Defining the epitope in anti-AMPA receptor encephalitis

描述（申请人提供）：谷氨酸是中枢神经系统中主要的兴奋性递质，不仅对突触传递至关重要，而且对突触可塑性和基因表达控制等神经元的长期变化也至关重要。谷氨酸的许多作用是通过一个特定的受体，n -甲基- d -天冬氨酸受体（NMDAR）发挥作用，该受体控制第二种谷氨酸受体，a-氨基-3-羟基-5-甲基-4-异氧唑丙酸受体（AMPAR）的运输。最近，我们与Josep Dalmau博士合作，确定了两种不同的脑病综合征，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功能减退类似的症状（健忘症、癫痫发作）。然而，该综合征在一些个体中可以通过肿瘤切除或血浆置换治疗，这表明它是由抗体直接介导的。这种综合征的患者产生针对AMPAR亚基GluR1和/或GluR2的细胞外部分的抗体。我们新的初步数据已经确定了GluR1/2的氨基末端结构域（ATD）的结构决定因素，这是对患者抗ampar抗体的免疫反应所必需的。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，并识别先前方法检测为阴性的可能患有抗ampar脑炎的个体。在本提案中，我们将继续创建新的工具来调查患者的抗AMPAR抗体，以评估该综合征是否明显未被诊断，并将病理生理学与特定的AMPAR部分联系起来。首先，我们将测试来自潜在脑炎个体的大量样本中抗AMPAR抗体和AMPAR上特定结构决定因素的抗体的存在。然后，我们将把结果与受试者的临床特征联系起来，并确定抗AMPAR脑炎的病理生理机制是否通过特定的表位介导。总的来说，这些目标的完成将导致对这种疾病的病理生理机制的更好理解，为进一步探索机制开发工具，并有可能创造抗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.