Autoimmunity Against Novel Antigens in Neuropsychiatric Dysfunction

描述(由申请人提供)：我们建议描述导致紧张症、自闭症行为和其他神经精神障碍的神经细胞表面和突触蛋白的自身免疫反应。2007年，我们报告了一组年轻女性，她们急性地发展出精神病行为或精神分裂样症状，随后出现记忆缺陷、紧张症、异常运动和自主神经功能障碍。使用一套我们优化的技术，我们发现所有患者都有针对N-甲基-D-天冬氨酸受体(NMDAR)NR1亚单位的抗体，NMDAR是一种参与突触传递和可塑性的谷氨酸受体。在大约60%的患者中，触发免疫反应的是卵巢畸胎瘤，其中含有表达NMDAR的异位神经组织。自那份报告以来，这种疾病的患者数量迅速增加，类似的临床和实验室策略应用于其他神经精神疾病患者，已发现6种针对细胞表面/突触自身抗原的新免疫反应，其中包括AMPA受体(AMPAR)的GluR1/2亚单位、GABA(B1)受体(GABA(B1)R)、富含亮氨酸的胶质瘤灭活1(LGI1)和联系相关蛋白2(Caspr2)。这项工作意义重大，因为：1)这些疾病影响年轻人，包括患有或不患有肿瘤的男性和儿童；2)他们对免疫治疗有反应；3)一些抗体定义了新的综合征；4)抗原的特征导致了明确的诊断测试；以及5)患者抗体对目标受体/蛋白质的功能具有效价依赖和可逆的影响。总体而言，这些发现导致了一种假设，即许多原因不明的亚急性精神障碍，包括紧张症或自闭症行为，无论是单独还是与其他神经系统表现相关，都可能是由影响细胞表面或突触位置的神经递质受体的抗体介导的。我们将在3个目标中检验这一假设。(1)我们将选择以下三种疾病中的一种：具有紧张性特征的快速进展性神经精神障碍、儿童和成人后天快速进行性自闭症行为谱以及儿童和青少年的边缘脑病。(2)我们将使用我们开发和优化的高灵敏度方法来检测神经细胞表面/突触抗原，从而确定这三种疾病中的自身抗原；以及(3)我们将使用体外和体内研究来确定患者针对新的细胞表面/突触抗原的抗体如何影响神经元和突触的结构和功能，以及抗体去除后这些抗体如何恢复。我们将建立导致紧张症、自闭症特征和边缘脑病的自身免疫过程以及潜在的细胞和突触机制。确定自身免疫机制将改善儿童和成人的这些疾病的治疗干预措施，这将对健康产生重大影响，并减轻神经和神经精神疾病的负担。 公共卫生相关性：我们建议对表现为紧张性特征的快速进行性神经精神障碍、儿童和成人后天快速进行性自闭症行为谱以及儿童和青少年边缘脑病的患者进行筛查，以确定是否存在自身免疫过程。我们推测，这些病因不明的亚急性精神障碍，单独发生或与神经系统表现相关，可能是由抗体介导的，这些抗体影响细胞表面或突触蛋白，导致电路功能障碍。我们将在这三种疾病中检验这一假设，因为我们有初步证据表明，患者的血清或脑脊液中含有针对细胞表面/突触蛋白的抗体。实现我们提出的目标将从根本上为自身免疫过程在这些症状中的作用提供新的见解，并揭示潜在的细胞、突触和电路机制。我们的工作可能会为这些对公共健康有重大影响的神经精神障碍带来治疗干预的新途径。

DESCRIPTION (provided by applicant): We propose to characterize the autoimmune responses to neuronal cell surface and synaptic proteins that result in catatonia, autistic behaviors and other neuropsychiatric disturbances. In 2007, we reported a group of young women who acutely developed psychotic behavior or schizophrenia-like symptoms, subsequently followed by memory defects, catatonia, abnormal movements, and autonomic dysfunction. Using a set of techniques that we optimized, we found that all patients had antibodies against the NR1 subunit of the N- methyl-D-aspartate receptor (NMDAR), a glutamate receptor involved in synaptic transmission and plasticity. In about 60% of these patients, the trigger of the immune response was an ovarian teratoma that contained ectopic nervous tissue expressing NMDAR. Since that report, the number of patients with this disorder has rapidly increased, and similar clinical and laboratory strategies applied to patients with other neuropsychiatric disorders have resulted in the discovery of 6 novel immune responses to cell surface/synaptic autoantigens, including among others the GluR1/2 subunits of the AMPA receptor (AMPAR), the GABA(B1) receptor (GABA(B1)R), Leucine rich glioma inactivated 1 (LGI1) and Contactin associated protein 2 (Caspr2). This work is significant because: 1) the disorders affect young adults, including men and children with or without tumors; 2) they are responsive to immunotherapy; 3) some antibodies define new syndromes; 4) the characterization of the antigens has resulted in unambiguous diagnostic tests; and 5) patient antibodies have titer dependent and reversible effects on the function of the target receptors / proteins. Overall, these findings have led to the hypothesis that many subacute psychiatric disorders of unknown etiology, including catatonia or autistic behaviors, either alone or in association with other neurologic manifestations, are likely mediated by antibodies that affect neurotransmitter receptors at cell surface or synaptic sites. We will test this hypothesis in 3 goals. (1) We will select patients with one of 3 disorders for which we have preliminary evidence of serum or CSF antibodies to cell surface/synaptic proteins: rapidly progressive neuropsychiatric disorders with catatonic features, the spectrum of acquired rapidly progressive autistic behavior in children and adults, and limbic encephalopathy in children and adolescents. (2) We will identify the autoantigens in these 3 disorders, using highly sensitive methods we have developed and optimized to detect neuronal cell surface / synaptic antigens; and (3) We will use in vitro and in vivo studies to determine how patients' antibodies against novel cell surface/synaptic antigens affect neuron and synaptic structure and function, and how these recover after antibodies are removed. We will establish the autoimmune processes that lead to catatonia, autistic features, and limbic encephalopathy and the underlying cellular and synaptic mechanisms. Identification of autoimmune mechanisms will result in improved therapeutic interventions for these disorders in children and adults that will have a significant health impact and reduce the burden of neurological and neuropsychiatric disease. PUBLIC HEALTH RELEVANCE: We propose to screen patients presenting with rapidly progressive neuropsychiatric disorders with catatonic features, the spectrum of acquired rapidly progressive autistic behavior in children and adults, and limbic encephalopathy in children and adolescents, for the presence of autoimmune processes. We hypothesize that these subacute psychiatric disorders of unknown etiology, that occur alone or in association with neurologic manifestations, are likely mediated by antibodies that affect cell surface or synaptic proteins, leading to circuit dysfunction. We will test this hypothesis in these 3 disorders because we have preliminary evidence that patients' serum or cerebrospinal fluid contain antibodies to cell surface/ synaptic proteins. Achieving the goals we propose will provide fundamentally new insights into the role of autoimmune processes in these symptoms and reveal the underlying cellular, synaptic and circuit mechanisms. Our work will likely lead to novel avenues for therapeutic intervention in these neuropsychiatric disorders that have a significant public health impact.