PRESENCE AND ROLE OF IMMUNE MARKERS IN ALZHEIMER'S BRAIN

PI实验室以前的发现表明：1) 免疫系统的经典标志物，包括IL-2受体，NK， 人类白细胞抗原-DP、人类白细胞抗原-DQ和人类白细胞抗原-DR在人脑中广泛表达； 2)人类白细胞抗原-DR的表达随年龄和阿尔茨海默病的增加而增加 疾病(AD)；3)HLA-DR免疫阳性细胞，包括 推测星形胶质细胞、小胶质细胞和巨噬细胞与 阿尔茨海默病的衰老斑块；4)这些细胞摄取并可能处理的斑块 阿尔茨海默病中异常的淀粉样蛋白；5)这类细胞表面 异常蛋白呈递所需的受体 活化的T细胞的抗原；6)活化的T细胞可以 在AD大脑中发现；以及7)假定的命题 具有脑胶质细胞的T细胞是抗原呈递所必需的，可以 被证明。 本提案体现了一种努力，以证明一项具体的 脑胶质细胞和巨噬细胞作为免疫相关细胞的作用 广泛性神经变性的主要决定因素 AD的特点。这既是一个新的想法，也是一个旧的想法-在 长期以来，人们一直认为大脑胶质细胞和巨噬细胞 参与清除阿尔茨海默病的病理碎片，但 新的信念是，他们可能是在免疫的背景下这样做的。 如果成功，拟议的实验将有助于证明 AD的新致病机制，并可能具有重要的 对其他几种神经紊乱也有影响(例如， 多发性硬化症)，已经有明确的神经免疫相关性。

Previous findings from the PI's laboratory demonstrate: 1) that classic markers of the immune system, including IL-2 receptors, NK, HLA-DP, HLA-DQ, and HLA-DR, are profusely expressed in human brain; 2) that HLA-DR expression increases with age and Alzheimer's disease (AD); 3) that HLA-DR immunopositive cells, including putative astrocytes, microglia, and macrophages, co-localize with the senile plaques of AD; 4) that such cells ingest and may process the abnormal protein amyloid in AD; 5) that such cells bear surface receptors necessary for presentation of abnormal proteins as antigens to activated T cells; 6) that activated T cells can be found in the AD brain; and 7) that the apposition of presumptive T cells with brain glia, necessary for antigen presentation, can be demonstrated. The present proposal embodies an effort to demonstrate a specific immune-related action of brain glia and macrophages as one of the primary determinants of the widespread neural degeneration characteristic of AD. This is both a new and an old idea-old in the sense that brain glia and macrophages have long been presumed to be involved in clearing away the pathologic debris of AD, but new in the belief that they may be doing so in an immune context. If successful, the proposed experiments will help demonstrate a novel pathogenetic mechanism in AD, and could have important implications as well for several other neurologic disorders (e.g., multiple sclerosis) which already have clear neuoimmune correlates.