Natural Killer Cell Subpopulations in COPD Exacerbations

COPD 恶化中的自然杀伤细胞亚群

• 批准号: 10012049
• 负责人: Michael Borchers
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012049
• 关键词: Accounting; Acute; Address; Biological Markers; Cell physiology; Cell surface; Cells; Chronic; Chronic Obstructive Airway Disease; Complex; Data; Data Analyses; Disease; Disease Progression; Environmental Exposure; Exhibits; FCGR3B gene; Failure; Flow Cytometry; Functional disorder; Future; Heart failure; Heterogeneity; Homeostasis; Immune; Immune response; Immune system; Individual; Infection; Inflammation; Injury; Interferon Type II; Lead; Ligands; Longitudinal Studies; Longitudinal prospective study; Lung; Lymphocyte; Molecular; Morbidity - disease rate; NCAM1 gene; Natural History; Natural Immunity; Natural Killer Cells; Patients; Phenotype; Population; Population Heterogeneity; Predisposition; Production; Quality of life; Recording of previous events; Research; Risk; Severities; Smoker; Smoking; Structure; Testing; Time; Veterans; adaptive immunity; base; cigarette smoke; cohort; cytokine; cytotoxicity; dimensional analysis; effective therapy; high dimensionality; immune function; individual variation; innovation; insight; longitudinal analysis; military veteran; mortality; never smoker; non-smoker; novel; pathogen; preservation; prospective; pulmonary function; pulmonary function decline; receptor; response

Despite decades of research, no effective therapies exist to circumvent the irreversible alterations in lung function associated with COPD. Further, complications of COPD arise from acute and chronic exacerbations that amplify ongoing injury and remodeling that increase morbidity and mortality. The pathophysiology of exacerbations is poorly understood, but is primarily due to inflammation from infections. Some patients are more susceptible to exacerbations and represent an `exacerbator phenotype' associated with COPD-dependent changes in innate and adaptive immunity. Natural killer (NK) cells are a heterogeneous population of lymphocytes that are important in the defense against infections. They are also involved in initiating and directing active immune responses through cytokine production. NK cells recognize pathogen-infected cells expressing ligands for an array of activating and inhibitory receptors. Research by our lab and others identified multiple effects of smoking on NK cell function that suggest these changes are significant in the pathophysiology of COPD exacerbations. Traditionally, NK cells were divided into immature and mature subpopulations based on CD16 and CD56 expression. Recently, high-dimensional analysis of NK cells revealed a surprisingly high degree of phenotypic diversity and that each individual has thousands of unique populations of NK cells. Although the expression of various NK cell surface markers provides clues about the function of subpopulations, the significance of each populations is unknown. Therefore, we probed NK cell phenotypes from a cohort of non-smokers, smokers, and COPD patients targeting NK cell activating and inhibitory receptors. These studies revealed several unique NK cell populations that differed between groups. Further analyses showed that the size of NK cell subsets associated with a previous exacerbation with 95% confidence. Based on these findings, we hypothesized that smoking alters NK cell heterogeneity which leads to the emergence of unique populations that can serve as biomarkers of increased risk of COPD exacerbations. We will test this hypothesis with the following Specific Aims: Aim 1: Define the natural history of NK cell diversity and plasticity in never smokers and smokers. Previous analyses of NK cell populations over time are based on limited phenotyping and high-dimensional analyses of NK cell populations have been derived from a single time point. To advance our understanding of the heterogeneity of NK cell populations over time, we will conduct a 3-year prospective longitudinal analysis of NK cell plasticity in never smokers and current smokers without COPD. Aim 2. Define whether alterations in NK cell populations precede or occur following exacerbations in COPD to determine the usefulness of NK cell phenotyping as a biomarker of future exacerbations. Preliminary data identify alterations in NK cell subsets associated with COPD exacerbations. However, we do not know if these alterations precede and predict future COPD exacerbations or if they arise as a consequence of exacerbations. Further, if COPD exacerbations trigger changes in NK cell populations, it is not known if these derangements persist finitely or indefinitely. Aim 3. Define the functional significance of unique NK cell populations associated with COPD exacerbations. We show that only 15-30% of bulk NK cells respond to cytokine stimulation to elaborate proinflammatory cytokines. This indicates that a specific subpopulation(s) is uniquely capable of generating a response. NK cells have obvious importance in immune homeostasis. Therefore, future treatment options for COPD exacerbations require a balanced approach reflecting the need to preserve/restore necessary effector functions without disarming or overstimulating the entirety of the NK cells. This Aim will provide a critical advance in our understanding of the functional heterogeneity of NK cells in COPD and reveal insight into the significance of the NK cell subpopulations associated with COPD exacerbations.

尽管经过了数十年的研究，仍然没有有效的疗法来规避不可逆的改变 肺功能与 COPD 相关。此外，COPD 的并发症由急性和慢性引起。 恶化会加剧持续的损伤和重塑，从而增加发病率和死亡率。这 对恶化的病理生理学知之甚少，但主要是由于感染引起的炎症。 一些患者更容易出现病情加重，并表现出与病情相关的“加重表型” 与慢性阻塞性肺病相关的先天性和适应性免疫的变化。自然杀伤 (NK) 细胞是 对防御感染很重要的异质淋巴细胞群。他们也是 通过细胞因子的产生参与启动和指导主动免疫反应。 NK 细胞识别 被病原体感染的细胞表达一系列激活和抑制受体的配体。研究人员 我们的实验室和其他人发现了吸烟对 NK 细胞功能的多种影响，表明这些变化是 在 COPD 恶化的病理生理学中具有重要意义。传统上，NK细胞被分为未成熟细胞 以及基于 CD16 和 CD56 表达的成熟亚群。最近，高维分析 NK 细胞显示出令人惊讶的高度表型多样性，每个个体都有数千个表型多样性 独特的 NK 细胞群。尽管各种NK细胞表面标志物的表达提供了线索 关于亚群体的功能，每个群体的意义是未知的。因此，我们探究了 一组非吸烟者、吸烟者和 COPD 患者针对 NK 细胞激活的 NK 细胞表型 和抑制性受体。这些研究揭示了几种独特的 NK 细胞群，它们之间存在差异 组。进一步的分析表明 NK 细胞亚群的大小与之前的病情恶化相关 95% 的信心。基于这些发现，我们假设吸烟会改变 NK 细胞异质性 这导致了可以作为慢性阻塞性肺病风险增加的生物标志物的独特人群的出现 病情加重。我们将通过以下具体目标来检验这一假设： 目标 1：定义自然历史 从不吸烟者和吸烟者的 NK 细胞多样性和可塑性。先前对 NK 细胞群的分析 随着时间的推移，基于有限的表型分析和 NK 细胞群的高维分析 从单个时间点得出。增进我们对 NK 细胞群异质性的理解 随着时间的推移，我们将对从不吸烟者的 NK 细胞可塑性进行为期 3 年的前瞻性纵向分析 以及目前没有慢性阻塞性肺病 (COPD) 的吸烟者。目标 2. 定义 NK 细胞群的改变是否先于或 发生在 COPD 恶化后，以确定 NK 细胞表型作为生物标志物的有用性 未来病情恶化。初步数据确定了与慢性阻塞性肺病相关的 NK 细胞亚群的变化 病情加重。然而，我们不知道这些改变是否先于并预测未来的慢性阻塞性肺病恶化 或者如果它们是由于病情恶化而出现的。此外，如果 COPD 恶化引发 NK 变化 细胞群中，尚不清楚这些紊乱是否有限地或无限期地持续。目标 3. 定义 与 COPD 恶化相关的独特 NK 细胞群的功能意义。我们表明 只有 15-30% 的大量 NK 细胞对细胞因子刺激产生反应，产生促炎细胞因子。这 表示特定的亚群具有独特的能力产生响应。 NK 细胞有 在免疫稳态中具有明显的重要性。因此，COPD 急性加重的未来治疗选择 需要一种平衡的方法，反映需要保留/恢复必要的效应器功能，而不需要 解除或过度刺激整个 NK 细胞。这一目标将在我们的 了解 COPD 中 NK 细胞的功能异质性并揭示其重要性 与 COPD 恶化相关的 NK 细胞亚群。