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：
10680363
负责人：
Emmanuel J Mignot
金额：
$ 63.97万
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/10680363
关键词：
Affect Aftercare Age Age of Onset Alleles Antigens Area Autoantibodies Autoimmune B-Lymphocytes Brain CNTNAP1 gene CSF1 gene Cancer Patient Central Nervous System Cerebellar Ataxia Clinical Clinical Data Communicable Diseases Complement Complex Country DNA Data Data Set Databases Demyelinating Diseases Disease Encephalitis Ethnic Origin 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 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 Syndrome T-Lymphocyte Techniques Testing Tissues Tumor Immunity Update Work amphiphysin cancer immunotherapy 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，血浆和/或CSF中存在自身抗体定义的新型神经免疫性疾病已定义被发现，最常见于副塑性综合症的背景下首次描述，后来也是发现与肿瘤无关。其中包括边缘性脑炎（例如，抗NMDAR，抗抑郁症，抗 - gababr，anti-lgi1，anti-caspr2），小脑共济失调（例如抗yo，抗dner，抗加德），僵硬的人综合征（抗GAD，抗抑制性，抗Glyr）等（抗HU）。虽然关于这些疾病的病理生理学，有些被认为是B细胞或T细胞介导的，主要是假设通过观察到的治疗反应和抗原的表面/细胞内性。参与 KIR和HLA在这些疾病中未开发。有趣的是，我们的初步数据支持强大的全基因组协会研究（GWAS）抗-NMDAR脑炎与激活KIR2DDS1，抗NMDAR脑炎的显着关联有史以来最强的KIR关联，表明KIR-NK细胞轴是这些疾病的关键调节剂。我们建议对这些疾病中的HLA和KIR曲目进行遗传调查。我们的具体目标1 和2，我们将对症状进行详细表征，并在2000例病例中收集血清和DNA（〜1000 案件已经收集）。我们的特定目标3将利用KIR和HLA的最新进展状态 - 生成测序以在情况和对照中执行高分辨率基因分型，此外，我们还将在所有情况和对照中执行全基因组单核苷酸键入，这将指导我们的关联分析。在我们的特定目标4中，我们将对基因组广泛基因分型进行关联分析，比较频率在情况和对照中的HLA和KIR等位基因。在我们的特定目标5中，任何患有KIR和/或HLA发现的疾病（S）我们将进行Kir-HLA相互作用分析，以使用已知HLA配体KIR进行。这将涉及比较在病例与对照组中相互作用的kir-hla配体对的频率；此外，我们将关联 KIR/HLA发现具有疾病严重程度或症状簇。这些疾病的研究将使神经病学受益，神经免疫学，癌症和传染病工作。这些疾病发生在增强的肿瘤免疫力是显着的，并且与癌症免疫疗法（一个生长区域）有关。这些数据集将通过Immport提供，这将使无数的研究人员优先考虑B的基础研究这些疾病和相关肿瘤中的细胞，T和NK细胞。