Anti-NMDA receptor antibodies from patients with limbic encephalitis

项目摘要： 抗NMDA受体脑炎是一种潜在的致命性脑炎，归因于针对N-甲基-D-天冬氨酸受体的自身抗体。 甲基-D-天冬氨酸受体（NMDAR）。抗NMDAR脑炎患者存在精神和 认知症状，然后进展为严重的神经功能障碍，包括癫痫发作，异常 运动、意识受损和自主神经不稳定，经常需要机械通气。在 尽管症状严重，但对于用以下药物治疗的患者， 免疫抑制疗法降低抗NMDAR抗体的滴度。尽管有很强的相关性 患者抗NMDAR抗体与临床综合征之间的关系，抗NMDAR的致病作用 这种疾病的抗体尚未确定。同样，抗NMDAR抗体的作用 对神经元的影响还不完全清楚。 确定性研究的主要障碍是缺乏从患者克隆的纯抗NMDAR抗体。之前 研究局限于可从患者血清获得的有限量的多克隆抗体 脑脊液。从患者中获得的单克隆抗NMDAR抗体将首次允许证明 认为抗NMDAR脑炎的病理生理学事件可归因于抗NMDAR， 单独的NMDAR抗体。这些抗体将能够研究它们如何影响细胞中的谷氨酸能信号传导。 脑，促进抗NMDAR脑炎的动物模型的开发，并允许结构建模 抗体-NMDAR复合物，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 神经元上受体的内化，导致NMDAR功能减退。我们的主要目标是测试这个 通过克隆抗NMDAR脑炎患者的抗体并使用它们来了解 这种疾病的特性。我们将从患有抗NMDAR脑炎的患者中收集B细胞， 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 mAb是否具有与疾病的主要作用一致的特征 发病机制它们将为动物模型的确定性实验奠定基础， 描述疾病相关免疫复合物分子结构的研究。 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