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：
10686336
负责人：
Dong Feng Chen
金额：
$ 71.78万
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/10686336
关键词：
Affect Age Antigens Attenuated Automobile Driving Axon Biological Markers Blindness Brain CD4 Positive T Lymphocytes Cell Count Cells Central Nervous System 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 Innate Immune Response Interferon Type II Link Massachusetts Mediating Medical Microglia Modeling Molecular Mus Natural Immunity Nerve Degeneration Neurodegenerative Disorders Neurons Optic Nerve Pathogenesis Pathogenicity Patients Persons Phase Physiologic Intraocular Pressure Pilot Projects Prevention Primary Open Angle Glaucoma Productivity Recording of previous events Regulatory T-Lymphocyte Reporting Research Personnel Research Proposals Retina Retinal Ganglion Cells Risk Factors Signal Induction Signal Transduction Signaling Protein Specialist Spinal Cord Stress T cell infiltration T cell response T-Cell Receptor T-Lymphocyte Techniques Technology Testing Up-Regulation Vision Visual Fields adaptive immune response adaptive immunity axon injury axonal degeneration cell injury cell type commensal microbes driving force extracellular glial activation immunogenic intravitreal injection mouse model neural neuroinflammation novel peripheral blood progressive neurodegeneration protein expression response retinal damage retinal ganglion cell degeneration single-cell RNA sequencing

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.

青光眼发病机制中的先天性和适应性免疫反应青光眼是全球范围内尚未解决的医学挑战，也是导致不可逆失明的主要原因。高架眼内压（IOP）是青光眼的主要危险因素；然而，临床上它既不是必要的也不是充分的造成神经元损伤。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，证明了潜在的免疫机制青光眼中的神经变性。我们在诱导型和遗传性青光眼小鼠模型中进行了展示升高的眼压会诱导热休克蛋白 (HSP)、视网膜小胶质细胞活化和 T 细胞的上调浸润/HSP特异性CD4+ T细胞反应和视网膜免疫反应是驱动力青光眼中进行性 RGC 和轴突变性。值得注意的是，在无菌小鼠中，它们缺乏 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，并且青光眼神经变性。这些结果有力地支持眼压升高会带来身体压力而不是直接损害 RGC 和轴突；这是压力诱发的事件，可能涉及先天和导致青光眼神经变性的适应性免疫反应。未回答的关键问题是升高的 IOP 如何激活小胶质细胞和 T 细胞反应以诱导 RGC 和轴突损伤？诱导青光眼中小胶质细胞和 T 细胞反应的分子信号。 HSP 表达，尤其是当已知从细胞中释放可以诱导先天性和适应性免疫反应。我们假设升高的 IOP 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，从而进而导致青光眼中的 RGC 变性。在本申请中，我们建议严格测试这一点从三个互补的角度提出假设：1）确定HSP信号传导是否负责启动两者视网膜的先天性和适应性免疫反应并诱导青光眼神经变性； 2）到研究 HSP 是否是驱动青光眼 T 细胞反应的关键致病抗原； 3) 测试是否青光眼患者外周血中的 HSP 特异性 T 细胞可以作为诊断或治疗的生物标志物青光眼进展的预测。拟议的研究将作为各方的合作努力进行马萨诸塞州眼耳科和麻省理工学院的研究人员和青光眼专家技术，他们拥有互补的专业知识和悠久的富有成效的合作历史。阐明青光眼神经变性的免疫机制将导致范式转变了解疾病发病机制，为基于机制的开发提供基础诊断、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影响大脑和脊髓的疾病。