AUTOANTIBODIES IN ALZHEIMER' S DISEASE AND NORMAL AGING

我的实验室积累了相当多的经验，可以使用 免疫学方法研究黄连化学成分 神经原纤维缠结是老年性阿尔茨海默病的主要病变 键入(SDAT)。最近，我们用Epstein建立了563个B细胞系 4例非霍奇金淋巴瘤患者血液中巴尔病毒(EBV)转化 SDAT的临床诊断。免疫荧光法和免疫荧光法初步研究 ABC免疫细胞化学显示，其中一些细胞系分泌 与神经原纤维缠结和其他神经元反应的自身抗体 组件。这是第一批已被证实的自身抗体。 对神经纤维缠结有反应。我们希望测试一下 认为自身免疫在慢性粒细胞白血病发病机制中起一定作用的假说 SDAT和利用自身抗体进一步探索其组成 神经原纤维缠结。提出了五个具体目标。(1) 年龄匹配的SDAT患者EB病毒转化B细胞株的建立 正常对照组、卒中后患者和正常青年个体。这些 实验意在确定特异性自身抗体的频率。 神经元、神经原纤维缠结和相关结构的选择性群 在这四组中。SDAT患者特有的自身抗体也将是 下定决心。(2)克隆有趣的分泌自身抗体的细胞系 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抗 孤立的神经原纤维缠结。特定于纠缠的将是 确定并用于与人类的研究进行比较 来自SDAT患者的自身抗体。(4)建立EBV转化B细胞 来自SDAT患者配偶和未受影响的成员的细胞系 选定有家族SDAT病史的家庭。演示了 家庭成员感兴趣的自身抗体将提供线索 环境因素与遗传因素在SDAT中的相对重要性。(5)制造 小鼠或大鼠抗人独特型单抗 神经原纤维特异性自身抗体或优先与其反应的自身抗体 缠结和相关结构。这些抗V区的单抗 将被用来对SDAT患者的尸检脑进行染色，试图 显示病变内有特异性免疫球蛋白沉积，即老年斑。 这种方法将为这些因素的作用提供直接证据 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 AS的发病机制和诊断的信息 并为重大可能的新治疗方法提供了理论基础。

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.