Mechanisms by which NMDA receptor antibodies mediate a novel autoimmune disease

描述（由申请人提供）：当对肿瘤的免疫反应与神经系统中的蛋白质交叉反应，导致神经元功能改变时，出现神经副肿瘤综合征。最近，我们的实验室与Josep Dalmau博士（宾夕法尼亚大学医院神经内科）的实验室合作，帮助鉴定了一种新的副肿瘤综合征，抗n -甲基- d -天冬氨酸受体（a- nmdar）脑炎。这种综合征发生在表达NMDARs的畸胎瘤患者身上，然后出现各种神经系统问题，包括健忘症、精神病和自主神经窘迫。我们在3年内发现了40多名患者，表明这种疾病经常未得到诊断和治疗，可能导致自主神经不稳定死亡。患者恢复血浆置换，表明抗体参与。虽然我们之前已经表明这些患者产生a-NMDA受体抗体，但尚不清楚这些抗体如何介导这种表型。NMDAR功能减退曾被认为与精神分裂症的发病机制有关；基于临床现象的相似性，对其进行了分析

DESCRIPTION (provided by applicant): Neural paraneoplastic syndromes arise when an immune response to a tumor cross reacts with a protein in the nervous system, causing alterations of neuronal function. Recently, our laboratory in collaboration with the laboratory of Dr. Josep Dalmau (Department of Neurology, Hospital of the University of Pennsylvania) has helped characterize a new paraneoplastic syndrome, anti-N-methyl-D-aspartate receptor (a-NMDAR) encephalitis. This syndrome develops in patients with teratomas that express NMDARs, who then present with a variety of neurological problems including amnesia, psychosis, and autonomic distress. We have found over 40 patients in 3 years, indicating that this disorder frequently goes undiagnosed and untreated, probably resulting in death from autonomic instability. Patients recover with plasmapheresis, indicating antibody involvement. While we have previously shown that these patients make a-NMDA receptor antibodies, it is unclear how these antibodies mediate this phenotype. NMDAR hypofunction has previously been implicated in the pathogenesis of schizophrenia; based on the similarities of the clinical phenomena, it is possible that a-NMDAR encephalitis represents an autoimmune disorder that mimics the neurological changes occurring in schizophrenia. I propose to investigate the mechanisms by which NMDAR antibodies trigger these neurological problems, which may provide broader insights into the general mechanisms of schizophrenia. To do so, I will use whole-cell patch clamp and Ca2+ imaging to determine if these antibodies have a direct effect on channel function. These antibodies could also change in the number of channels on the cell surface or the location of those channels, possibly by disrupting an interaction with an anchoring protein. I will examine this possibility with cell-surface labeling techniques, primarily biotinylations. Finally, I will map the main immunogen of the receptor by transfecting HEK293 cells with mutant NMDAR subunits that are missing portions of the receptor, as well as chimeric receptors. Finding the epitope could help develop an immunodiagnostic test, preventing unnecessary deaths. PUBLIC HEALTH RELEVANCE: One of the major theories of the cause of schizophrenia is hypofunction of the NMDA receptor. Anti-NMDAR encephalitis, therefore, in which individuals make antibodies to the NMDAR that then cause psychological symptoms similar to schizophrenia, presents a unique opportunity for studying the specific contribution of this receptor. In addition to this possible mechanistic connection to schizophrenia, however, this disease was only recently discovered and seems to frequently go undiagnosed and therefore untreated. Developing a better test for this condition, which this research could help do, would help solve this problem.