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

摘要 最近，由血浆和/或脑脊液中自身抗体的存在定义的新的神经免疫性疾病 被发现，最常首先在副肿瘤综合征的背景下被描述，只是后来也 被发现与肿瘤无关。这些包括边缘脑炎(例如，抗NMDAR、抗AMPAR、抗-AMPAR、 GABABR，抗LGI1，抗CASPR2)，小脑性共济失调(如抗Yo，抗DNER，抗GAD)，僵硬的人 综合征(抗GAD、抗两栖类、抗GlyR)和其他(抗Hu)。尽管人们对此知之甚少 这些疾病的病理生理学，有些被认为更多的是B细胞或T细胞介导的，假说大多 由观察到的治疗反应和抗原的表面/细胞内性质提示。牵涉到 KIR和人类白细胞抗原在这些疾病中的作用尚不清楚。有趣的是，我们的初步数据支持强大的全基因组 相关性研究(GWAS)抗NMDAR脑炎与激活的KIR2DS1显著相关 迄今报道的KIR相关性最强，提示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人类白细胞抗原和KIR谱系进行遗传学调查。我们的具体目标1 2、我们将对2000例(~1000例)患者进行详细的症状描述和血清及DNA采集 已收集的病例)。我们的具体目标3将利用KIR和HLANEXT的最新进展- 世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，我们将执行全基因组基因分型的关联分析，比较频率 病例组和对照组中人类白细胞抗原和KIR等位基因的分布。在我们的特定目标5中，任何具有KIR和/或人类白细胞抗原发现的障碍(S) 我们将进行KIR-HLA相互作用分析，重点是KIR与已知的人类白细胞抗原配体。这将涉及到 比较相互作用的KIR-HLA配体对在病例和对照组中的频率；进一步，我们将相关 有疾病严重程度或症状簇的KIR/HLA表现。对这些疾病的研究将有助于神经学， 神经免疫学、癌症和传染病的研究。事实上，这些障碍发生在 肿瘤免疫力的提高是值得注意的，与癌症免疫治疗相关，这是一个不断增长的领域。这些数据集 将通过ImmPort提供，这将允许无数研究人员优先考虑B组的基础研究 这些疾病和相关肿瘤中的细胞、T和NK细胞。

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.