Innate and Adaptive Immunity in the Pathogenesis of Glaucoma

青光眼发病机制中的先天性和适应性免疫

• 批准号: 10584665
• 负责人: Dong Feng Chen
• 金额: $ 18.13万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584665
• 关键词: Affect; Antigens; Automobile Driving; Axon; Biological Markers; Blindness; Brain; CD4 Positive T Lymphocytes; Cells; Clinical; Collaborations; Development; Diagnosis; Diagnostic; Disease; Ear; Event; Eye; Eye diseases; Germ-Free; Glaucoma; Heat shock proteins; Immune; Immune response; Inherited; Institutes; Lead; Light; Massachusetts; Medical; Microglia; Modeling; Molecular; Mus; Natural Immunity; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathogenicity; Patients; Persons; Physiologic Intraocular Pressure; Prevention; Recording of previous events; Research Personnel; Retina; Risk Factors; Signal Transduction; Signaling Protein; Specialist; Spinal Cord; Stress; T cell response; T-Lymphocyte; Technology; Testing; Tumor-infiltrating immune cells; Up-Regulation; adaptive immune response; adaptive immunity; axon injury; axonal degeneration; base; driving force; mouse model; peripheral blood; protein expression

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.

青光眼是全球未满足的医学挑战，也是不可逆转的失明的主要原因。高架 眼内压（IOP）是青光眼的主要危险因素。但是，从临床上讲，既不需要 导致神经元损害。青光眼神经变性的基础机制并非完全 理解。最近，我们提供了第一个令人信服的证据，证明了免疫机制 青光眼中的基本神经变性。我们在诱导和遗传的青光眼中展示了 升高IOP诱导热激蛋白（HSP）上调的小鼠模型，视网膜小胶质细胞 激活和T细胞浸润/HSP特异性CD4+ T细胞反应，视网膜免疫反应是 促进性RGC和青光眼中轴突变性的驱动力。值得注意的是，在无细菌的小鼠中 IOP升高缺乏HSP特异性T细胞，无法诱导小胶质细胞激活，HSP特异性T细胞 反应和青光眼神经变性。这些结果强烈支持IOP提升 身体压力，而不是直接损害RGC和轴突；这是压力诱发的事件，可能涉及 固有和适应性免疫反应引起青光眼神经退行性反应。钥匙 未解决的问题是IOP升高如何激活小胶质细胞和T细胞反应诱导RGC和 轴突损伤以及诱导小胶质细胞和T细胞反应的分子信号是什么。 HSP表达，尤其是从细胞释放时，已知可以诱导先天和适应性免疫 回答。我们假设IOP升高会诱导HSP信号传导，导致小胶质细胞激活和HSP- 特异性T细胞反应，进而导致青光眼的RGC变性。在本应用程序中，我们 提议从三个互补角度批判性检验这一假设：1）确定HSP信号是否为 负责在视网膜中引发先天和适应性免疫反应并诱发青光眼 神经变性； 2）研究HSP是否是关键的致病抗原，驱动T细胞反应 青光眼; 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 用作诊断或鉴定青光眼进展的生物标志物。拟议的研究将进行 在马萨诸塞州的研究人员和青光眼专家之间的合作努力 和马萨诸塞州技术研究所，他们拥有互补的专业知识和悠久的历史 富有成效的合作。阐明青光眼神经变性中的免疫机制将 导致理解疾病发病机理的范式转移，并为 开发基于机制的诊断，预防和治疗。鉴于视网膜长期以来一直是 作为中枢神经系统的模型，拟议的研究也可以阐明 其他神经退行性疾病的发病机制困扰着大脑和脊髓。