AUTOANTIBODIES IN ALZHEIMERS DISEASE AND NORMAL AGING

阿尔茨海默病（Alzheimer's disease，AD）的病因和发病机制尚未完全阐明， 被明确划定。 同样， 神经纤维缠结（NFT）和淀粉样斑块，病理性 AD的特征仍有待确定。 在过去的几年里， 已经积累了大量证据来支持免疫学理论， 某些因素可能在这种疾病中起一定作用。 我们正在描述 通过单克隆自身抗体（自身抗体）检测的反应性抗原（Ag） 由通过外周血淋巴细胞的EBV转化建立的细胞系分泌 AD和相关疾病患者的血液B细胞。 自动抗体 β-淀粉样蛋白（β-AP）在淀粉样斑块和体外有 从源自AD患者（MRE）的四种细胞系中鉴定。 在 此外，通过对编码V-H和V-L的cDNA进行测序， 这些自动Abs，其中三个是相关的，因为它们具有相同的 编码序列 因此，它们由B细胞从共同的 祖先 相应的生殖系基因的重和轻 已经鉴定了V链区域， 已在编码这些V区的cDNA中得到证实。 存在 多种循环B细胞分泌相同的自身抗体， 突变的V区增加了对自体抗体应答的理论的支持， β-AP是一个银驱动的过程，虽然它是不确定的， β-AP或具有类似结构的另一种Ag是激发免疫原。 具体目的是：1.对编码V-H和V-L的cDNA进行测序， 来自患者MRE的Ab，在ELISA中与β-AP蛋白反应 但不与原位淀粉样斑块反应。 2：要对 编码与NFT和其他神经结构反应的自身抗体的cDNA。 第三章： 鉴定与JGR 80反应的34 kD蛋白，并证明JGR 80的免疫反应性与JGR 80的免疫反应性有关。 蛋白在AD脑中过度表达。 4：确定是否自动Abs 针对淀粉样前体蛋白（APP）的其他表位， 存在于β-AP中，并针对新描述的非APP组分， 淀粉样纤维存在于EBV转化的B细胞的上清液中 AD患者和对照的细胞系，并开发CD-40系统 进一步培养AD患者和对照的外周血B细胞， 确定是否存在分泌IgG的循环B细胞， 与β-AP和其他感兴趣的自身抗原反应的IgM更普遍 在AD患者中。 拟议的研究将提供新的信息 关于神经纤维瘤和淀粉样斑块的成分 AD发病机制中的免疫因素。

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.