Alpha-Synuclein-Specific T cells in Parkinson's Disease Pathogenesis

帕金森病发病机制中的α-突触核蛋白特异性 T 细胞

• 批准号: 10752172
• 负责人: Connor Monahan
• 金额: $ 4.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752172
• 关键词: Adoptive Transfer; Affect; Affinity; Alleles; Autoimmune Responses; Autoimmunity; Binding; Brain; CD4 Positive T Lymphocytes; Cell physiology; Cells; Central Nervous System; Chronic; Circulation; Clinical; Complex; Constipation; Data; Development; Disease; Disease Progression; Encephalomyelitis; Enteral; Experimental Autoimmune Encephalomyelitis; Flow Cytometry; Generations; Homing; Human; Immune; Immune response; Immune system; Immunization; Immunize; Immunohistochemistry; Infiltration; Inflammation; Intestines; Knowledge; Lewy Bodies; Lewy body pathology; Lewy neurites; Link; MHC Class II Genes; Mediating; Methods; Microglia; Midbrain structure; Modeling; Multiple Sclerosis; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Peptides; Peripheral; Phenotype; Play; Process; Proteins; Publishing; Reporting; Role; Stimulus; Substantia nigra structure; T cell infiltration; T cell response; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Time; Transgenic Mice; Transgenic Organisms; Tyrosine 3-Monooxygenase; Viral; adaptive immune response; alpha synuclein; autoreactive T cell; autoreactivity; cohort; combinatorial; density; disease diagnosis; dopamine transporter; dopaminergic neuron; genome wide association study; humanized mouse; ileum; immune activation; immune cell infiltrate; immunomodulatory therapies; motor deficit; mouse model; neurodegenerative phenotype; neuroinflammation; neuron loss; novel; overexpression; receptor; risk variant; single-cell RNA sequencing; synuclein

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by pathological hallmarks that include dopaminergic neuron death in the substantia nigra, a-synuclein (a-syn) aggregates in Lewy bodies and neurites, neuroinflammation, and immune cell infiltration into the parenchyma. The mechanisms which cause neurodegeneration in PD patients are not fully understood. Moreover, the ways in which immune infiltration into the central nervous system (CNS) affects PD pathogenesis are unclear. Previously published data by our group demonstrates that PD patients have T cells that recognize a-syn, suggesting a role for autoreactive T cells in PD. This data also identified a risk allele, HLA DRB1*15:01, which binds to the a-syn32- 46 peptide with high affinity. Based on these findings, we tested how activation of the adaptive immune response to a-syn in the periphery via immunization with a-syn32-46 in HLA DRB1*15:01 expressing mice may cause PD- like pathology in the CNS. Interestingly, there was no CNS immune or neurodegenerative phenotype, but there was a constipation phenotype and neuron loss in the intestines. This data suggests that activation of the immune response against a-syn alone was insufficient to promote immune infiltration and subsequent PD pathology in the healthy brain. Other mouse models for PD show that a-syn overexpression in the CNS induces infiltration of T cells from the periphery, but it is unclear how infiltrating a-syn-specific T cells contribute to PD pathology. The central hypothesis of this proposal is that activation of the immune response to a-syn in the periphery in combination with a-syn accumulation in the brain promotes immune infiltration, neuroinflammation and neurodegeneration. Aim 1 will assess neuroinflammation and neurodegeneration due to the combinatorial effects of a-syn accumulation in the CNS and peripheral immune activation to the a-syn32-46 peptide using the established immunization model combined with transgenic and viral a-syn overexpression mouse models. Aim 2 will dissect whether a-syn-specific T cells alone are sufficient to induce neuroinflammation and neurodegeneration using adoptive T cell transfer of a-syn-specific T cells from a-syn-immunized mice into unimmunized mice which overexpress a-syn in the CNS. The proposed studies will reveal whether autoreactive a-syn-specific T cells infiltrate the CNS and promote PD pathogenesis. This knowledge may implicate autoimmunity to a-syn as a major driver of PD, and promote the use of immunomodulatory therapies as a PD treatment.

项目摘要/摘要 帕金森病(PD)是第二常见的神经退行性疾病，以病理性为特征 特征包括黑质多巴胺能神经元死亡，a-突触核蛋白(a-syn)聚集在 路易小体和神经突起，神经炎症，免疫细胞渗入实质。这个 导致帕金森病患者神经退行性变的机制尚不完全清楚。此外，进入中国的途径 中枢神经系统(CNS)的免疫浸润对帕金森病发病机制的影响尚不清楚。先前 我们小组公布的数据显示，帕金森病患者有识别a-syn的T细胞，这表明 帕金森病患者的自身反应性T细胞。该数据还确定了一个危险等位基因，HLADRB1*15：01，它与a-syn32- 46肽具有较高的亲和力。基于这些发现，我们测试了适应性免疫反应的激活 在表达HLADRB1*15：01的小鼠中用a-syn32-46免疫外周血中的a-syn可能引起PD- 就像中枢神经系统的病理学一样。有趣的是，没有中枢神经系统免疫或神经退行性表型，但有 是一种便秘表型和肠道神经元丢失。这一数据表明，免疫系统的激活 单独针对a-syn的反应不足以促进免疫渗透和随后的帕金森病病理 健康的大脑。其他帕金森病小鼠模型显示，a-syn在中枢神经系统的过度表达诱导了 来自外周的T细胞，但尚不清楚渗透的a-SYN特异性T细胞如何参与PD的病理过程。这个 这一建议的中心假设是激活了对外周a-syn的免疫反应 与a-syn在大脑中的积聚相结合，可促进免疫渗透、神经炎症和 神经退行性变。目标1将评估由于组合效应引起的神经炎症和神经变性 A-syn在中枢神经系统中的蓄积和对a-syn32-46肽的外周免疫激活 建立转基因和病毒a-syn过表达小鼠联合免疫模型。目标 2将分析单独的a-syn特异性T细胞是否足以引起神经炎症和 过继转移来自a-syn免疫小鼠的a-syn特异性T细胞至 未免疫的小鼠在中枢神经系统过度表达a-syn。拟议的研究将揭示自体反应 A-SYN特异性T细胞侵袭中枢神经系统，促进帕金森病的发病。这一知识可能会牵连到 自身免疫作为帕金森病的主要驱动力，并促进免疫调节疗法作为帕金森病的使用 治疗。