Autoimmunity Against Novel Antigens in Neuropsychiatric Dysfunction

神经精神功能障碍中针对新抗原的自身免疫

• 批准号: 8658474
• 负责人: RITA J. BALICE-GORDON
• 金额: $ 32万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658474
• 关键词: AMPA Receptors; Adolescent; Adult; Affect; Antibodies; Antigen Targeting; Antigens; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; Autonomic Dysfunction; Behavior; Biological Assay; Brain; Catatonia; Cell surface; Cells; Cerebrospinal Fluid; Child; Clinical; Collection; Complementary DNA; Confocal Microscopy; Culture Media; Databases; Defect; Diagnostic tests; Disease; Dyskinetic syndrome; Encephalopathies; Etiology; Excision; Functional disorder; Genetic; Glutamate Receptor; Goals; Health; Human; Immune response; Immunoprecipitation; Immunotherapy; In Vitro; Incubated; Infusion procedures; Laboratories; Lead; Mass Spectrum Analysis; Mediating; Memory; Mental disorders; Methods; Modeling; Mus; Mutation; N-Methyl-D-Aspartate Receptors; NR1 gene; Nerve Tissue; Neurologic; Neurologic Manifestations; Neurons; Neurotransmitter Receptor; Ovarian Teratoma; Patients; Peripheral Nerves; Property; Proteins; Psychotic Disorders; Public Health; Refractory; Reporting; Rodent; Role; Sampling; Schizophrenia; Seizures; Serum; Site; Slice; Specimen; Structure; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; Techniques; Testing; Therapeutic Intervention; Voltage-Gated Potassium Channel; Western Blotting; Whole-Cell Recordings; Work; autistic behaviour; contactin; crosslink; density; gamma-Aminobutyric Acid; human LGI1 protein; improved; in vivo; insight; men; neural circuit; neuropsychiatry; novel; protein complex; receptor; research study; synaptic function; tumor; young adult; young woman

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.

描述（由申请人提供）：我们建议表征对神经元细胞表面和突触蛋白的自身免疫反应，这些反应会导致紧张症、自闭症行为和其他神经精神障碍。 2007年，我们报道了一群年轻女性急性出现精神病行为或精神​​分裂症样症状，随后出现记忆缺陷、紧张症、运动异常和自主神经功能障碍。使用我们优化的一套技术，我们发现所有患者都具有针对 N-甲基-D-天冬氨酸受体 (NMDAR) NR1 亚基的抗体，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，免疫反应的触发因素是卵巢畸胎瘤，其中含有表达 NMDAR 的异位神经组织。自该报告发布以来，患有这种疾病的患者数量迅速增加，并且对其他神经精神疾病患者应用类似的临床和实验室策略，发现了针对细胞表面/突触自身抗原的 6 种新的免疫反应，其中包括 GluR1 AMPA 受体 (AMPAR)、GABA(B1) 受体 (GABA(B1)R)、富含亮氨酸的神经胶质瘤失活 1 (LGI1) 和 Contactin 的 /2 亚基相关蛋白 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）它们对免疫疗法有反应； 3）一些抗体定义了新的综合征； 4) 抗原的表征已导致明确的诊断测试； 5) 患者抗体对目标受体/蛋白质的功能具有效价依赖性且可逆的影响。总的来说，这些发现导致了这样的假设：许多病因不明的亚急性精神疾病，包括紧张症或自闭症行为，无论是单独的还是与其他神经系统表现相关，可能是由影响细胞表面或突触位点的神经递质受体的抗体介导的。我们将在 3 个目标中检验这个假设。 (1) 我们将选择患有以下 3 种疾病之一的患者，我们有初步证据表明其血清或脑脊液中有针对细胞表面/突触蛋白的抗体：具有紧张性特征的快速进展性神经精神疾病、儿童和成人获得性快速进展性自闭症行为谱系，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元细胞表面/突触抗原，从而鉴定这3种疾病中的自身抗原； (3)我们将利用体外和体内研究来确定患者针对新型细胞表面/突触抗原的抗体如何影响神经元和突触结构和功能，以及这些抗体在去除后如何恢复。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。自身免疫机制的识别将改善儿童和成人这些疾病的治疗干预措施，这将对健康产生重大影响，并减轻神经系统和神经精神疾病的负担。

项目成果

Autoimmunity, seizures, and status epilepticus.

• DOI: 10.1111/epi.12276
• 发表时间: 2013-09
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Davis R;Dalmau J
• 通讯作者: Dalmau J

Autoimmune encephalitis as differential diagnosis of infectious encephalitis.

自身免疫性脑炎作为感染性脑炎的鉴别诊断。

• DOI: 10.1097/wco.0000000000000087
• 发表时间: 2014-06
• 期刊: Current opinion in neurology
• 影响因子: 4.8
• 作者: Armangue T;Leypoldt F;Dalmau J
• 通讯作者: Dalmau J

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A New Challenging Entity for Consultation-Liaison Psychiatrist.

抗-N-甲基-D-天冬氨酸受体脑炎：咨询联络精神病学家的新挑战。

• 发表时间: 2016
• 期刊: Brain disorders & therapy
• 作者: Maccaferri,GE;Rossetti,AO;Dalmau,J;Berney,A
• 通讯作者: Berney,A

Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis.

• DOI: 10.1002/ana.24195
• 发表时间: 2014-07
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Moscato, Emilia H.;Peng, Xiaoyu;Jain, Ankit;Parsons, Thomas D.;Dalmau, Josep;Balice-Gordon, Rita J.
• 通讯作者: Balice-Gordon, Rita J.

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.

• DOI: 10.1016/s1474-4422(13)70299-0
• 发表时间: 2014-03
• 期刊: The Lancet. Neurology
• 作者: Petit-Pedrol M;Armangue T;Peng X;Bataller L;Cellucci T;Davis R;McCracken L;Martinez-Hernandez E;Mason WP;Kruer MC;Ritacco DG;Grisold W;Meaney BF;Alcalá C;Sillevis-Smitt P;Titulaer MJ;Balice-Gordon R;Graus F;Dalmau J
• 通讯作者: Dalmau J