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

基本信息

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
项目类别：
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

项目摘要

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，从而导致Catatonia，自闭症行为和其他神经精神疾病。 2007年，我们报道了一群年轻女性，她们急性发展精神病行为或类似精神分裂症的症状，随后发生记忆缺陷，Catatonia，异常运动和自主功能障碍。使用我们优化的一组技术，我们发现所有患者均对NR1亚基的N-甲基-D-天冬氨酸受体（NMDAR）（NMDAR）（一种参与突触传播和可塑性涉及的谷氨酸受体）的抗体。在这些患者中，大约60％的人是免疫反应的触发因素是卵巢畸胎瘤，其中包含表达NMDAR的异位神经组织。 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神经胶质瘤灭活1（LGI1）和接触蛋白相关蛋白2（CASPR2）。这项工作很重要，因为：1）疾病影响年轻人，包括有或没有肿瘤的男人和儿童； 2）它们对免疫疗法有反应； 3）一些抗体定义了新综合征； 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 /蛋白质功能具有滴度依赖性和可逆作用。总体而言，这些发现导致了以下假设：许多未知病因的亚急性精神疾病，包括catatonia或自闭症行为，无论是单独的还是与其他神经系统表现的相关性，可能都是由影响细胞表面或突触部位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）我们将选择患有三种疾病之一的患者，我们有针对细胞表面/突触蛋白的血清或CSF抗体的初步证据：迅速进行性渐进性神经精神疾病具有息肉性特征，这是儿童和成人以及林木妇女和二氧化二指的儿童和二氧化二胞种症和a夫的患者和二氧化二指的自闭症行为的范围。（2）我们将使用已经开发和优化的高敏感方法来鉴定这三种疾病中的自身抗原，以检测神经元细胞表面 /突触抗原；（3）我们将使用体外和体内研究来确定患者对新型细胞表面/突触抗原的抗体如何影响神经元和突触结构和功能，以及这些抗体如何去除抗体后如何恢复。我们将建立导致Catatonia，自闭症特征以及边缘性脑病以及潜在的细胞和突触机制的自身免疫过程。自身免疫机制的鉴定将改善儿童和成人的这些疾病的治疗干预措施，这些疾病将对健康产生重大影响并减轻神经系统和神经精神病的负担。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。

DOI：
发表时间：
2016
期刊：
Brain disorders & therapy
影响因子：
0
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
影响因子：
0
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