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的主要兴奋性递质，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长期神经元变化也是至关重要的。谷氨酸的许多作用是通过一种特殊的受体--N-甲基-D-天冬氨酸受体(NMDAR)实现的，该受体控制着第二种谷氨酸受体--α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)的转运。最近，我们与Josep Dalmau博士合作，发现了两种不同的脑炎综合征，其中一种与NMDAR抗体直接相关，另一种与AMPAR抗体直接相关。在抗AMPAR脑炎中，出现类似于AMPAR功能减退的症状(健忘症、癫痫发作)的受试者。然而，在一些人中，这种综合征可以通过肿瘤切除或血浆置换来治疗，这表明它直接由抗体介导。患有这种综合征的患者会产生针对AMPAR亚单位GluR1和/或GluR2胞外部分的抗体。我们新的初步数据已经确定了GluR1/2氨基末端结构域(ATD)上的结构决定因素，这些结构决定因素对于患者抗AMPAR抗体的免疫反应是必要的。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。在这项建议中，我们将继续创造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，我们将从一大批潜在脑炎患者的样本中检测抗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相关联，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。总而言之，完成这些目标将有助于更好地理解这种疾病的病理生理机制，开发进一步探索机制的工具，并有可能创造出抗AMPAR脑炎的新治疗方法。 公共卫生相关性：该提案阐述了抗体导致神经功能障碍的机制，这种疾病被称为抗AMPA受体脑炎。通过对这一过程的理解，该提案可能有助于预防这种疾病和其他形式脑炎的损害的治疗。它还将提供工具来研究人类记忆丧失的机制。

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. PUBLIC HEALTH RELEVANCE: The proposal addresses the mechanisms by which antibodies cause neurological dysfunction in the disorder known as anti-AMPA receptor encephalitis. Through understanding of this process, the proposal may facilitate therapies for preventing damage in this disorder and other forms of encephalitis. It will also provide tools to investigate mechanisms of memory loss in people.