Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

摘要 在回应PA-20-272呼吁为NIH提供以阿尔茨海默氏症为重点的行政补充时， 赠款不集中在阿尔茨海默病（AD），本申请建议扩大对 现有的奖项（5 R 01 EY 031696 -02），以确定新的发病机制和生物标志物的AD。 目前，对于AD没有确定的治愈或疾病改善治疗，这主要是由于缺乏治疗。 明确疾病的发病机制。眼睛为我们提供了一个了解大脑许多方面的窗口 功能和健康。在AD中观察到广泛的眼部相关并发症。其中包括 视网膜神经节细胞（RGC）的损失和视网膜神经纤维层（RNFL）的变薄， 青光眼的症状新出现的证据也表明， 青光眼和AD。我们最近报道了一种新的免疫成分，涉及全身性T细胞 青光眼发病机制的潜在反应，这意味着一个范式转变的概念， 神经变性我们证明青光眼的慢性神经退行性变与 诱导对热休克蛋白特异性的CD 4 + T辅助1（Th 1）细胞的系统性应答 （HSP）。对神经元的急性损伤和应激，例如与缺血、损伤或升高相关的损伤和应激。 眼内压，引起小胶质细胞活化，启动HSP特异性T细胞反应， 神经元丧失的延长阶段此外，通过本合同（EY 031696）获得的数据 进一步表明，不仅原发性开角型青光眼患者表现出显着增加， 外周血中HSP特异性T细胞的频率与对照组相比，但HSP- 特异性T细胞计数与RNFL变薄相关。这些结果表明， 的系统性T细胞介导的机制，在神经元损伤。越来越多的证据 表明外周活化的CD 4 + T细胞可以进入CNS，血脑屏障完整。 总之，这些都导致了我们的假设的扩展，即类似的免疫机制涉及 青光眼中的全身性T细胞反应是导致AD神经退行性变永久化的原因。因此我们 建议扩展目前的研究，以严格检查HSP特异性Th 1细胞在动物中的作用， 模型和AD患者。我们将问：（1）如果小鼠和人类AD患者表现出增加 与对照组相比，外周血中HSP特异性T细胞频率，以及（2）如果过继转移 从AD小鼠中提取的HSP特异性T细胞的过量会加剧受体小鼠大脑中的AD病理学。的 拟议的研究可能会发现新的见解，AD发病机制，并确定外周血 和血清生物标志物可能导致新的诊断方法，用于筛查AD和/或 监测疾病进展。

ABSTRACT In responding to the PA-20-272 that calls for Alzheimer's-focused administrative supplements for NIH grants that are not focused on Alzheimer's Disease (AD), this application proposes to expand on the existing award (5 R01 EY031696-02) to the identification of novel pathogenesis and biomarkers of AD. There is, at present, no established cure or disease-modifying treatment for AD, largely due to the lack of clear understanding of the disease pathogenesis. The eyes provide a window into many aspects of brain function and health. Extensive eye-related complications have been observed in AD. These include the loss of retinal ganglion cells (RGCs) and thinning of the retinal nerve fiber layer (RNFL), the main cell type affected in glaucoma. Emerging evidence also suggests an overlap between the molecular mechanisms of glaucoma and those of AD. We recently reported a novel immune component involving systemic T cell responses underlying the pathogenesis of glaucoma, that signifies a paradigm shift concept in neurodegeneration. We demonstrated that chronic neurodegeneration in glaucoma is critically associated with the induction of systemic responses of CD4+ T helper 1 (Th1) cells specific to heat shock proteins (HSPs). Acute insults and stress to neurons, such as those associated with ischemia, injury, or elevated intraocular pressure, evoke microglial activation that initiates HSP-specific T cell responses to contribute to a prolonged phase of neuron loss. Moreover, data acquired through the current award (EY031696) showed further that not only patients with primary open angle glaucoma exhibited significantly increased frequencies of HSP-specific T cells in the peripheral blood compared to control subjects, but the HSP- specific T cell counts correlated with the thinning of RNFL. These results demonstrate the human relevance of a systemic T cell-mediated mechanism in glaucomatous neuronal damage. Accumulating evidence showed that peripherally activated CD4+ T cells could enter the CNS with an intact blood-brain-barrier. Together, these have led to the extension of our hypothesis that the similar immune mechanism involving systemic T cell responses in glaucoma is at the play to perpetuate neurodegeneration in AD. We therefore propose to expand the current studies to critically examine the roles of HSP-specific Th1 cells in animal models and human patients with AD. We will ask: (1) if mice and human patients with AD exhibit increased HSP-specific T cell frequencies in the peripheral blood compared to controls, and (2) if adoptive transfer of HSP-specific T cells taken from AD mice exacerbates AD pathology in the recipient mouse brains. The proposed studies may uncover novel insights into AD pathogenesis, and identification of peripheral blood and serum biomarkers may lead to new diagnostic method for screening individuals at risk for AD and/or monitoring disease progression.