Clinical significance of invariant natural killer T cells and IL-5 in acute eosinophilic pneumonia
Clinical significance of invariant natural killer T cells and IL-5 in acute eosinophilic pneumonia
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恒定自然杀伤T细胞和IL-5在急性嗜酸性肺炎中的临床意义
DOI：
10.1016/j.alit.2020.09.013
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发表时间：
2021
影响因子：
6.8
通讯作者：
Hizawa Nobuyuki
中科院分区：
文献类型：
--
作者：
Yoshida Kazufumi;Morishima Yuko;Ishii Yukio;Matsuno Yosuke;Kiwamoto Takumi;Matsuyama Masashi;Hizawa Nobuyuki
急性嗜酸性粒细胞性肺炎（AEP）是一种过敏性肺部炎症，与急性发热、严重低氧血症、弥漫性肺浸润和BAL液中嗜酸性粒细胞增多有关。尽管目前尚不清楚AEP的发病机制是否与其他嗜酸性粒细胞性肺病（如慢性嗜酸性粒细胞性肺炎（CEP））不同，但与CEP患者相比，AEP患者往往会出现更严重和更快速进展的症状，包括发热、呼吸急促和胸痛。先前暴露于烟草烟雾或其他吸入物质被认为有助于AEP的发展，但不是CEP。1 Th 2淋巴细胞和Th 2细胞因子，如IL-4、IL-5和IL-13，在过敏性炎症反应中具有充分表征的作用。然而，炎症细胞和细胞因子促进嗜酸性粒细胞炎症的机制，特别是在AEP中，仍然不清楚。以前的研究表明，自然杀伤（NK）细胞和NK T（NKT）细胞也可能调节嗜酸性粒细胞性肺炎。2虽然该研究没有区分AEP和CEP患者，但数据很有趣，因为它们表明使用有限数量的T细胞受体（TCR）Va和Vb链的不变NKT（iNKT）细胞亚群可以影响免疫应答早期的Th细胞极化并诱导Th 2偏向性应答。3在此，我们旨在确定iNKT细胞是否参与AEP的发病机制。在2000年6月至2020年5月期间，我们招募了14名AEP患者、40名CEP患者和14名健康志愿者参与本研究（补充表1）。本研究已获得筑波大学医院研究伦理委员会的批准（批准代码H24-140）。所有受试者均按照机构指南和赫尔辛基宣言提供知情同意书。14例AEP患者包括4例男性和10例女性，年龄15 - 31岁，其中11例为当前吸烟者，3例为从不吸烟者。AEP的诊断基于典型的临床表现，即急性发热伴呼吸急促持续时间小于2周，胸片上弥漫性肺浸润，以及BAL液中嗜酸性粒细胞占总白细胞的25%以上。40例CEP患者包括23例男性和17例女性，年龄31 - 83岁，其中10例为当前吸烟者，11例为既往吸烟者，19例为从不吸烟者。CEP的诊断基于慢性肺炎，症状为持续数周的轻微发热和呼吸急促;双侧肺浸润，以外周为主分布;肺泡嗜酸性粒细胞增多，与AEP相同。14名健康受试者包括11名男性和3名女性，年龄16 - 38岁，其中4名为当前吸烟者，10名为从不吸烟者。方法学详情见补充方法。与健康受试者相比，AEP和CEP患者BAL液中的嗜酸性粒细胞数量显著较高，但两组嗜酸性粒细胞性肺炎之间无显著差异（补充表1）。与CEP患者或健康对照相比，AEP患者的BAL液中iNKT细胞（定义为TCRVa 24 + Vb 11+）的百分比和数量显著更高（图1A，B），而总Th细胞（CD 3 + CD 4+）在这些组中没有差异。关于吸烟对iNKT细胞的肺泡浸润的影响，我们发现在任何组中，BAL液中iNKT细胞的数量不受吸烟状态（当前吸烟者与非吸烟者或前吸烟者）的影响：AEP（134.2±36.1 vs. 74.9±58.0; p= 0.44），CEP（3.8±1.3 vs. 74.9±58.0; p = 0.44）。
Acute eosinophilic pneumonia (AEP) is an allergic lung inflammation associated with acute fever, severe hypoxemia, diffuse pulmonary infiltration, and eosinophilia in BAL fluid. Although it is not known whether the pathogenesis of AEP differs from that of other eosinophilic lung diseases, such as chronic eosinophilic pneumonia (CEP), patients with AEP tend to experience more severe and more rapidly progressing symptoms, including fever, shortness of breath, and chest pain, as compared with patients with CEP. Preceding exposure to tobacco smoke or other inhaled substances has been suggested to contribute to the development of AEP but not CEP. 1 Th2 lymphocytes and Th2 cytokines, such as IL-4, IL-5, and IL-13, have well-characterized roles in allergic inflammatory responses. However, the mechanisms by which inflammatory cells and cytokines promote eosinophilic inflammation, especially in AEP, are still obscure. A previous study suggested that natural killer (NK) cells and NK T (NKT) cells may also regulate eosinophilic pneumonias. 2 Although that study did not differentiate between patients with AEP and CEP, the data were interesting because they showed that a subset of invariant NKT (iNKT) cells, which use a limited number of T-cell receptor (TCR) Va and Vb chains, can affect the Th cell polarization early in an immune response and induce a Th2-biased response. 3 Here, we aimed to determine whether iNKT cells could contribute to the pathogenesis of AEP. Between June 2000 and May 2020, we recruited 14 patients with AEP, 40 patients with CEP, and 14 healthy volunteers to participate in this study (Supplementary Table 1). This study was approved by the Research Ethics Committee of the University of Tsukuba Hospital (approval code H24-140). All subjects provided informed consent in accordance with institutional guidelines and the Declaration of Helsinki. The 14 patients with AEP included 4 men and 10 women aged 15e31 years, of whom 11 were current smokers and 3 were never-smokers. AEP was diagnosed on the basis of typical clinical presentation, ie, acute fever with shortness of breath of less than 2 weeks’ duration, diffuse pulmonary infiltrates on chest radiographs, and the presence of eosinophils as more than 25% of total leukocytes in the BAL fluid. The 40 CEP patients included 23 men and 17 women aged 31e83 years, of whom 10 were current smokers, 11 were ex-smokers, and 19 were neversmokers. CEP was diagnosed on the basis of chronic pneumonia with symptoms of slight fever and shortness of breath persisting over several weeks; bilateral pulmonary infiltrates, with peripheral dominant distribution; and alveolar eosinophilia as for AEP. The 14 healthy subjects included 11 men and 3 women aged 16e38 years, of whom 4 were current smokers and 10 were never-smokers. Methodological details can be found in the Supplementary Methods.The eosinophil numbers in BAL fluid were significantly higher in both AEP and CEP patients as compared with healthy subjects, but there was no significant difference between the two eosinophilic pneumonia groups (Supplementary Table 1). The percentage and number of iNKT cells (defined as TCRVa24+ Vb11+) in BAL fluid were markedly higher for AEP patients compared with CEP patients or healthy controls (Fig. 1 A, B), whereas total Th cells (CD3+ CD4+) did not differ among these groups. Regarding the effect of smoking on the alveolar infiltration of iNKT cells, we found that the numbers of iNKT cells in BAL fluid were not affected by smoking status (current smoker vs. non-or ex-smoker) in any groups: AEP (134.2±36.1 vs. 74.9±58.0; p= 0.44), CEP (3.8±1.3 vs. 7 …