Distinct molecular endotypes in CD8+ T cells contribute to the pathogenesis of patients with the combination of COPD and asthma.

慢性阻塞性肺疾病(COPD)通常与吸烟有关，其特征是肺功能进行性丧失、严重残疾和死亡。然而，考虑到患者之间的异质性，额外的风险和遗传因素导致肺功能下降。相当一部分患者同时具有COPD和哮喘的特征。与单独患有COPD的患者相比，合并COPD和哮喘的患者的结果，包括与健康相关的生活质量损害，更糟糕。目前，对COPD和哮喘患者更严重的疾病和治疗难治性的定义机制的信息很少。我们假设的核心是T淋巴细胞的一个亚群，CD8 T细胞，是更严重疾病的主要贡献者。在严重的类固醇耐药哮喘患者和小鼠模型中，我们表征了CD8T细胞在具有不同细胞和分子特征的特应性(IL-4)环境中能够产生IL-13的重要作用。CD8T细胞与CD4T细胞不同，它对类固醇不敏感。此外，由于CD8T细胞在肺组织中的优势，CD8T细胞被认为与COPD有关。与激素抵抗型哮喘患者相似，肺实质和小气道中的CD8 T细胞数量与肺功能和哮喘相关的炎症途径(2型、IL-13)呈负相关。人们有兴趣探索与不同COPD表型相关的细胞和分子机制(内型型)，包括COPD患者合并哮喘。目前的建议解决了这一重要但尚未得到满足的需求，即使用候选方法结合非靶向方法了解COPD和哮喘在同一患者中的后果。分析患有或不患有哮喘的COPD患者外周血CD8 T细胞的细胞和分子编程将首次阐明COPD患者亚群之间不同的致病途径。COPD不是一种统一的疾病，但通过这种方法，将开发新的识别器来区分和分类COPD患者的不同亚组。我们将进一步阐明有或没有哮喘的COPD患者的烟雾暴露如何改变导致致病CD8T细胞的网络和途径。这项工作的一个重要推论是，有可能确定可能从维生素D治疗和新型IL-4/IL-13双受体拮抗剂dupilumab中受益的患者子集。作为延伸，我们将能够发现与COPD和哮喘伴随诊断的患者特有的新靶基因。实现这些里程碑将使我们能够朝着个性化药物的方向发展，并改善慢性呼吸道疾病患者的临床实践。

Chronic obstructive pulmonary disease (COPD), most often tobacco smoke-related, is characterized by a progressive loss of lung function, significant disability, and mortality. However, given the heterogeneity among patients, additional risk and genetic factors contribute to the decline in pulmonary function. A significant subset of patients have features of both COPD and asthma. Outcomes, including health-related quality of life impairment, are worse for patients with concomitant COPD and asthma compared to individuals with COPD alone. Presently, little information is available defining mechanisms accounting for more severe disease and treatment refractoriness in patients with COPD and asthma. Central to our hypothesis is that a subset of T lymphocytes, CD8+ T cells, are major contributors to more severe disease. In severe steroid-resistant asthmatics as well as in mouse models, we characterized an important role for CD8+ T cells capable of IL-13 production in an atopic (IL-4) environment with distinct cellular and molecular signatures. CD8+ T cells, unlike CD4+ T cells, are steroid-insensitive. Moreover, CD8+ T cells have been implicated in COPD because of their predominance in lung tissue. Similar to steroid-resistant asthmatics, CD8+ T cell numbers in the lung parenchyma and small airways inversely correlated with lung function and asthma-associated inflammatory pathways (type 2, IL-13) have been shown to contribute to the disease pathogenesis.Substantial interest exists to explore cellular and molecular mechanisms (endoytpes) that can be associated with different COPD phenotypes including COPD patients with co-existing asthma. The current proposal addresses this significant but unmet need to understand the consequences of COPD and asthma in the same patient using a candidate approach coupled with an untargeted approach. Analyzing the cellular and molecular programming of peripheral blood CD8+ T cells from COPD patients with or without asthma will elucidate, for the first time, distinct disease-causing pathways between subsets of COPD patients. COPD is not a uniform disease but with this approach novel identifiers to distinguish and classify different subsets of COPD patients will be developed. We will further elucidate how smoke exposure in COPD patients with or without asthma shifts networks and pathways leading to pathogenic CD8+ T cells. An important corollary to this work is the potential to identify a subset of patients who may benefit from Vitamin D treatment and the novel IL-4/IL-13 dual receptor antagonist, dupilumab. As an extension, we will be able to discover new target genes specific to patients with a concomitant diagnosis of COPD and asthma. Achieving these milestones will allow us to progress towards personalized medicine and to improve clinical practice in patients with chronic respiratory diseases.