KIR and HLA effects in CNS paraneoplastic syndromes and related neuroimmune conditions

KIR 和 HLA 对 CNS 副肿瘤综合征和相关神经免疫性疾病的影响

基本信息

批准号：
10266033
负责人：
Emmanuel J Mignot
金额：
$ 64.29万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10266033
关键词：
Affect Aftercare Age Age of Onset Alleles Antigens Area Autoantibodies Autoimmune B-Lymphocytes Brain CSF1 gene Cancer Patient Cells Cerebellar Ataxia Clinical Clinical Data Communicable Diseases Complement Complex Country DNA Data Data Set Databases Demyelinating Diseases Disease Encephalitis Exclusion Frequencies Functional disorder GEM gene Gene Dosage Gene Frequency Gene-Modified Genes Genetic Genetic Polymorphism Genotype Haplotypes Herpes encephalitis Heterogeneity Immune system Immunotherapy In Vitro LGI1 gene Lambert-Eaton Myasthenic Syndrome Ligands Limbic Encephalitis Literature Malignant Neoplasms Mediating Modeling Multiple Sclerosis Myasthenia Gravis Narcolepsy Natural Killer Cells Nature Nervous System Paraneoplastic Syndromes Neuraxis Neuroimmune Neurology Neuromyelitis Optica Nucleotides Outcome Ovarian Teratoma Paraneoplastic Syndromes Parkinson Disease Pathology Peripheral Nervous System Diseases Plasma Rare Diseases Reaction Reporting Research Research Personnel Resolution Role Sample Size Sampling Serum Severity of illness Signal Transduction Single Nucleotide Polymorphism Stiff-Person Syndrome Stratification Surface Surveys Symptoms T-Lymphocyte Techniques Testing Tissues Tumor Immunity Update Work amphiphysin base cancer immunotherapy case control dosage genome wide association study genome-wide genome-wide analysis neuroimmunology next generation sequencing novel prevent sample collection sex symptom cluster treatment response tumor

项目摘要

Abstract Novel neuroimmune disorders defined by the presence of autoantibodies in plasma and/or CSF have recently been discovered, most often first described in the context of paraneoplastic syndromes, only later to be also found unassociated with tumors. These include limbic encephalitis (e.g., anti-NMDAR, anti-AMPAR, anti- GABABR, anti-LGI1, anti-CASPR2), cerebellar ataxias (e.g., anti-Yo, anti-DNER, anti-GAD), stiff-person syndrome (anti-GAD, anti-amphiphysin, anti-GlyR) and others (anti-Hu). Although little is known regarding the pathophysiology of these disorders, some are believed to be more B-cell or T-cell mediated, hypotheses mostly suggested by observed therapeutic responses and the surface/intracellular nature of antigens. Involvement of KIR and HLA is unexplored in these disorders. Intriguingly, our preliminary data support a strong Genome-Wide Association Study (GWAS) significant association of anti-NMDAR encephalitis with activatory KIR2DS1, the strongest KIR association ever reported, suggesting KIR-NK cell axis to be a key regulator for these disorders. We propose to conduct a genetic survey of the HLA and KIR repertoires in these diseases. Our specific aims 1 and 2, we will do a detailed characterization of symptoms and collect serum and DNA on 2000 cases (~1000 cases already collected). Our specific aim 3 will leverage state of the art advances in KIR and HLA next- generation sequencing to perform high resolution genotyping in cases and controls, in addition, we will also perform genome-wide single nucleotide typing in all cases and controls which will guide our association analysis. In our specific aim 4, we will perform association analyses of the genome wide genotyping, compare frequencies of HLA and KIR alleles in cases and controls. In our specific aim 5, any disorder with KIR and/or HLA finding(s) we will conduct KIR-HLA interaction analyses focusing on KIR with known HLA ligands. This will involve comparing frequencies of interacting KIR-HLA ligand pairs in cases versus controls; further, we will correlate KIR/HLA findings with disease severity or symptom clusters. The study of these disorders will benefit neurology, neuroimmunology, cancer, and infectious disease work. The fact these disorders are occurring in the setting of heightened tumor immunity is notable and relevant to cancer immunotherapy, a growing area. These datasets will be made available through ImmPort, which will allow countless researchers to prioritize basic studies of B cells, T and NK cells in these disorders and associated tumors.

抽象的最近，由血浆和/或脑脊液中存在自身抗体定义的新型神经免疫性疾病被发现，最常首先在副肿瘤综合征的背景下描述，后来才被发现与肿瘤无关。这些包括边缘脑炎（例如，抗 NMDAR、抗 AMPAR、抗 GABABR、抗 LGI1、抗 CASPR2）、小脑共济失调（例如抗 Yo、抗 DNER、抗 GAD）、僵人综合征（抗 GAD、抗两性蛋白、抗 GlyR）和其他（抗 Hu）。尽管人们对这方面知之甚少这些疾病的病理生理学，有些被认为更多是 B 细胞或 T 细胞介导的，大多数假设通过观察到的治疗反应和抗原的表面/细胞内性质表明。参与 KIR 和 HLA 在这些疾病中的作用尚未被探索。有趣的是，我们的初步数据支持强大的全基因组关联研究 (GWAS) 抗 NMDAR 脑炎与激活的 KIR2DS1 显着关联，迄今为止报道的最强的 KIR 关联，表明 KIR-NK 细胞轴是这些疾病的关键调节因子。我们建议对这些疾病的 HLA 和 KIR 谱进行基因调查。我们的具体目标1 2、我们将对 2000 例病例（约 1000 例）进行详细的症状表征并收集血清和 DNA 案例已收集）。我们的具体目标 3 将利用 KIR 和 HLA 领域最先进的进展 - 世代测序以在病例和对照中进行高分辨率基因分型，此外，我们还将在所有病例和对照中进行全基因组单核苷酸分型，这将指导我们的关联分析。在我们的具体目标 4 中，我们将对全基因组基因分型进行关联分析，比较频率病例和对照中的 HLA 和 KIR 等位基因。在我们的具体目标 5 中，任何具有 KIR 和/或 HLA 发现的疾病我们将进行 KIR-HLA 相互作用分析，重点关注 KIR 与已知 HLA 配体。这将涉及到比较病例与对照中 KIR-HLA 配体对相互作用的频率；进一步，我们将关联 KIR/HLA 结果表明疾病严重程度或症状群。对这些疾病的研究将有益于神经学、神经免疫学、癌症和传染病工作。事实上，这些疾病发生在肿瘤免疫力的提高是值得注意的，并且与癌症免疫治疗这一不断发展的领域相关。这些数据集将通过 ImmPort 提供，这将使无数研究人员优先考虑 B 的基础研究这些疾病和相关肿瘤中的细胞、T 细胞和 NK 细胞。