Anti-NMDA receptor antibodies from patients with limbic encephalitis

边缘叶脑炎患者的抗 NMDA 受体抗体

基本信息

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
项目类别：
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

项目摘要

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

项目摘要：抗NMDA受体脑炎是一种潜在的致命性脑炎，归因于自身抗体针对N- 甲基-D-天冬氨酸受体（NMDAR）。患有抗NMDAR脑炎的患者患有精神病和认知症状，然后发展为严重的神经功能障碍，包括癫痫发作，异常运动，意识受损和自主不稳定，经常需要机械通气。在症状严重程度，治疗的患者可以大量康复减少抗NMDAR抗体的滴度的免疫抑制疗法。尽管相关性很强在患者抗NMDAR抗体和临床综合征之间，抗NMDAR的致病作用该疾病中的抗体尚未确定。同样，抗NMDAR抗体的作用关于神经元的知识不完全理解。确定研究的主要障碍是缺乏从患者克隆的纯抗NMDAR抗体。事先的研究仅限于可从患者血清中获得的多克隆抗体的数量有限， CSF。从患者获得的单克隆抗NMDAR抗体首次允许示范据信抗NMDAR脑炎的病理生理事件可归因于仅NMDAR抗体。这些抗体将能够研究它们如何影响谷氨酸能信号传导大脑，促进抗NMDAR脑炎动物模型的发展，并允许结构建模抗体-NMDAR复合物的构成，然后可以指导靶向疗法的设计。我们的假设是，在抗NMDAR脑炎中，NMDAR细胞外区域的抗体导致受体在神经元上的内在化，导致NMDAR功能低下。我们的主要目标是测试通过克隆抗NMDAR脑炎患者的克隆抗体的假设并使用它们来理解这种疾病的特性。我们将从抗NMDAR脑炎患者那里收集B细胞，克隆其抗体，并表征其NMDAR结合特性以及对受体功能的影响。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。他们将在动物模型和结构上为确定性实验奠定基础研究描述与疾病相关免疫复合物的分子结构的研究。 1

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

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