AUTOANTIBODIES IN ALZHEIMER' S DISEASE AND NORMAL AGING

阿尔茨海默病和正常衰老中的自身抗体

• 批准号: 3117336
• 负责人: FELICIA GASKIN
• 金额: $ 13.47万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-12-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3117336
• 关键词: Alzheimer's disease; B lymphocyte; Downs syndrome; aging; antigens; astrocytes; autoantibody; cell line; cholinergic receptors; clone cells; dementia; enzyme linked immunosorbent assay; human tissue; immunoglobulin G; immunoprecipitation; laboratory mouse; monoclonal antibody; multiple sclerosis; neurofibrillary tangles; neurons; western blottings

Considerable experience has been accumulated in my laboratory to use immunological approaches to study the chemical composition of neurofibrillary tangles, a major lesion in senile dementia of Alzheimer type (SDAT). Recently, we have established 563 B cell lines by Epstein Barr Virus (EBV) transformation from the blood of four patients with a clinical diagnosis of SDAT. Preliminary studies by immunofluorescence and ABC immunocytochemistry show that some of these cell lines secrete autoantibodies reactive with neurofibrillary tangles and other neuronal components. These represent the first autoantibodies which have been shown to be reactive with neurofibrillary tangles. We wish to test the hypothesis that autoimmunity plays a certain role in the pathogenesis of SDAT and to utilize the autoantibodies to explore further the composition of neurofibrillary tangles. Five specific aims are proposed. (1) Establish EBV transformed B cell lines from patients with SDAT, age-matched normal controls, post-stroke patients and normal young individuals. These experiments intend to ascertain frequencies of autoantibodies specific for selective groups of neurons, neurofibrillary tangles and related structures in these four groups. Autoantibodies unique to SDAT patients will also be determined. (2) Clone interesting cell lines which secrete autoantibodies and identify their reactive antigens with established immunocytochemical and serological approaches. (3) Make mouse or rat monoclonal antibodies to isolated neurofibrillary tangles. Those specific for tangles will be identified and used for comparison with studies with the human autoantibodies derived from SDAT patients. (4) Establish EBV transformed B cell lines from spouses of SDAT patients and from unaffected members of selected families with a history of familial SDAT. The demonstration of autoantibodies of interest in family members will provide clues to the relative importance of environmental vs genetic factors in SDAT. (5) Make mouse or rat monoclonal anti-idiotypic antibodies against human autoantibodies specific for or preferentially reactive with neurofibrillary tangles and related structures. These monoclonal anti-V region antibodies will be used to stain autopsied brain from SDAT patients in an attempt to demonstrate specific Ig depositation in the lesions, i.e. senile plaques. This approach will provide direct evidence for the role of these autoantibodies in the pathogenesis of SDAT. The proposed studies will provide information regarding the pathogenesis and diagnosis of SDAT as well as a rationale for significant possible new therapeutic approaches.

在我的实验室里积累了相当多的经验， 免疫学方法来研究化学成分 神经元缠结是Alzheimer病的主要损害 类型（SDAT）。 最近，我们建立了563 B细胞系， 从四名患有急性白血病的患者的血液中检测到巴尔病毒（EBV）转化。 SDAT的临床诊断 通过免疫荧光和 ABC免疫细胞化学显示，其中一些细胞系分泌 与神经元缠结和其他神经元缠结反应的自身抗体 件. 这些代表了第一个自身抗体， 对神经系统缠结有反应 我们希望测试 假设自身免疫在发病机制中起一定作用， SDAT，并利用自身抗体进一步探讨其组成 神经系统缠结 提出了五个具体目标。 （一） 从年龄匹配的SDAT患者中建立EBV转化的B细胞系 正常对照组、中风后患者和正常青年个体。 这些 实验旨在确定特异性自身抗体的频率， 神经元、神经纤维缠结和相关结构的选择性组 在这四个组中。 SDAT患者特有的自身抗体也将被 测定 (2)克隆分泌自身抗体的感兴趣的细胞系 并用已建立的免疫细胞化学方法鉴定其反应性抗原 和血清学方法。 (3)制备小鼠或大鼠的单克隆抗体， 孤立的神经系统缠结 那些具体的缠结将是 确定并用于与人类研究进行比较 来自SDAT患者的自身抗体。 (4)建立EBV转化B 来自SDAT患者配偶和来自未受影响成员的细胞系 选择有家族性SDAT病史的家族。 的示范 家庭成员中感兴趣的自身抗体将提供线索， SDAT中环境因素与遗传因素的相对重要性。 (5)使 鼠抗人抗独特型单克隆抗体 特异性或优先反应性自身抗体 缠结和相关结构。 这些单克隆抗V区抗体 将用于染色SDAT患者的尸检大脑， 证实了病变即老年斑中的特异性IG沉积。 这种方法将为这些作用提供直接证据。 自身抗体在SDAT发病机制中的作用。 拟议的研究将 提供有关SDAT的发病机制和诊断的信息， 以及重要的可能的新治疗方法的基本原理。