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，其特征是肺功能逐渐丧失、严重残疾和死亡。然而，考虑到患者的异质性，额外的风险和遗传因素会导致肺功能的下降。相当一部分患者同时具有COPD和哮喘的特征。结果，包括与健康相关的生活质量损害，合并COPD和哮喘患者比单独患有COPD的患者更差。目前，关于慢性阻塞性肺病和哮喘患者出现更严重疾病和治疗难治性的机制的信息很少。我们假设的核心是T淋巴细胞的一个亚群，CD8+ T细胞，是导致更严重疾病的主要因素。在严重类固醇抵抗性哮喘患者以及小鼠模型中，我们发现CD8+ T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。与CD4+ T细胞不同，CD8+ T细胞对类固醇不敏感。此外，由于CD8+ T细胞在肺组织中的优势地位，它们与COPD有关。与类固醇耐受性哮喘患者类似，肺实质和小气道中的CD8+ T细胞数量与肺功能和哮喘相关炎症途径（2型，IL-13）呈负相关，已被证明有助于疾病的发病机制。探索与不同COPD表型相关的细胞和分子机制（内型），包括COPD合并哮喘患者，存在很大的兴趣。目前的建议解决了这一重要但未满足的需求，即使用候选方法结合非靶向方法来了解同一患者COPD和哮喘的后果。分析伴有或不伴有哮喘的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。慢性阻塞性肺病不是一种统一的疾病，但通过这种方法，将开发新的标识符来区分和分类不同亚群的慢性阻塞性肺病患者。我们将进一步阐明烟雾暴露在伴或不伴哮喘的COPD患者中如何改变导致致病性CD8+ T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一部分可能受益于维生素D治疗和新型IL-4/IL-13双受体拮抗剂dupilumab的患者。作为扩展，我们将能够发现COPD和哮喘合并诊断患者特异性的新靶基因。实现这些里程碑将使我们在个性化医疗方面取得进展，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.