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: 9538271
• 负责人: JEREMY M. BOSS
• 金额: $ 33.74万
• 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/9538271
• 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; Immunotherapy; Individual; Inflammation; Inflammatory; Interferon Type II; 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

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 IFNγ-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 IFNγ, 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 α-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，它与晚发型帕金森病（PD）的风险显著相关。风险等位基因（GG）纯合子个体患PD的风险比低风险等位基因（AA）纯合子个体高1.7倍。rs3129882位于主要组织相容性复合体II类（MHC-II）人类白细胞抗原(HLA)-DRA基因的第一个内含子上，提供了PD与这个关键免疫系统位点之间的第一个遗传联系。本研究提出的难题是HLA- dra是单态的，并且在本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太可能是致病的遗传病变。相反，我们提出了一种新的假设，即rs3129882与一种新的调控元件有关，该元件改变了存在和/或浸润到大脑中的抗原呈递细胞中位点的表达，从而在炎症事件后增加了疾病的风险。事实上，在PD患者的黑质致密部中已经报道了表达hla - dr的小胶质细胞、CD4+ T细胞和抗cns蛋白抗体，支持适应性免疫反应在PD疾病进展中的作用。此外，我们假设MHC-II基因的遗传和/或表观遗传调控的变化可能与rs3129882有关，并解释了这种疾病的随机性和散发性。初步研究发现，无论疾病状态如何，经ifn γ处理的GG PD患者单核细胞均比AA患者单核细胞表达HLA-DR和HLA-DQ蛋白的程度更高。此外，在IFNγ的作用下，GG单核细胞表达的DR和DQ mrna水平比AA细胞高300倍。因此，GG基因型的高风险与MHC-II mRNA和蛋白水平升高有关。鉴定rs3129882与调节机制的直接联系将为神经免疫调节和新疗法提供特异性靶点，以延缓、预防或减轻疾病。为了为寻求针对MHC-II表达及其通路的治疗提供科学依据，我们提出在模型系统中确定rs3129882与PD相关的调控基础，确定MHC-II异常表达和PD样神经病理的因果关系，具体目的如下：目的1，确定rs3129882基因型对MHCII表达和t细胞亚群频率的影响程度；目的2：确定rs3129882相关基因表达变化的分子基础；确定髓细胞特异性（包括小胶质细胞）MHC-II表达的调节在多大程度上决定了raav -人α-突触核蛋白诱导的多巴胺能神经变性的易感性。总之，这些分析将阐明理解这一重要遗传关联的分子机制，并可能为帕金森病和其他炎症起作用的神经退行性疾病提供新的治疗方法。