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: 9326351
• 负责人: JEREMY M. BOSS
• 金额: $ 33.67万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326351
• 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（由适用提供）：一项大型基因组关联研究确定了一种常见的非编码单核丁基多态性（SNP），RS3129882，这与晚期帕金森氏病（PD）的风险显着相关。纯合的风险等位基因（GG）的个体比具有低风险等位基因（AA）的纯合子的PD风险高1.7倍。 RS3129882位于主要​​组织相容性综合体的第一个内含子中 II（MHC-II）人类白细胞抗原（HLA）-DRA基因，提供了PD与这个关键免疫系统基因座之间的第一个遗传联系。这项研究引入的难题是HLA-DRA是单态的，并且在这项研究中未发现多态性HLA基因与PD相关，这表明蛋白质编码多态性不可能是致病性遗传病变。取而代之的是，我们提出了一种新的假设，即rs3129882与一种新的调节元件有关，该元素改变了抗原呈现在抗原呈递细胞中和/或浸润到大脑中的细胞中的表达，因此炎症事件后疾病的风险增加了。实际上，已经报道了PD患者的Nigra Pars Compacta中报道了HLA-DR表达的小胶质细胞，CD4+ T细胞和抗CNS蛋白抗体，这支持了PD疾病进展中适应性免疫调查的作用。我们还确认，MHC-II基因的遗传和/或表观遗传调节的变化可以与RS3129882相关，并解释该疾病的随机和零星性质。初步研究表明，与疾病状态无关的是，来自PD共表达HLA-DR和HLA-DQ蛋白质的IFNRETATIFNIFNRETATIFNRATIFNRATIFNRATECHETACETIFN2。此外，针对IFN，GG单核细胞表达的DR和DQ mRNA水平高达300倍，而不是AA细胞。高风险，GG基因型与MHC-II mRNA和蛋白质水平升高有关。将RS3129882与调节机制直接连接的鉴定将为神经免疫调节和新颖的疗法提供一个特定的靶标，以延迟，预防或减轻疾病。为了提供科学基础，以寻求靶向MHC-II表达和这种途径，我们建议确定RS3129882与PD关联的调节基础，并确定MHC-II异常表达的因果作用，并确定MHC-II异常表达和PD样神经病理学在以下特定的范围内通过以下特定的范围来确定MHCI的频率： RS3129882基因型； AIM 2，确定基因表达中与RS3129882相关的变化的分子碱基； AIM 3，确定髓样特异性（包括小胶质细胞）MHC-II表达的调节程度确定了对Raav-Human-突触核蛋白诱导的多巴胺能神经变性的脆弱性。总之，这些分析将阐明理解这种重要遗传关联的分子机制，并有可能为炎症起作用的PD和其他神经退行性疾病提供新的疗法。