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.

项目概要/摘要 帕金森病（PD）是第二常见的神经退行性疾病，其特征是病理性的 标志包括黑质中的多巴胺能神经元死亡、a-突触核蛋白 (a-syn) 聚集在 路易体和神经突、神经炎症和免疫细胞浸润到实质中。这 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，方法中 免疫浸润中枢神经系统 (CNS) 影响 PD 发病机制的机制尚不清楚。之前 我们小组发表的数据表明，PD 患者具有识别 a-syn 的 T 细胞，这表明 PD 患者具有识别 a-syn 的 T 细胞 用于 PD 中的自身反应性 T 细胞。该数据还确定了一个风险等位基因 HLA DRB1*15:01，它与 a-syn32- 结合 46肽具有高亲和力。基于这些发现，我们测试了适应性免疫反应的激活如何 通过在 HLA DRB1*15:01 表达小鼠中使用 a-syn32-46 进行免疫接种，将外周的 a-syn 转化为 a-syn 可能会导致 PD- 就像中枢神经系统的病理一样。有趣的是，没有中枢神经系统免疫或神经退行性表型，但有 是便秘表型和肠道神经元损失。该数据表明免疫的激活 单独针对 a-syn 的反应不足以促进免疫浸润和随后的 PD 病理学 健康的大脑。其他 PD 小鼠模型表明，中枢神经系统中 a-syn 过度表达会诱导 来自外周的 T 细胞，但目前尚不清楚浸润的 a-syn 特异性 T 细胞如何促进 PD 病理学。这 该提议的中心假设是，外周细胞对 a-syn 的免疫反应的激活 与大脑中a-syn积累相结合，促进免疫浸润、神经炎症和 神经变性。目标 1 将评估组合效应引起的神经炎症和神经变性 使用 a-syn32-46 肽在中枢神经系统中积累和外周免疫激活 建立了结合转基因和病毒α-syn过表达小鼠模型的免疫模型。目的 2 将剖析单独的 a-syn 特异性 T 细胞是否足以诱导神经炎症和 使用过继性 T 细胞将 a-syn 特异性 T 细胞从 a-syn 免疫小鼠体内转移至神经退行性疾病 中枢神经系统中过度表达 a-syn 的未免疫小鼠。拟议的研究将揭示是否存在自身反应 a-syn 特异性 T 细胞浸润 CNS 并促进 PD 发病机制。这些知识可能涉及 a-syn 自身免疫是 PD 的主要驱动因素，并推广免疫调节疗法作为 PD 的使用 治疗。