Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

先天性和适应性免疫应答在青光眼发病中的作用 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。昏迷性神经退行性变的机制还不完全清楚。 最近，我们提供了第一个令人信服的证据，证明了免疫机制的基础， 青光眼的神经变性我们在诱导型和遗传性肿瘤小鼠模型中发现， 升高的IOP诱导热休克蛋白（HSPs）、视网膜小胶质细胞活化和T细胞活化， 浸润/HSP特异性CD 4 + T细胞应答和视网膜免疫应答是 青光眼中的进行性RGC和轴突变性。值得注意的是，在无菌小鼠中， 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， 昏迷性神经变性。这些结果有力地支持了IOP升高是一种物理应激 而不是对RGCs和轴突的直接损伤;这是压力诱发的事件，可能涉及先天和先天性的， 适应性免疫反应导致昏迷性神经变性关键的未解之谜是 眼压升高如何激活小胶质细胞和T细胞反应以诱导RGC和轴突损伤， 青光眼中诱导小胶质细胞和T细胞反应的分子信号。HSP表达，特别是当 已知从细胞释放的抗体可诱导先天性和适应性免疫应答。我们假设 升高的IOP诱导HSP信号传导，导致小胶质细胞活化和HSP特异性T细胞应答， 进而导致青光眼中RGC变性。在本申请中，我们提出对此进行批判性测试。 假设从三个互补的角度：1）确定HSP信号传导是否负责启动 视网膜中的先天性和适应性免疫反应并诱导神经退行性疾病; 2） 研究热休克蛋白是否是青光眼中驱动T细胞应答的关键致病抗原;以及3）测试 青光眼患者外周血中的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： 马萨诸塞州眼耳和马萨诸塞州眼耳研究所的研究人员和青光眼专家说， 他们拥有互补的专业知识和悠久的生产合作历史。阐明 昏迷性神经退行性变的免疫机制将导致 了解疾病的发病机理，为制定机理型提供依据 诊断、预防和治疗。鉴于视网膜长期以来一直被用作中枢神经系统的模型， 神经系统，拟议的研究也可能揭示其他神经退行性疾病的发病机制， 折磨大脑和脊髓的疾病。

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.