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

摘要 由血浆和/或CSF中自身抗体的存在定义的新型神经免疫性疾病最近已被发现。 被发现，最常见的是在副肿瘤综合征的背景下首次描述，只是后来也 与肿瘤无关。这些包括边缘系统脑炎（例如，抗NMDAR、抗AMPAR、抗 GABABR、抗LGI 1、抗CASPR 2）、小脑共济失调（例如，抗Yo，抗DNER，抗GAD），僵硬人 综合征（抗GAD、抗两栖素、抗GlyR）和其他（抗Hu）。虽然我们对它知之甚少， 这些疾病的病理生理学，一些被认为是更多的B细胞或T细胞介导的，大多数假设 这是由观察到的治疗反应和抗原的表面/细胞内性质所暗示的。参与 KIR和HLA在这些疾病中尚未探索。有趣的是，我们的初步数据支持一个强大的全基因组 相关性研究（GWAS）显示抗NMDAR脑炎与活化KIR 2DS 1显著相关， 这表明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中的HLA和KIR库进行遗传调查。我们的具体目标1 2、对2000例（~1000 已收集的案例）。我们的具体目标3将利用KIR和HLA的最新进展- 第二代测序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，我们将进行全基因组基因分型的关联分析，比较频率， HLA和KIR等位基因在病例组和对照组中的分布。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，重点是KIR与已知的HLA配体。这将涉及 比较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 KIR/HLA发现与疾病严重程度或症状群。对这些疾病的研究将有益于神经病学， 神经免疫学、癌症和传染病的工作。事实上，这些疾病发生在 增强的肿瘤免疫力是值得注意的，并且与癌症免疫治疗相关，这是一个不断发展的领域。这些数据集 将通过ImmPort提供，这将使无数研究人员能够优先进行B的基础研究 细胞、T细胞和NK细胞在这些疾病和相关肿瘤中的作用。

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.