Role of HLA/MHCII in Parkinson's Disease Pathogenesis

 描述（由申请人提供）：一项大型全基因组关联研究确定了一种常见的非编码单核苷酸多态性（SNP）rs3129882，与晚发性帕金森病（PD）的风险显著相关。风险等位基因（GG）纯合子个体患PD的风险是低风险等位基因（AA）纯合子个体的1.7倍。rs3129882位于主要组织相容性复合体类的第一内含子中 II（MHC-II）人类白细胞抗原（HLA）-HLA基因，提供了PD和这个关键免疫系统位点之间的第一个遗传联系。本研究引入的难题是HLA-β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性遗传病变。相反，我们提出了一种新的假设，即rs3129882与一种新的调节元件有关，该元件改变了抗原呈递细胞中该位点的表达，这些抗原呈递细胞位于和/或浸润到大脑中，从而增加了炎症事件后的疾病风险。事实上，HLA-DR表达小神经胶质细胞，CD 4 + T细胞，抗CNS蛋白抗体已被报道在PD患者的黑质丘脑部，支持适应性免疫反应在PD疾病进展中的作用。我们还证实，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。初步研究表明，IFN γ处理的单核细胞从GG个人与PD共表达HLA-DR和HLA-DQ蛋白的程度高于单核细胞从AA个人，无论疾病状态。此外，在响应IFN γ，GG单核细胞表达高达300倍的DR和DQ mRNA的水平比AA细胞。因此，高风险，GG基因型，与MHC-II mRNA和蛋白水平的增加有关。鉴定rs3129882与调节机制的直接联系将为神经免疫调节和延迟、预防或减轻疾病的新疗法提供特异性靶点。为了为寻求靶向MHC-II表达和该途径的治疗提供科学依据，我们建议通过以下特定目的确定rs3129882与PD相关的调控基础，并确定模型系统中MHC-II异常表达和PD样神经病理学的因果关系：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;和目的3，确定骨髓特异性（包括小胶质细胞）MHC-II表达的调节决定对rAAV-人α-突触核蛋白诱导的多巴胺能神经变性的脆弱性的程度。总之，这些分析将阐明理解这种重要遗传关联的分子机制，并可能为PD和其他炎症起作用的神经退行性疾病提供新的治疗方法。

 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.