MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK Department of Pediatric Respiratory Medicine, Imperial College London, London, UK.
MRC & Asthma UK Centre for Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, UK.
Thorax. 2014 Jun;69(6):508-15. doi: 10.1136/thoraxjnl-2013-203421. Epub 2013 Dec 17.
Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children.
Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1α,25-dihydroxyvitamin D3.
Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p<0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p<0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p<0.001) and decreasing IL-13 (p<0.001) but unexpectedly enhanced IL-17A production in all groups-most strikingly in the STRA cohort (p<0.001). The inclusion of the active form of vitamin D, 1α,25-dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p<0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p<0.01).
These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA.
对哮喘免疫机制的理解源于成人研究。越来越多的人认识到，无论是在免疫学上还是在新型疗法的发展方面，成人的反应都不能准确预测儿童的反应。
我们使用经过明确定义的严重治疗抵抗性哮喘（STRA）患儿队列，通过分析支气管肺泡灌洗液来研究气道中的细胞因子谱。还评估了外周血单核细胞（PBMC）在无或存在地塞米松和 1α，25-二羟维生素 D3 的情况下，在体外经多克隆 T 细胞激活后的细胞因子产生能力。
与非哮喘对照组相比（p<0.001），患有中度和 STRA 的儿童的气道灌洗液样本中的抗炎性白细胞介素（IL）-10 水平明显降低。他们的 PBMC 在培养中也表现出明显受损的 IL-10 分泌能力（p<0.001）。地塞米松调节 PBMC IL-10 和 IL-13 产生之间的平衡，增加 IL-10 分泌（p<0.001）并减少 IL-13（p<0.001），但出乎意料的是，所有组的 IL-17A 产生都增强了-在 STRA 队列中最为明显（p<0.001）。在培养物中加入活性形式的维生素 D，1α，25-二羟维生素 D3，增强了地塞米松诱导的 IL-10（p<0.05），而对 IL-13 或 IL-17A 的产生没有明显影响。此外，全身维生素 D 状态与气道 IL-10 直接相关（r=0.6，p<0.01）。
这些发现表明，儿科哮喘中存在外周和局部 IL-10 合成减少，并支持在严重、难以治疗的哮喘中增强低循环维生素 D 的治疗作用，以纠正受损的 IL-10 水平。相反，类固醇增强了 IL-17A 水平，因此维生素 D 的任何类固醇节省特性在 STRA 中可能具有额外的益处。
