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。青光眼神经退行性变的机制尚不完全 明白了。最近，我们提供了第一个令人信服的证据来证明免疫机制。 青光眼潜在的神经变性。我们在诱发性青光眼和遗传性青光眼中均有表现 高眼压小鼠模型诱导热休克蛋白、视网膜小胶质细胞表达上调 活化和T细胞浸润/HSP特异性的CD4+T细胞反应和视网膜免疫反应是 青光眼进行性RGC和轴突变性的驱动力。值得注意的是，在无菌小鼠中， 均缺乏HSP特异性T细胞，眼压升高未能诱导小胶质细胞活化，HSP特异性T细胞 反应和青光眼神经变性。这些结果有力地支持了高眼压表现为 物理应激而不是对视网膜节细胞和轴突的直接损伤；它是应激诱发的事件，可能涉及 导致青光眼神经变性的先天和获得性免疫反应。钥匙 悬而未决的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 青光眼的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。 热休克蛋白的表达，尤其是当从细胞中释放出来时，已知可以诱导先天免疫和获得性免疫。 回应。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，进而导致青光眼患者RGC变性。在本申请中，我们 建议从三个互补的角度对这一假设进行批判性检验：1)确定HSP信号是否 负责启动视网膜的先天和获得性免疫反应，并导致青光眼 2)研究热休克蛋白是否是驱动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细胞水平是否可以 作为诊断或预测青光眼进展的生物标志物。建议的研究将会进行。 作为马萨诸塞州眼耳科研究人员和青光眼专家的合作成果 和麻省理工学院，他们有互补的专业知识和悠久的历史 富有成效的协作。阐明青光眼神经变性的免疫机制将 导致了对疾病发病机制的理解的范式转变，并为 发展以机制为基础的诊断、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，拟议的研究也可能揭示 影响大脑和脊髓的其他神经退行性疾病的发病机制。