Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

青光眼是全球未解决的医学挑战，也是导致不可逆失明的主要原因。升高 眼内压（IOP）是青光眼的主要危险因素;然而，临床上既不需要也不足以 导致神经元损伤。昏迷性神经变性的机制还不完全清楚， 明白最近，我们提供了第一个令人信服的证据，证明免疫机制 青光眼的潜在神经变性我们发现在诱导型和遗传性肿瘤中 升高IOP的小鼠模型诱导热休克蛋白（HSP）、视网膜小胶质细胞（RGCs） 活化和T细胞浸润/HSP特异性CD 4 + T细胞应答，视网膜免疫应答是免疫应答的主要机制。 青光眼中进行性RGC和轴突变性的驱动力。值得注意的是，在无菌小鼠中， 缺乏HSP特异性T细胞，IOP升高未能诱导小胶质细胞活化，HSP特异性T细胞 反应和昏迷性神经变性。这些结果强烈支持IOP升高是一种 物理应激而不是对RGC和轴突的直接损伤;它是应激诱发的事件，可能涉及 先天性和适应性免疫反应导致神经退行性疾病。关键 尚未回答的问题是升高的IOP如何激活小胶质细胞和T细胞反应以诱导RGC， 轴突损伤以及青光眼中诱导小胶质细胞和T细胞反应的分子信号是什么。 HSP的表达，特别是当从细胞中释放时，已知可诱导先天性和适应性免疫。 应答我们假设眼压升高诱导HSP信号传导，导致小胶质细胞活化和HSP-1表达。 特异性T细胞反应，这反过来又导致青光眼中的RGC变性。在本申请中，我们 我建议从三个互补的角度来批判性地检验这一假设：1）确定HSP信号是否是 负责启动视网膜中的先天性和适应性免疫反应并诱导视网膜水肿。 2）研究HSP是否是驱动神经退行性疾病中T细胞应答的关键致病抗原; 青光眼;和3）测试青光眼患者外周血中HSP特异性T细胞的水平是否可以 用作诊断或预测青光眼进展的生物标志物。拟议的研究将在 这是马萨诸塞州眼耳中心的研究人员和青光眼专家共同努力的结果 和马萨诸塞州理工学院，他们有互补的专业知识和悠久的历史， 富有成效的合作。阐明昏迷性神经变性的免疫机制将 导致对疾病发病机制的理解的范式转变，并为 发展基于机制的诊断、预防和治疗。鉴于视网膜长期以来 作为中枢神经系统的模型，拟议的研究也可能揭示 其他神经退行性疾病的发病机制困扰大脑和脊髓。

Glaucoma is a globally unmet medical challenge and a leading cause of irreversible blindness. Elevated intraocular pressure (IOP) is a major risk factor of glaucoma; yet, clinically it is neither required nor sufficient to cause neuronal damage. The mechanisms underlying glaucomatous neurodegeneration are not fully understood. Recently, we have provided the first convincing evidence demonstrating an immune mechanism underlying neurodegeneration in glaucoma. We showed in both the inducible and inherited glaucomatous mouse models that elevated IOP induced upregulation of heat shock proteins (HSPs), retinal microglial activation and T cell infiltration/HSP-specific CD4+ T cell responses and that retinal immune responses are the driving force for progressive RGC and axon degeneration in glaucoma. Remarkably, in germ free mice, which are deficient in HSP-specific T cells, IOP elevation failed to induce microglial activation, HSP-specific T cell responses, and glaucomatous neurodegeneration. These results strongly support that elevated IOP presents a physical stress rather than direct damage to RGCs and axons; it is the stress-evoked events, likely involving both innate and adaptive immune responses that cause glaucomatous neurodegeneration. The key unanswered questions are how elevated IOP activates microglia and T cell responses to induce RGC and axon damage and what are the molecular signals that induce microglial and T cell responses in glaucoma. HSP expression, especially when released from the cell, is known to induce both innate and adaptive immune responses. We hypothesize that elevated IOP induces HSP signaling, leading to microglial activation and HSP- specific T cell responses, which in turn cause RGC degeneration in glaucoma. In the present application, we propose to critically test this hypothesis from three complementary angles: 1) to determine if HSP signaling is responsible for initiating both innate and adaptive immune responses in the retina and inducing glaucomatous neurodegeneration; 2) to investigate if HSPs are key pathogenic antigens driving T cell responses in glaucoma; and 3) to test if levels of HSP-specific T cells in the peripheral blood of patients with glaucoma can serve as biomarkers for diagnosis or predication of glaucoma progression. The proposed studies will be carried out as a collaborative effort among investigators and glaucoma specialist at the Massachusetts Eye and Ear and Massachusetts Institute of Technology, who have complementary expertise and a long history of productive collaboration. Elucidation of the immune mechanisms in glaucomatous neurodegeneration would lead to a paradigm shift in the understanding of the disease pathogenesis and provide a basis for the development of mechanism-based diagnosis, prevention and treatments. Given that the retina has long been served as a model for the central nervous system, the proposed studies may also shed light on the pathogenesis of other neurodegenerative disorders afflicting the brain and spinal cord.