Role of HLA/MHCII in Parkinson's Disease Pathogenesis

HLA/MHCII 在帕金森病发病机制中的作用

• 批准号: 9481657
• 负责人: JEREMY M. BOSS
• 金额: $ 0.22万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-12-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9481657
• 关键词: ATAC-seq; Adaptive Immune System; Address; Alleles; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Attenuated; B-Lymphocytes; Biochemical; Biological Assay; Biological Models; Brain; CD4 Positive T Lymphocytes; Cell surface; Cells; Chromatin; Code; DNA Methylation; Data; Dendritic Cells; Diagnosis; Disease; Disease Progression; Elements; Epigenetic Process; Event; Frequencies; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genotype; HLA Antigens; Human; Immune response; Immune system; Immunologics; Individual; Inflammation; Inflammatory; Interferon Type II; Interferons; Introns; Lesion; Link; Linkage Disequilibrium; MHC Class II Genes; Maintenance; Major Histocompatibility Complex; Messenger RNA; Microglia; Molecular; Mus; Myelogenous; Myeloid Cells; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuroimmune; Onset of illness; Other Genetics; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Population; Predisposition; Proteins; RNA; Recombinant adeno-associated virus (rAAV); Regulatory Element; Reporting; Research; Risk; Role; Single Nucleotide Polymorphism; Substantia nigra structure; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Untranslated RNA; adaptive immune response; adaptive immunity; age related; alpha synuclein; base; clinical care; cohort; differential expression; disorder risk; epigenetic regulation; genetic association; genetic variant; genome wide association study; high risk; immunoregulation; macrophage; monocyte; neuroinflammation; neuropathology; novel; novel therapeutics; overexpression; pars compacta; prevent; public health relevance; response; risk variant; synuclein

 DESCRIPTION (provided by applicant): A large genome-wide association study identified a common non-coding, single nucleotide polymorphism (SNP), rs3129882, which was significantly associated with risk for late-onset Parkinson's disease (PD). Individuals homozygous for the risk allele (GG) have a 1.7 fold higher risk for PD than homozygous individuals with the low risk allele (AA). rs3129882 is located in the first intron of the Major Histocompatibility Complex class II (MHC-II) Human Leukocyte Antigen (HLA)-DRA gene, providing the first genetic link between PD and this critical immune system locus. The conundrum introduced by this study was the fact that HLA-DRA is monomorphic and the polymorphic HLA genes were not found to be associated with PD in this study, suggesting that a protein coding polymorphism is unlikely to be the causative genetic lesion. Instead, we suggest the novel hypothesis that rs3129882 is linked to a novel regulatory element that alters the expression of the locus in antigen presenting cells that reside in and/or infiltrate into the brain, such that there is an increased risk for disease following an inflammatory event. Indeed, HLA-DR-expressing microglia, CD4+ T cells, and anti-CNS protein antibodies have been reported in the substantia nigra pars compacta of PD patients, supporting a role for adaptive immune responses in PD disease progression. We additionally posit that changes in genetic and/or epigenetic regulation of MHC-II genes could be linked to rs3129882 and explain the stochastic and sporadic nature of this disease. Preliminary studies revealed that IFNtreated monocytes from GG individuals with PD co-express HLA-DR and HLA-DQ proteins to a higher degree than monocytes from AA individuals irrespective of disease state. Furthermore, in response to IFN, GG monocytes expressed up to 300-fold higher levels of both DR and DQ mRNAs than AA cells. Thus, the high risk, GG genotype, is associated with increased levels of MHC-II mRNA and protein. Identification of a direct linkage of rs3129882 to a regulatory mechanism would provide a specific target for neuroimmune modulation and novel therapy to delay, prevent, or attenuate disease. To provide a scientific basis for pursuing treatments to target MHC-II expression and this pathway, we propose to determine the regulatory bases for rs3129882 association with PD and determine a causal role for MHC-II aberrant expression and PD-like neuropathology in a model system through the following specific aims: Aim 1, Determine the extent to which MHCII expression and T-cell subset frequency are influenced by rs3129882 genotype; Aim 2, Identify the molecular bases for rs3129882-related changes in gene expression; and Aim 3, Determine the extent to which modulation of myeloid-specific (including microglia) MHC-II expression determines vulnerability to rAAV-human -synuclein-induced dopaminergic neurodegeneration. Together, these analyses will elucidate the molecular mechanism for understanding this important genetic association and potentially provide novel therapies for PD and other neurodegenerative diseases where inflammation plays a role.

 描述（由申请人提供）：一项大型全基因组关联研究发现了一种常见的非编码单核苷酸多态性（SNP）rs3129882，它与晚发性帕金森病（PD）纯合子个体的风险显着相关。风险等位基因 (GG) 的 PD 风险比具有低风险等位基因 (AA) 的纯合个体高 1.7 倍。位于主要组织相容性复合体类的第一个内含子 II (MHC-II) 人类白细胞抗原 (HLA)-DRA 基因，提供了 PD 与这一关键免疫系统基因座之间的第一个遗传联系。这项研究带来的难题是 HLA-DRA 是单态性的，而 HLA 基因是多态性的。在本研究中未发现 rs3129882 与 PD 相关，这表明蛋白质编码多态性不太可能是致病的遗传病变，相反，我们提出了 rs3129882 与 PD 相关的新假设。一种新的调节元件，可以改变驻留在和/或渗透到大脑中的抗原呈递细胞中的基因座的表达，从而导致炎症事件后患病的风险增加，事实上，表达HLA-DR的小胶质细胞CD4+。据报道，PD 患者的黑质致密部存在 T 细胞和抗 CNS 蛋白抗体，这支持了适应性免疫反应在 PD 疾病进展中的作用。 MHC-II 基因可能与 rs3129882 相关，并解释了这种疾病的随机性和散发性。初步研究表明，与 PD 患者相比，IFN-γ 处理的 GG 个体的单核细胞共表达 HLA-DR 和 HLA-DQ 蛋白的程度更高。此外，无论疾病状态如何，来自 AA 个体的单核细胞对 IFN-作出反应，GG 单核细胞的表达水平高出 300 倍。 DR 和 DQ mRNA 的含量均高于 AA 细胞，因此，高风险 GG 基因型与 MHC-II mRNA 和蛋白质水平的增加有关，鉴定 rs3129882 与调节机制的直接联系将为神经免疫提供特定靶点。为了为寻求针对 MHC-II 表达和该途径的治疗提供科学依据，我们建议确定 MHC-II 表达和该途径的调节基础。 rs3129882 与 PD 的关联，并通过以下具体目标确定模型系统中 MHC-II 异常表达和 PD 样神经病理学的因果作用： 目标 1，确定 rs3129882 对 MHCII 表达和 T 细胞子集频率的影响程度基因型；目标 2，识别 rs3129882 相关基因表达变化的分子基础；目标 3，确定其程度；骨髓特异性（包括小胶质细胞）MHC-II 表达的调节决定了对 rAAV-人 α-突触核蛋白诱导的多巴胺能神经变性的脆弱性，这些分析将阐明理解这种重要遗传关联的分子机制，并可能为 PD 提供新的治疗方法。以及炎症发挥作用的其他神经退行性疾病。