Paraneoplastic Disorders of the CNS: Autoantigen Profiling

中枢神经系统副肿瘤性疾病：自身抗原分析

基本信息

批准号：
8516611
负责人：
Josep O. Dalmau
金额：
$ 43.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516611
关键词：
AMPA Receptors Acute Affect Animals Antibodies Antigen Targeting Antigens Ataxia Autoantigens Autoimmune Process Autoimmunity Behavior Blood Tests Catatonia Cell Surface Proteins Cell surface Central Nervous System Diseases Characteristics Child Clinical Clinical Management Cognition Complement Data Dementia Detection Development Diagnosis Diagnostic Diagnostic tests Disease Dyskinetic syndrome Encephalitis Encephalitis Lethargica Etiology Excision Foundations Functional disorder Funding Future Goals Grant Immune Immune response Immunotherapy Incidence Individual Inflammatory Infusion procedures Ion Channel Limbic Encephalitis Location Malignant Neoplasms Mediating Memory Methods Myoclonus N-Methylaspartate Nervous System Paraneoplastic Syndromes Nervous System Physiology Nervous system structure Neurologic Neurologic Symptoms Neurological outcome Neurons Opsoclonus Organ Outcome Patients Proteins Recombinant Proteins Refractory Relapse Research Rodent Schizophrenia Screening for cancer Seizures Serologic tests Serum Subgroup Surface Antigens Synapses Syndrome System Techniques Testing Time Work base clinical Diagnosis clinical practice effective therapy improved in vivo Model medical specialties neoplastic cell nervous system disorder novel receptor response screening synaptic function theories tumor

项目摘要

DESCRIPTION (provided by applicant): The identification of immune responses against neuronal proteins in patients with cancer and neurologic disorders, known as paraneoplastic neurologic disorders (PNDs), has uncovered the existence of antigens shared by some cancers and the nervous system. As part of the immune response patients develop characteristic serum and cerebrospinal antibodies. Detection of these antibodies in a patient with neurologic disease of unknown etiology establishes the diagnosis of PND and focuses the search of the tumor to a few organs. This is important because, 1) in most patients the presence of a cancer is unknown at the time the PND develops, and 2) prompt diagnosis and treatment of the tumor is critical for improving the neurologic outcome. Of all patients suspected of having a PND, only 60% harbor antibodies to known target antigens. The hypothesis of this proposal is that antibody-associated PND are more frequent than believed. We postulate that the current techniques of antibody detection underestimate the true incidence of antibody-associated PND. Moreover, we postulate that some antibody-associated neurological syndromes may occur with or without cancer. To support our hypothesis we developed and validated a highly sensitive strategy for the rapid identification of antibodies in patients previously considered antibody-negative. This resulted in the isolation of 10 novel antibody associated disorders, targeting intracellular proteins and cell surface ion channels or receptors (AMPA, NMDA, GABAB receptors) with critical synaptic functions. While the intracellular antigens are important as surrogate diagnostic markers of PND and specific tumors, the cell surface antigens are notable for 4 reasons: 1) the associated disorders can occur with or without cancer and affect young individuals and children, 2) they are treatment-responsive, 3) the antibodies have direct effects on the target antigens, suggesting they are pathogenic, and 4) some antibodies define new syndromes. These novel antibody/antigen associations not only provide diagnostic tests but also direct the treatment approach. This proposal is an extension of this work and focuses on the comprehensive identification of autoantigens in four disorders: 1) rapidly progressive dementia with CSF inflammatory/autoimmune features, 2) opsoclonus-myoclonus-ataxia, 3) acute encephalitis with dyskinesias, and 4) encephalitis with refractory-relapsing seizures. The long-range goal is to develop autoantigen arrays to facilitate diagnosis and guide therapy. The two specific aims are: 1) To identify autoantigens of PND and similar syndromes using modified highly sensitive methods for the presence of antibodies to intracellular and neuronal cell surface antigens, and 2) To characterize the target synaptic antigens and determine the effects of patients' antibodies on the antigens and synapses in neuronal cultures.

描述（由申请人提供）：在癌症和神经系统疾病患者中鉴定针对神经元蛋白的免疫反应，称为副塑性神经系统疾病（PNDS），已经发现了一些癌症和神经系统共享的抗原的存在。作为免疫反应的一部分，患者会形成特征性的血清和脑脊液抗体。对病因的神经系统疾病患者中这些抗体的检测确定了PND的诊断，并将肿瘤的搜索集中在一些器官上。这很重要，因为1）在PND发展时，大多数患者的癌症存在尚不清楚，而2）及时诊断和治疗肿瘤对于改善神经系统结果至关重要。在所有涉嫌患有PND的患者中，只有60％的患者含有对已知靶抗原的抗体。该提议的假设是，抗体相关的PND比认为的更频繁。我们假设当前的抗体检测技术低估了抗体相关PND的真实发生率。此外，我们假设有或没有癌症的某些抗体相关的神经系统综合症。为了支持我们的假设，我们制定并验证了一种高度敏感的策略，用于快速鉴定以前认为抗体阴性的患者中的抗体。这导致了10种新型抗体相关疾病的分离，靶向具有关键的突触功能的细胞内蛋白和细胞表面离子通道或受体（AMPA，NMDA，GABAB受体）。虽然细胞内抗原很重要，因为PND和特定肿瘤的替代诊断标志物很重要，但细胞表面抗原值得注意的是4个原因：1）相关疾病可能发生在或没有癌症的情况下并影响年轻人和儿童，2）它们是治疗响应性的，3）抗体对目标抗原具有直接的影响，暗示它们是固定的，以及4）interip somenip somenip somenip，4）。这些新型的抗体/抗原关联不仅提供诊断测试，还提供治疗方法。 This proposal is an extension of this work and focuses on the comprehensive identification of autoantigens in four disorders: 1) rapidly progressive dementia with CSF inflammatory/autoimmune features, 2) opsoclonus-myoclonus-ataxia, 3) acute encephalitis with dyskinesias, and 4) encephalitis with refractory-relapsing seizures.远程目标是开发自身抗原阵列，以促进诊断和指导治疗。这两个具体目的是：1）使用改良的高度敏感方法鉴定PND和类似综合征的自身抗原，以实现对细胞内和神经元细胞表面抗原的抗体的存在，以及2）来表征靶标突触抗原并确定患者对抗抗原和神经元培养基的影响。