Immunometabolic phenotypes in adult severe asthma and disease progression

摘要 拟议中的实验将检验这一假设：广泛的纵向和免疫代谢 表型分析将促进我们对SA异质性机制的理解，并提供信息 未来的治疗发展和临床管理策略。具体地说，全面 表型分析将揭示SA患者不同的生物学机制和临床结果 持续性的2型炎症，非2型疾病，和有缺陷的解决。 重症哮喘(SA)的特征是持续的呼吸道炎症，呼吸道高反应性，以及 尽管使用了糖皮质激素，但肺功能下降。在这里，我们建议延长NHLBI重症哮喘 研究计划(SARP)，用于对SA进行平移的、纵向的机械研究。这项纵向研究 设计代表了提供关于SA内表型和稳定性的信息的必要的下一步 它们与疾病严重程度和进展的关系。 对SA呼吸道炎症的研究发现了异质性的病理生物学。约50%的 患者的特点是2型(T2)炎症增加；最近的发现导致了新的T2 有针对性的治疗。仍然需要继续和迫切地进一步阐明潜在的机制 SA亚群的不同病理生物学为风险分层提供分子表型，新 治疗发展，特别是针对非T2炎症的治疗，以及精确的临床管理。 在过去的6年里，SARP招募了一大批美国的SA患者。受试者是全面的 以基线为特征，然后经过三年的纵向跟踪监测，导致显著 对SA的临床、结构、功能和免疫代谢障碍的新见解。在进行中的工作中， 3年纵向随访分析确定了3种主要免疫表型：(1)持续性T2 炎症，(2)间歇性T2炎症，(3)持续性非T2炎症。免疫表型 在演示时既有相似之处，也有不同之处，差异在3年内进一步演变 纵向随访(例如，支气管扩张剂反应性的变化、恶化的风险；见下文)。在……里面 除肺部特异性炎症外，许多SA患者还有全身炎症、代谢功能障碍 以及解决机制上的缺陷。为了解决我们的主要假设，我们提出了一个全国性的多中心 采用机械化翻译方法的协作学习，有4个具体目标，以严格和 全面研究SA免疫代谢表型的分子和细胞来源及其机制 与疾病进展的关系。

Abstract The proposed experiments will test the hypothesis: Extensive longitudinal and immunometabolic phenotyping will advance our understanding of the heterogeneous mechanisms for SA and inform future therapeutic development and clinical management strategies. Specifically, comprehensive phenotyping will reveal distinct biological mechanisms and clinical outcomes for SA patients with persistent type 2 inflammation, non-type 2 disease, and defective resolution. Severe asthma (SA) is characterized by persistent airway inflammation, airway hyper-responsiveness, and decreased lung function despite glucocorticoids. Here, we are proposing to extend the NHLBI Severe Asthma Research Program (SARP) for a translational, longitudinal mechanistic study of SA. This longitudinal study design represents an essential “next step” to provide information on the stability of SA endophenotypes and their relationship to disease severity and progression. Investigation into SA airway inflammation has uncovered heterogeneous pathobiology. Approximately 50% of patients are characterized by increased type 2 (T2) inflammation; discoveries that led recently to new T2 targeted therapies. There remains a continuing and critical need to further elucidate mechanisms underlying the distinct pathobiology in subpopulations of SA to provide molecular phenotyping for risk stratification, new therapeutic development, especially for non-T2 inflammation, and precision clinical management. Over the last 6 years, SARP has recruited a large US cohort of SA patients. Subjects were comprehensively characterized at baseline and then monitored over three years of longitudinal follow up, leading to significant new insights into clinical, structural, functional and immunometabolic disturbances in SA. In work in progress, analyses of 3-year longitudinal follow-up has established 3 principal immunophenotypes: (1) persistent T2 inflammation, (2) intermittent T2 inflammation, and (3) persistent non-T2 inflammation. The immunophenotypes had both similarities and differences at presentation with differences evolving further over 3 years of longitudinal follow up (e.g., changes in bronchodilator responsiveness, risk for exacerbations; vide infra). In addition to lung specific inflammation, many SA patients have systemic inflammation, metabolic dysfunction and defects in resolution mechanisms. To address our main hypothesis, we propose a national, multicenter collaborative study with a mechanistic translational approach with 4 specific aims to rigorously and comprehensively investigate the molecular and cellular origin of SA immunometabolic phenotypes and their relationship to disease progression.