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

基本信息

批准号：
10298994
负责人：
Dong Feng Chen
金额：
$ 76.04万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/10298994
关键词：
Affect Age Antigens Attenuated Automobile Driving Axon Biological Markers Blindness Brain CD4 Positive T Lymphocytes Cell Count Cells Clinical Collaborations Deterioration Development Diagnosis Diagnostic Disease Ear Event Exhibits Eye Eye diseases Frequencies Germ-Free Glaucoma HSPB1 gene Heat shock proteins Human Immune Immune Tolerance Immune response Immunologic Markers Individual Inflammation Inflammatory Inflammatory Response Inherited Institutes Interferon Type II Lead Light Link Massachusetts Mediating Medical Microglia Modeling Molecular Mus Natural Immunity Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Optic Nerve Pathogenesis Pathogenicity Patients Phase Physiologic Intraocular Pressure Pilot Projects Prevention Primary Open Angle Glaucoma Recording of previous events Regulatory T-Lymphocyte Reporting Research Personnel Research Proposals Retina Retinal Ganglion Cells Risk Factors Signal Transduction Signaling Protein Specialist Spinal Cord Stress T cell response T-Cell Receptor T-Lymphocyte Techniques Technology Testing Tumor-infiltrating immune cells Up-Regulation Vision Visual Fields adaptive immune response adaptive immunity axon injury axonal degeneration base cell injury cell type commensal microbes driving force extracellular immunogenic intravitreal injection mouse model neuroinflammation novel peripheral blood progressive neurodegeneration protein expression relating to nervous system response retinal damage retinal ganglion cell degeneration single-cell RNA sequencing

Affect Age Antigens Attenuated Automobile Driving Axon Biological Markers Blindness Brain CD4 Positive T Lymphocytes Cell Count Cells Clinical Collaborations Deterioration Development Diagnosis Diagnostic Disease Ear Event Exhibits Eye Eye diseases Frequencies Germ-Free Glaucoma HSPB1 gene Heat shock proteins Human Immune Immune Tolerance Immune response Immunologic Markers Individual Inflammation Inflammatory Inflammatory Response Inherited Institutes Interferon Type II Lead Light Link Massachusetts Mediating Medical Microglia Modeling Molecular Mus Natural Immunity Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Optic Nerve Pathogenesis Pathogenicity Patients Phase Physiologic Intraocular Pressure Pilot Projects Prevention Primary Open Angle Glaucoma Recording of previous events Regulatory T-Lymphocyte Reporting Research Personnel Research Proposals Retina Retinal Ganglion Cells Risk Factors Signal Transduction Signaling Protein Specialist Spinal Cord Stress T cell response T-Cell Receptor T-Lymphocyte Techniques Technology Testing Tumor-infiltrating immune cells Up-Regulation Vision Visual Fields adaptive immune response adaptive immunity axon injury axonal degeneration base cell injury cell type commensal microbes driving force extracellular immunogenic intravitreal injection mouse model neuroinflammation novel peripheral blood progressive neurodegeneration protein expression relating to nervous system response retinal damage retinal ganglion cell degeneration single-cell RNA sequencing

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项目摘要

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.

青光眼发病机理中的先天和适应性免疫反应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尚不完全了解。最近，我们提供了第一个令人信服的证据，证明了一种免疫机制青光眼中的神经变性。我们在诱导和遗传的青光眼小鼠模型中展示了 IOP升高引起的热激蛋白（HSP），视网膜小胶质细胞激活和T细胞上调浸润/HSP特异性CD4+ T细胞反应，视网膜免疫反应是驱动力青光眼的进行性RGC和轴突变性。值得注意的是，在不足的无菌小鼠中 HSP特异性T细胞，IOP升高未能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提升的身体压力而不是直接损害RGC和轴突；这是压力诱发的事件，可能涉及先天和引起青光眼神经退行性的自适应免疫反应。关键的未解决问题是 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，什么是在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，尤其是当已知从细胞释放出来会诱导先天和适应性免疫反应。我们假设这一点升高的IOP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，这些反应反过来导致青光眼的RGC变性。在本应用程序中，我们建议对此进行批判性测试来自三个互补角的假设：1）确定HSP信号是否负责启动两者视网膜中的先天和适应性免疫反应并诱导青光眼神经退行性反应； 2）到研究HSP是否是驱动青光眼中T细胞反应的关键致病抗原； 3）测试是否水平青光眼患者外周血中的HSP特异性T细胞可以作为诊断或青光眼进展的预测。拟议的研究将以合作的努力进行马萨诸塞州眼睛和耳朵和马萨诸塞州的研究人员和青光眼专家技术，具有互补的专业知识和悠久的生产协作历史。阐明青光眼神经变性中的免疫机制将导致范式转移了解疾病发病机理，并为发展基于机制的发展提供了基础诊断，预防和治疗。考虑到视网膜长期以来一直是中央的模型神经系统，拟议的研究还可以阐明其他神经退行性的发病机理困扰大脑和脊髓的疾病。