Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

青光眼发病机制中的先天免疫和获得性免疫反应 青光眼是全球尚未满足的医学挑战，也是导致不可逆转失明的主要原因。高架 眼压(IOP)是青光眼的主要危险因素；然而，在临床上，它既不是必需的，也不足以 造成神经元损伤。青光眼神经变性的机制尚不完全清楚。 最近，我们提供了第一个令人信服的证据，证明了 青光眼的神经变性。我们在诱导性和遗传性青光眼小鼠模型中都显示了这一点 高眼压导致热休克蛋白(HSPs)上调、视网膜小胶质细胞活化和T细胞 浸润性/热休克蛋白特异性的CD4T细胞反应和视网膜免疫反应是 青光眼中进行性RGC和轴突变性。值得注意的是，在无菌小鼠中，缺乏 HSP特异性T细胞，眼压升高不能诱导小胶质细胞激活，HSP特异性T细胞反应，以及 青光眼神经变性。这些结果有力地支持了眼压升高带来的生理压力。 而不是直接损害视网膜节细胞和轴突；它是压力诱发的事件，可能涉及先天和 导致青光眼神经变性的适应性免疫反应。尚未回答的关键问题是 高眼压如何激活小胶质细胞和T细胞反应以诱导RGC和轴突损伤？ 诱导青光眼小胶质细胞和T细胞反应的分子信号。HSP表达，尤其是当 从细胞中释放出来，已知可以诱导先天和获得性免疫反应。我们假设 高眼压诱导HSP信号，导致小胶质细胞激活和HSP特异性T细胞反应，从而 进而导致青光眼的RGC变性。在本申请中，我们建议对此进行批判性测试 从三个互补的角度提出假设：1)确定HSP信号是否对两者的启动负责 视网膜的先天和获得性免疫反应和诱导青光眼神经变性；2) 研究热休克蛋白是否是驱动青光眼患者T细胞反应的关键致病抗原；以及3)检测 青光眼患者外周血中HSP特异性T细胞可作为诊断或治疗青光眼的生物标志物 青光眼进展的预测。拟议的研究将作为以下方面的合作努力进行 马萨诸塞州眼耳和麻省理工学院的研究人员和青光眼专家 他们拥有互补的专业知识和长期的富有成效的合作历史。澄清： 青光眼神经变性的免疫机制将导致 为了解该病的发病机制和发展机制提供了基础 诊断、预防和治疗。鉴于视网膜长期以来一直是中央神经系统的模型 神经系统方面，拟议的研究也可能为其他神经退行性变的发病机制提供帮助 困扰大脑和脊髓的疾病。

Innate and Adaptive Immune Responses in the Pathogenesis of Glaucoma 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.