GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY

NK 细胞缺陷 (NKD) 是原发性免疫缺陷疾病/先天性免疫缺陷 (IEI) 的一个子集 其中NK细胞异常代表了临床上主要的免疫缺陷。 NK细胞异常的患者 容易受到致命病毒感染和某些癌症的影响，这为我们提供了一个独特的窗口来了解这些病毒如何 关键的免疫细胞发挥作用。 15 年来，我们一直在照顾和研究这些复杂的患者， 应用基因组技术发现致病基因并阐明 NK 细胞生物学。有了这个应用程序， 我们渴望更新我们协调一致的 NKD 发现计划，最终目标是了解如何 护理这些患者以及如何最好地使用 NK 细胞进行治疗。在过去的5年里我们 计划中，我们定义了影响 NK 细胞的 2 种新的 NKD 遗传原因和 8 种新的 IEI 原因。我们 建立并发展了 NKD 患者的国际转诊网络，磨练了临床和治疗方法 免疫学上定义这些罕见的患者，成熟我们的基因组评估/发现途径，以及 优化以患者为中心的功能基因组学和 NK 细胞生物学技术，所有这些都是为了推动进展 了解 NKD。目前，我们有 156 名患者参与我们的 NK 细胞评估和研究（NEAR） 哥伦比亚大学项目：其中 70 人已在贝勒医学院接受外显子组测序 (ES)，13 人 已经找到了针对其疾病的遗传解决方案，其中 11 人已鉴定出有希望的基因，而 36 人仍未解决。 在此更新期间，我们将在成功的基础上再接再厉，将新的 NKD 患者纳入我们的治疗计划中。 通过使用数据库、先进的临床和免疫学方法来定义他们的疾病 生物统计技术和研究水平的表型和功能评估（目标 1），增加新的 基因组发现和分析技术，如全基因组测序和 RNA 测序，带来 向 NKD 基因仍然“未解决”的患者澄清（目标 2），并应用尖端功能 基因组学和 NK 细胞生物学技术来证明我们的基因突变的影响和相关性 发现（目标 3）。我们利用领域内外强有力的、长期的合作 免疫缺陷，以便最好地定义我们识别的基因突变如何影响 NK 细胞的功能 人类健康。通过这样做，我们的目标不仅是更好地诊断和护理这些复杂的患者，而且 更好地了解 NK 细胞如何保护人类免受病毒和癌症的侵害。

NK cell deficiency (NKD) is a subset of primary immunodeficiency diseases/inborn errors of immunity (IEI) in which the NK cell abnormality represents the main clinical immunodeficiency. Patients with abnormal NK cells are susceptible to lethal virus infections and certain cancers, offering us a unique window into how these critical immune cells work. For over 15 years we have cared for and investigated these complex patients, applying genomic techniques to discover causative genes and illuminate NK cell biology. With this application, we aspire to renew our coordinated NKD discovery program, with the ultimate goals of understanding how to care for these patients as well as how to best use NK cells therapeutically. Over the past 5 years of our program, we have defined 2 new genetic causes of NKD and 8 new causes of IEI that affect NK cells. We established and grew an international referral network for NKD patients, honed methods to clinically and immunologically define these rare patients, matured our genomic evaluation/discovery pathways, and optimized patient-focused functional genomics and NK cell biological techniques, all to advance progress in understanding NKD. At present, we have 156 patients enrolled in our NK cell evaluation and research (NEAR) program at Columbia: of these, 70 have undergone exome sequencing (ES) at Baylor College of Medicine, 13 have found genetic solutions for their disease, 11 have a promising gene identified, and 36 remain unsolved. During this renewal period, we will build on our successful momentum, adding new NKD patients to our pipeline, clinically and immunologically defining their disease through the use of databases, advanced biostatistical techniques and research level phenotypic and functional assessments (Aim 1), adding new genomic discovery and analytic techniques like whole genome sequencing and RNA sequencing to bring clarity to the patients whose NKD genes remain “unsolved” (Aim 2), and applying cutting-edge functional genomics and NK cell biological techniques to demonstrate the impact and relevance of the gene mutations we discover (Aim 3). We capitalize on strong, long-standing collaborations both within and beyond the field of Immunodeficiency in order to best define how the gene mutations we identify impact how NK cells function in human health. In so doing, we aim to not only better diagnose and care for these complex patients, but to better understand how NK cells protect humans from viruses and cancer.