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Immunopathobiology of chronic lung disease.
Clinical & Translational Immunology ( IF 4.6 ) Pub Date : 2020-08-24 , DOI: 10.1002/cti2.1170
Cecilia M Prêle 1, 2, 3 , Gerard F Hoyne 2, 4
Affiliation  

The lung epithelium is a cellular barrier that protects the lung from environmental exposure to pathogens and chemical insults that could otherwise compromise its physiological role in gas exchange during respiration. In the distal lung, the exchange of oxygen and carbon dioxide occurs within the alveoli, facilitated by type I alveolar epithelial cells (AECs). In addition to their important role in gas exchange, mucus and surfactant secreted by AECs contain a range of host‐defence proteins which aid epithelial barrier function and protection from invading pathogens. The lung epithelium is supported by a network of mesenchymal cells including fibroblasts that form the basement membrane that acts as a further layer of protection to prevent access of microbes to the underlying tissue.

Many interstitial lung diseases (ILDs) share similar clinical symptoms and findings on radiographic or pathologic assessment often making diagnosis difficult. The accurate diagnosis of an ILD is critical for the long‐term management of the disease and can inform the choice of treatment a patient receives and their prognosis. We are beginning to appreciate the importance that immune status has on disease progression and clinical outcome. In this Special Feature of Clinical & Translational Immunology, the reviews include a broad range of topics examining the clinical challenges associated with the diagnosis of ILDs and the nature of the innate and adaptive immune responses elicited following tissue damage in ILDs and in lung regeneration. This series of articles explores how the immune response is modulated during lung cancer and how novel immunotherapeutic approaches are being explored to treat this disease. The use of animal models to study the pathobiology of ILDs is discussed and highlights how these models may inform novel therapeutic strategies to treat ILDs or lung cancer in humans.

The review by McLean‐Tooke and colleagues examines the challenges associated with the accurate diagnosis of ILDs in patients.1 There are over 200 different entities of ILDs that have been described. Many exhibit low occurrence rates within the human population which can impact on the accuracy of clinical diagnosis and the ability to study disease pathogenesis. The authors focus on two main diseases: idiopathic pulmonary fibrosis, (IPF) which develops late in life and has a poor prognosis of 2–5 years, and interstitial pneumonia with autoimmune features (IPAF), a feature associated with connective tissue disorders (CTD) that include rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Patients who do not meet the specific criteria of CTD are given a diagnosis of IPAF. Both IPF and IPAF share similar disease symptoms, as well as radiologic and pathologic features, making clinical diagnosis difficult. Some IPAF patients can progress to become CTD, while others do not. The review examines the various diagnostic criteria of histopathology and autoimmune serology to screen for various autoantibodies to systemic autoantigens. Although previous genome‐wide association studies have identified a number of genes that influence susceptibility to familial IPF and IPAF, including MUC5B, SPC (epithelial cells), TOLLIP (innate immune cells) or PARN, TERT (telomere genes),2-4 genetic screening of IPF or IPAF for diagnostic purposes is not yet routine.

The reviews by Warheit‐Niemi et al.5 and Denneney et al.6 examine innate immune function in chronic lung disease. The discovery of pattern recognition receptors (PRRs) and their ability to bind both pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs) have helped our understanding of the intimate connection between the innate and adaptive immune system.7 Triggering of PRRs on epithelial cells or innate cells such as macrophages and neutrophils stimulates the release of proinflammatory cytokines/chemokines and effector responses (phagocytosis) to help control infection and promote tissue repair mechanisms to limit inflammation. Warheit‐Niemi et al.5 provide a comprehensive overview of the innate immune response to lung immunity and fibrosis. They discuss various preclinical models in mice that have been used to dissect the effector response in lung fibrosis. Consideration is also given to the role of microbial infection as a driver of lung fibrosis. As epithelial cells, fibroblasts and innate immune cells share the ability to express PRRs, they play a pivotal role in directing the nature and chronicity of the inflammatory response. Therefore, it is crucial to understand how recognition of common respiratory pathogens or commensal organisms within the lung microbiota may impact on lung fibrosis. Denenney et al.6 focus on the role of mucins and their receptors in chronic lung disease. Mucus secreted by epithelial cells forms a natural barrier to protect the surface of the lung epithelium from microbes. The mucus is composed of a range of mucin proteins, and these can have important immunomodulatory effects on the innate and adaptive immune responses. The functions of various mucins are examined in both health and disease with a focus on pulmonary fibrosis and other chronic lung conditions such as COPD, asthma, bronchiectasis and lung cancer.

Lucas et al.8 provide an overview of the cellular and molecular mechanisms that underpin regenerative processes in the lung following acute or chronic damage. They provide insights into the role of innate and adaptive immune responses in this process. The early response to lung damage involves recognition of PAMPS or DAMPs by PRRs on tissue‐resident innate or memory T cells. The balance of TH1/TH17 and Tregs appears crucial for tissue repair processes mediated via interleukin (IL)‐17, IL‐23, IL‐10 and IL‐22. Dysregulated immune responses are the hallmark of chronic inflammatory diseases such as COPD and IPF. Lucas et al. describe a range of preclinical mouse studies using various anti‐cytokine therapy approaches and cytokine gene knockout models. Although some of these approaches have shown promise, this success has not yet been translated to human patients. Collectively, the three reviews by Warheit‐Niemi et al., Denneney et al. and Lucas et al. highlight the important role of innate and adaptive immune responses in tissue damage and repair mechanisms.

Miles et al.9 investigate a range of animal models that have been used to study the disease pathogenesis of human IPF. Some animals (e.g. dogs and horses) develop a spontaneous form of interstitial lung disease which resembles many of the clinical features of IPF by radiologic criteria. In contrast, mice do not normally develop spontaneous pulmonary fibrosis. Rather, the delivery of various chemical or drug insults can induce acute lung injury that develops into tissue fibrosis. Although the use of some of these animal models and their relevance to human disease has been debated over the years, it is generally accepted that they provide valuable insight into the cellular and molecular mechanisms driving the fibrogenic process. Furthermore, the mouse immune system is highly analogous to that of humans, and the ease of genetic manipulation in mice has made them a common choice to study disease pathogenesis. Genetic studies in congenic mouse strains have helped define genetic loci that predispose to pulmonary fibrosis following bleomycin treatment. Some of the genes are involved in activation of TCRγδ cells10 which are known to play crucial roles in mucosal immune regulation in mouse and humans.

The final review by Neeve et al.11 examines the role of T cells in the control of lung cancer. Anti‐tumor responses in the immune system require a coordinated response by both innate and adaptive immune cells. The activation of tumor‐specific CD8+ cytotoxic T cells is critical for eliminating cancer cells and reducing tumor burden. However, it is now known that tumor cells can subvert the immune system by expressing checkpoint ligands which bind to inhibitory receptors on T cells, rendering them ineffective for tumor surveillance and eradication. A range of checkpoint inhibitory receptors and ligands have been defined and are being evaluated in a range of clinical trials in cancer. Checkpoint therapy has revolutionised cancer therapy for melanoma, and it is being evaluated for the treatment of lung cancer and other cancer types. Early indications are that monotherapies of checkpoint inhibitors in lung cancer may not be effective in all tumors, thus prompting the use of combination therapies.12

Chronic diseases of the lung, such as pulmonary fibrosis or lung cancer, can disrupt the delicate tissue architecture and compromise gas exchange across alveoli. If disease pathology is not arrested, it can severely impact the quality of life and long‐term survival of the patient. We need to better understand the complex relationship between host genetics, the environment, and the host immune response, and how this shapes disease pathogenesis within the lung. Improved diagnostics will be developed with integration of new emerging technologies such as immune cell phenotyping, transcriptomics and metabolomics that may help to better stratify patients into appropriate clinical subgroups. This may have the benefit of improving the outcome of clinical trials of novel interventions that may be targeted to a specific response pathway.



中文翻译:


慢性肺病的免疫病理学。



肺上皮是一种细胞屏障,可保护肺部免受环境暴露于病原体和化学损伤的影响,否则可能会损害其在呼吸过程中气体交换的生理作用。在远端肺中,氧气和二氧化碳的交换发生在肺泡内,由 I 型肺泡上皮细胞 (AEC) 促进。除了在气体交换中的重要作用外,AEC 分泌的粘液和表面活性剂还含有一系列宿主防御蛋白,有助于上皮屏障功能和防止病原体入侵。肺上皮由间充质细胞网络支持,其中包括形成基底膜的成纤维细胞,基底膜充当进一步的保护层,以防止微生物进入下面的组织。


许多间质性肺疾病 (ILD) 具有相似的临床症状和放射学或病理评估结果,往往使诊断变得困难。 ILD 的准确诊断对于疾病的长期管理至关重要,可以为患者接受的治疗选择及其预后提供信息。我们开始认识到免疫状态对疾病进展和临床结果的重要性。在本期《临床与转化免疫学》专题中,综述涵盖了广泛的主题,探讨了与 ILD 诊断相关的临床挑战,以及 ILD 组织损伤和肺再生后引发的先天性和适应性免疫反应的性质。本系列文章探讨了肺癌期间免疫反应是如何调节的,以及如何探索新的免疫治疗方法来治疗这种疾病。讨论了使用动物模型研究 ILD 的病理学,并强调了这些模型如何为治疗人类 ILD 或肺癌提供新的治疗策略。


McLean‐Tooke 及其同事的综述探讨了准确诊断患者间质性肺病 (ILD) 所面临的挑战。 1已描述了 200 多种不同的 ILD 实体。许多疾病在人群中的发生率较低,这可能会影响临床诊断的准确性和研究疾病发病机制的能力。作者重点关注两种主要疾病:特发性肺纤维化 (IPF),其在生命晚期发生,预后不良,2-5 年;具有自身免疫特征的间质性肺炎 (IPAF),一种与结缔组织疾病 (CTD) 相关的特征),包括类风湿性关节炎、系统性红斑狼疮和系统性硬化症。不符合 CTD 特定标准的患者将被诊断为 IPAF。 IPF和IPAF都有相似的疾病症状以及放射学和病理特征,使得临床诊断变得困难。一些 IPAF 患者可能会发展为 CTD,而其他患者则不会。该综述检查了组织病理学和自身免疫血清学的各种诊断标准,以筛选针对全身性自身抗原的各种自身抗体。尽管之前的全基因组关联研究已经确定了许多影响家族性IPF和IPAF易感性的基因,包括MUC5BSPC (上皮细胞)、 TOLLIP (先天免疫细胞)或PARNTERT (端粒基因)、 2-4个遗传基因。用于诊断目的的 IPF 或 IPAF 筛查尚未成为常规。


Warheit‐Niemi等人的评论。 5和丹尼尼等人6检查慢性肺部疾病的先天免疫功能。模式识别受体(PRR)的发现及其结合病原体相关分子模式(PAMP)和危险相关分子模式(DAMP)的能力有助于我们理解先天免疫系统和适应性免疫系统之间的密切联系。 7触发上皮细胞或巨噬细胞和中性粒细胞等先天细胞上的 PRR 会刺激促炎细胞因子/趋化因子的释放和效应反应(吞噬作用),以帮助控制感染并促进组织修复机制以限制炎症。 Warheit-Niemi等人图 5全面概述了对肺免疫和纤维化的先天免疫反应。他们讨论了用于剖析肺纤维化效应反应的小鼠的各种临床前模型。还考虑了微生物感染作为肺纤维化驱动因素的作用。由于上皮细胞、成纤维细胞和先天免疫细胞都具有表达 PRR 的能力,因此它们在指导炎症反应的性质和慢性方面发挥着关键作用。因此,了解肺微生物群内常见呼吸道病原体或共生生物的识别如何影响肺纤维化至关重要。丹尼尼等人6重点关注粘蛋白及其受体在慢性肺部疾病中的作用。上皮细胞分泌的粘液形成天然屏障,保护肺上皮表面免受微生物侵害。 粘液由一系列粘蛋白组成,这些蛋白对先天性和适应性免疫反应具有重要的免疫调节作用。在健康和疾病中检查各种粘蛋白的功能,重点关注肺纤维化和其他慢性肺部疾病,如慢性阻塞性肺病、哮喘、支气管扩张和肺癌。


卢卡斯等人图8概述了支持急性或慢性损伤后肺部再生过程的细胞和分子机制。他们提供了关于先天性和适应性免疫反应在此过程中的作用的见解。对肺损伤的早期反应涉及组织驻留先天或记忆 T 细胞上的 PRR 识别 PAMPS 或 DAMP。 TH1/TH17 和 Tregs 的平衡对于白细胞介素 (IL)-17、IL-23、IL-10 和 IL-22 介导的组织修复过程至关重要。免疫反应失调是慢性阻塞性肺病和特发性肺纤维化等慢性炎症性疾病的标志。卢卡斯等人。描述了使用各种抗细胞因子治疗方法和细胞因子基因敲除模型进行的一系列临床前小鼠研究。尽管其中一些方法已显示出希望,但这种成功尚未转化为人类患者。总的来说,Warheit-Niemi人、Denneney等人的三篇评论。和卢卡斯等人。强调先天性和适应性免疫反应在组织损伤和修复机制中的重要作用。


迈尔斯等人9研究了一系列用于研究人类 IPF 疾病发病机制的动物模型。一些动物(例如狗和马)会出现自发性间质性肺疾病,根据放射学标准,其与 IPF 的许多临床特征相似。相反,小鼠通常不会发生自发性肺纤维化。相反,各种化学或药物损伤的传递会引起急性肺损伤,进而发展成组织纤维化。尽管这些动物模型的使用及其与人类疾病的相关性多年来一直存在争议,但人们普遍认为它们为驱动纤维形成过程的细胞和分子机制提供了有价值的见解。此外,小鼠的免疫系统与人类的免疫系统高度相似,并且小鼠易于进行基因操作,使其成为研究疾病发病机制的常见选择。对同系小鼠品系的遗传学研究有助于确定博来霉素治疗后易发生肺纤维化的遗传位点。其中一些基因参与 TCRγδ 细胞10的激活,已知这些细胞在小鼠和人类的粘膜免疫调节中发挥着至关重要的作用。


Neeve等人的最终审查。图11检查了T细胞在控制肺癌中的作用。免疫系统中的抗肿瘤反应需要先天性免疫细胞和适应性免疫细胞的协调反应。肿瘤特异性 CD8 +细胞毒性 T 细胞的激活对于消除癌细胞和减轻肿瘤负荷至关重要。然而,现在已知肿瘤细胞可以通过表达与 T 细胞上的抑制性受体结合的检查点配体来破坏免疫系统,从而使它们无法有效监视和根除肿瘤。一系列检查点抑制受体和配体已被定义,并正在一系列癌症临床试验中进行评估。检查点疗法彻底改变了黑色素瘤的癌症治疗方法,并且正在评估其对肺癌和其他癌症类型的治疗效果。早期迹象表明,肺癌检查点抑制剂的单一疗法可能并非对所有肿瘤都有效,因此促使联合疗法的使用。 12


肺部慢性疾病,例如肺纤维化或肺癌,会破坏脆弱的组织结构并损害肺泡之间的气体交换。如果疾病病理没有得到遏制,可能会严重影响患者的生活质量和长期生存。我们需要更好地了解宿主遗传学、环境和宿主免疫反应之间的复杂关系,以及它如何影响肺部疾病的发病机制。将通过整合免疫细胞表型、转录组学和代谢组学等新兴技术来开发改进的诊断方法,这可能有助于更好地将患者分为适当的临床亚组。这可能有利于改善针对特定反应途径的新型干预措施的临床试验结果。

更新日期:2020-08-25
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