A prominent role for the IL1 pathway and IL15 in susceptibility to chronic cavitary pulmonary aspergillosis
A prominent role for the IL1 pathway and IL15 in susceptibility to chronic cavitary pulmonary aspergillosis
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DOI：
10.1111/1469-0691.12473
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发表时间：
2014-08-01
影响因子：
14.2
通讯作者：
Denning, D. W.
中科院分区：
文献类型：
--
作者：
Smith, N. L. D.;Hankinson, J.;Denning, D. W.
慢性空洞性肺曲霉病（CCPA）是一种进行性肺部疾病，年死亡率为10-30%。虽然明显免疫活性，但患者可能存在某些免疫遗传缺陷。为了研究CCPA中可能的免疫遗传缺陷，我们分析了112名CCPA患者和279名健康对照的生物学上合理的候选基因，这些基因参与了对烟曲霉菌的识别后免疫反应的基因的遗传关联研究。我们还比较了在基线和A.烟熏。与健康受试者的巨噬细胞相比，CCPA巨噬细胞在整个实验过程中显示出IL 1A、IL 1B、IL 6、IRAK 2和TRAF 6的无限制升高，并且在9 h时缺乏TGF β 1的表达。在IL 1B（n = 2）、IL 1 RN和IL 15（n = 3）中发现了与CCPA相关的单核苷酸多态性（SNP）。IL 1和IL 6的不受控制的表达以及这些细胞因子的持续高水平可能导致持续的细胞内流和促炎反应，抑制疾病消退并促进CCPA中的疾病进展。IL 1B、IL 1 RN和IL 15中的SNP与CCPA的关联支持了IL 1途径的作用，以及暗示了IL 15基因在对CCPA的易感性中的作用。
Chronic cavitary pulmonary aspergillosis (CCPA) is a progressive lung condition with a 10-30% annual mortality. Although overtly immunocompetent, some immunogenetic defect in patients is likely. To investigate a possible immunogenetic defect in CCPA, we analysed biologically plausible candidate genes in 112 CCPA patients and 279 healthy controls in a genetic association study of genes involved in the post-recognition immune response to Aspergillus fumigatus. We also compared gene expression in monocyte-derived macrophages from subjects with and without disease, both at baseline and during stimulation with A. fumigatus. Compared with macrophages from healthy subjects, CCPA macrophages showed unrestrained rises in IL1A, IL1B, IL6, IRAK2 and TRAF6 throughout the experiment, and a lack of expression of TGFB1 at 9 h. Single nucleotide polymorphisms (SNPs) associated with CCPA were found in IL1B (n = 2), IL1RN and IL15 (n = 3). Uncontrolled expression of IL1 and IL6 and continuing high levels of these cytokines may result in continuing cellular influx and pro-inflammatory responses, inhibiting disease resolution and contributing to disease progression in CCPA. The association of SNPs in IL1B, IL1RN and IL15 with CCPA supports a role for the IL1 pathway, as well as implicating the IL15 gene, in susceptibility to CCPA.