Defining the epitope in anti-AMPA receptor encephalitis

描述（由申请人提供）：谷氨酸是中枢神经系统中主要的兴奋性递质，不仅对于突触传递至关重要，而且对于突触可塑性和基因表达控制等长期神经元变化也至关重要。谷氨酸的许多作用是通过特定受体 N-甲基-D-天冬氨酸受体 (NMDAR) 发挥的，它控制第二种谷氨酸受体 - α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 的运输。最近，我们与 Josep Dalmau 博士合作，发现了两种不同的脑炎综合征，一种综合征与 NMDAR 抗体直接相关，另一种综合征与 AMPAR 抗体直接相关。在抗 AMPAR 脑炎中，受试者表现出与 AMPAR 功能减退时预计会发生的症状类似的症状（健忘症、癫痫发作）。然而，某些个体可以通过肿瘤切除或血浆置换来治疗该综合征，这表明该综合征是由抗体直接介导的。患有这种综合征的患者会产生针对 AMPAR 亚基 GluR1 和/或 GluR2 的细胞外部分的抗体。我们的新初步数据已经确定了 GluR1/2 氨基末端结构域 (ATD) 中的结构决定因素，这些结构决定因素对于患者抗 AMPAR 抗体的免疫反应是必需的。我们还使用来自这些区域的融合蛋白来证明免疫反应的多样性，并识别出可能患有抗 AMPAR 脑炎且通过之前的方法检测呈阴性的个体。在本提案中，我们将继续创建新的工具来研究患者的抗 AMPAR 抗体，以评估这种综合征是否被严重低估，并将病理生理学与特定的 AMPAR 部分联系起来。首先，我们将在来自一大群潜在脑炎个体的样本中测试抗 AMPAR 抗体和针对 AMPAR 上特定结构决定因素的抗体的存在。然后，我们将结果与受试者的临床特征相关联，并确定抗 AMPAR 脑炎的病理生理机制是否是通过特定表位介导的。总而言之，这些目标的完成将导致人们更好地了解这种疾病的病理生理机制，开发进一步探索该机制的工具，并有可能创造出抗 AMPAR 脑炎的新治疗方法。

DESCRIPTION (provided by applicant): Glutamate, the major excitatory transmitter in the central nervous system, is crucial not only for synaptic transmission but also for long-term neuronal changes such as synaptic plasticity and control of gene expression. Many of the actions of glutamate are exerted through a specific receptor, the N-methyl-D- aspartate receptor (NMDAR), which controls the trafficking of a second glutamate receptor, the a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR). Recently, in collaboration with Dr. Josep Dalmau, we identified two distinct encephalitic syndromes, associated directly with antibodies to NMDAR in one syndrome and with antibodies to the AMPAR in the other. In antiAMPAR encephalitis, subjects present with symptomatology (amnesia, seizures) analogous to that predicted to occur with AMPAR hypofunction. However, the syndrome can be treated in some individuals by tumor removal or plasmapheresis, suggesting that it is mediated directly by antibodies. Patients with this syndrome make antibodies to the extracellular portion of the AMPAR subunits GluR1 and/or GluR2. Our new preliminary data have identified structural determinants in the amino terminal domain (ATD) of GluR1/2 that are necessary for immunoreactivity to patients' antiAMPAR antibodies. We have also used fusion proteins from these regions to demonstrate diversity in the immune response and to identify individuals with possible antiAMPAR encephalitis who tested negatively by previous approaches. In this proposal we will continue to create new tools for investigation of patients' antiAMPAR antibodies in order to assess whether this syndrome is dramatically under diagnosed, and to link the pathophysiology to specific AMPAR portions First, we will test for the presence of antiAMPAR antibodies and antibodies to specific structural determinants on the AMPAR in samples from a large cohort of individuals with potential encephalitis. We will then correlate the results with clinical features of the subjects and determine whether pathophysiological mechanisms in anti AMPAR encephalitis are mediated through specific epitopes. Cumulatively, completion of these aims will lead to improved understanding of the pathophysiological mechanisms in this disorder, develop tools for further exploration of the mechanisms, and potentially allow creation of novel therapeutic approaches for antiAMPAR encephalitis.