AUTOANTIBODIES IN ALZHEIMERS DISEASE AND NORMAL AGING

阿尔茨海默病(AD)的病因和发病机制尚未得到证实 已经被清楚地描绘出来了。类似地，完整的分子组成 神经纤维缠结(NFT)和淀粉样斑块 AD的特征仍有待确定。在过去几年中， 已经积累的证据支持了免疫学的观点 一些因素可能在这种疾病中起到一定的作用。我们正在刻画 用单抗检测反应性抗原 外周EBV转化建立的细胞系分泌 阿尔茨海默病及相关疾病患者外周血B细胞的变化自动取消对 β-淀粉样蛋白(β-AP)在淀粉样斑块和体外有 从一名AD患者(MRE)的四个细胞系中鉴定出。在……里面 此外，对编码V/H和V/L的基因进行了测序。 这些自动抗体中的三个是相关的，因为它们具有相同的 编码序列。因此，它们是由共同的B细胞分泌的 先祖。轻、重品种相应的种系基因 已经确定了链V区域和许多核苷酸替换 已在编码这些V区的cDNAs中被证实。他的存在 多个循环中的B细胞分泌相同的自身抗体和高度的 突变的V区增加了对自身抗体反应的支持 β-AP是一个由Ag驱动的过程，尽管尚不确定 β-AP或具有相似结构的另一种抗原是激发免疫原。 具体目的有：1.对猪传染性支气管炎病毒V/H和V/L基因进行序列测定 从患者MRE中提取的与β-AP蛋白有反应的ABS 但与原位的淀粉样斑块无反应。2：要对 编码与NFT等神经结构反应的自身抗体的cDNA.3： 鉴定与JGR80反应的34kD蛋白，并记录 蛋白质在阿尔茨海默病的脑内过度表达。4：确定自动切换是否 抗淀粉样前体蛋白(APP)的其他表位 出现在beta-AP中，并与新描述的非应用程序组件 EB病毒转化的B细胞上清液中存在淀粉样纤维 AD患者和对照组的CD-40系统的建立 进一步培养AD患者和对照组的外周血B细胞以 确定循环B细胞是否存在分泌免疫球蛋白G和 与β-AP和其他感兴趣的自体抗原反应的IgM更为普遍 在AD患者中。拟议的研究将提供新的信息 关于NFT和淀粉样斑块的组成和见解 探讨阿尔茨海默病发病的免疫学因素。

The etiology and the pathogenesis of Alzheimer's disease (AD) have not been clearly delineated. Similarly, the complete molecular composition of the neurofibrillary tangle (NFT) and the amyloid plaque, the pathological hallmarks of AD remain to be determined. During the past several years, evidence has been accumulated to support the thesis that immunological factors may play some role in this disease. We are characterizing the reactive antigens (Ags) detected by monoclonal autoantibodies (auto-Abs) secreted by cell lines established by EBV-transformation of peripheral blood B cells of patients with AD and related disorders. Auto-Abs against beta-amyloid protein (beta-AP) in the amyloid plaques and in vitro have been identified from four cell lines derived from an AD patient (MRE). In addition, it was shown by sequencing the cDNA encoding the V/H and V/L of these auto-Abs that three of them are related because they have identical coding sequences. Thus, they are secreted by B cells from a common progenitor. The corresponding germ line genes of the heavy and light chain V regions have been identified and many nucleotide substitutions have been demonstrated in the cDNA encoding these V regions. The presence of multiple circulating B cells secreting the same auto-Ab and the highly mutated V regions add support to the thesis that the auto-Ab response to beta-AP was an Ag-driven process although it is not certain whether the beta-AP or another Ag with a similar structure is the inciting immunogen. Specific Aims are 1: To sequence the cDNA encoding for the V/H and V/L of Abs from patient MRE, which are reactive with the beta-AP protein in ELISA but non-reactive with the amyloid plaques in situ. 2: To sequence the cDNA encoding auto-Abs reactive with NFT and other neural structures. 3: To identify a 34kD protein reactive with JGR80 and to document that the protein is over-expressed in AD brain. 4: To determine whether auto-Abs against other epitopes of amyloid precursor protein (APP) which are not present in beta-AP, and against the newly described non APP component of amyloid fibrils are present in supernatants of EBV-transformed B cell lines from AD patients and controls, and to develop the CD-40 system further to culture peripheral blood B cells of AD patients and controls to determine whether the presence of circulating B cells secreting IgG and IgM reactive with beta-AP and other auto-Ag of interest is more prevalent in AD patients. The proposed studies will provide new information regarding the composition of the NFT and the amyloid plaque and insights into the immunological factors in the pathogenesis of AD.