor (NMDAR). Patients with anti-NMDAR encephalitis present with psychiatric and cognitive symptoms, and then progresses to severe neurological dysfunction, including seizures, abnormal movements, impaired consciousness, and autonomic instability, frequently requiring mechanical ventilation. In spite of the severity of the symptoms, substantial recovery is possible for patients treated with immunosuppressive therapies that reduce titers of anti-NMDAR antibodies. Despite the strong correlation between patient anti-NMDAR antibodies and the clinical syndrome, the pathogenic role of anti-NMDAR antibodies in the disease has not been definitively established. Likewise, the actions of anti-NMDAR antibodies on neurons are incompletely understood. The primary obstacle to definitive study is the lack of pure anti-NMDAR antibodies cloned from patients. Prior studies have been restricted to the limited amounts of polyclonal antibodies obtainable from patient sera and CSF. Monoclonal anti-NMDAR antibodies obtained from patients would, for the first time, allow demonstration that the pathophysiological events believed to underlie anti-NMDAR encephalitis are attributable to anti- NMDAR antibodies alone. The antibodies would enable study of how they affect glutamatergic signaling in the brain, facilitate the development of animal models for anti-NMDAR encephalitis, and permit structural modeling of the antibody-NMDAR complex, which could then direct the design of targeted therapies. Our hypothesis is that, in anti-NMDAR encephalitis, antibodies to the extracellular region of the NMDAR lead to internalization of receptors on neurons, leading the NMDAR hypofunction. Our primary objective is to test this hypothesis by cloning antibodies from patients with anti-NMDAR encephalitis and using them to understand the properties of this disease. We will collect B-cells from patients with anti-NMDAR encephalitis, clone their antibodies, and characterize their NMDAR binding properties and effects on receptor function. These experiments will establish whether anti-NMDAR mAbs have features consistent with a primary role in disease pathogenesis. They will lay a foundation for definitive experiments in animal models as well as structural studies to delineate the molecular structure of disease-related immune complexes. 1