Anti-NMDA receptor antibodies from patients with limbic encephalitis

边缘叶脑炎患者的抗 NMDA 受体抗体

• 批准号: 9338305
• 负责人: DAVID ROBINSON LYNCH
• 金额: $ 20.81万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338305
• 关键词: Affect; Animal Disease Models; Animal Model; Antibodies; Antibody Diversity; Antigen-Antibody Complex; Autoantibodies; B-Lymphocytes; Binding; Blocking Antibodies; Brain; Cell hybridization; Cells; Clinical; Cloning; Complex; Conscious; Dangerousness; Development; Disease; Dyskinetic syndrome; Encephalitis; Enzyme-Linked Immunosorbent Assay; Event; Excision; Fc Receptor; Foundations; Functional disorder; Future; Glutamates; Hallucinations; Hippocampus (Brain); Hybrid Cells; Hybridomas; IgG Receptors; Immunosuppression; Immunotherapy; Impairment; Individual; Lead; Limbic Encephalitis; Long-Term Potentiation; Mechanical ventilation; Mediating; Memory Loss; Methods; Molecular Structure; Monoclonal Antibodies; N-Methyl-D-Aspartate Receptors; Neurobehavioral Manifestations; Neurologic Dysfunctions; Neurons; Paranoia; Pathogenesis; Pathogenicity; Pathology; Patients; Physiological; Property; Recovery; Research; Role; Seizures; Serum; Severities; Specificity; Structural Models; Structure; Surface; Symptoms; Synapses; Syndrome; System; Testing; Therapeutic; Therapeutic immunosuppression; Time; Work; animal model development; design; experimental study; extracellular; glutamatergic signaling; innovation; motor impairment; novel; polyclonal antibody; psychiatric symptom; receptor binding; receptor function; receptor internalization; targeted treatment; therapeutic evaluation

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

项目概要： 抗 NMDA 受体脑炎是一种潜在致命性脑炎，归因于抗 N-MDA 的自身抗体 甲基-D-天冬氨酸受体（NMDAR）。抗 NMDAR 脑炎患者会出现精神和症状 认知症状，然后发展为严重的神经功能障碍，包括癫痫发作、异常 运动、意识障碍和自主神经不稳定，经常需要机械通气。在 尽管症状很严重，接受治疗的患者还是有可能大幅康复的。 降低抗 NMDAR 抗体滴度的免疫抑制疗法。尽管相关性很强 患者抗 NMDAR 抗体与临床综合征之间、抗 NMDAR 的致病作用 该疾病中的抗体尚未明确确定。同样，抗 NMDAR 抗体的作用 对神经元的作用尚不完全了解。 确定性研究的主要障碍是缺乏从患者克隆的纯抗 NMDAR 抗体。事先的 研究仅限于从患者血清中获得的有限数量的多克隆抗体 脑脊液。从患者身上获得的单克隆抗 NMDAR 抗体将首次能够进行演示 据认为，抗 NMDAR 脑炎的病理生理学事件可归因于抗 单独的 NMDAR 抗体。这些抗体将有助于研究它们如何影响谷氨酸信号传导 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，NMDAR 细胞外区域的抗体会导致 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一点 通过克隆抗 NMDAR 脑炎患者的抗体并利用它们来理解这一假设 这种疾病的特性。我们将从抗 NMDAR 脑炎患者身上收集 B 细胞，克隆其 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 是否具有与疾病中主要作用一致的特征 发病。他们将为动物模型和结构实验的确定性实验奠定基础 研究描绘疾病相关免疫复合物的分子结构。 1

项目成果

Membrane-bound and soluble forms of an NMDA receptor extracellular domain retain epitopes targeted in auto-immune encephalitis.

• DOI: 10.1186/s12896-018-0450-1
• 发表时间: 2018-06-27
• 期刊: BMC biotechnology
• 影响因子: 3.5
• 作者: Sharma R;Al-Saleem FH;Puligedda RD;Rattelle A;Lynch DR;Dessain SK
• 通讯作者: Dessain SK

Monoclonal antibodies from a patient with anti-NMDA receptor encephalitis.

• DOI: 10.1002/acn3.592
• 发表时间: 2018-08
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Sharma R;Al-Saleem FH;Panzer J;Lee J;Puligedda RD;Felicori LF;Kattala CD;Rattelle AJ;Ippolito G;Cox RH;Lynch DR;Dessain SK
• 通讯作者: Dessain SK