Wang Ni, Brix Susanne, Larsen Jeppe M, Thysen Anna H, Rasmussen Morten A, Workman Christopher T, Stokholm Jakob, Bønnelykke Klaus, Bisgaard Hans, Chawes Bo L
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Gentofte, Denmark.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
Clin Exp Allergy. 2021 Jul;51(7):892-901. doi: 10.1111/cea.13900. Epub 2021 May 29.
Several childhood asthma risk loci that relate to immune function have been identified by genome-wide association studies (GWAS), but the underlying mechanisms remain unknown.
Here, we examined whether perturbed innate immune responses mediate the association between known genetic risk variants and development of childhood asthma.
Peripheral blood mononuclear cells from 336 six-month-old infants from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC ) cohort were stimulated in vitro with six different innate ligands (LPS, CpG, poly(I:C), R848, HDMAPP and aluminium hydroxide together with low levels of LPS) followed by quantification of 18 released cytokines and chemokines 40 h after the stimulations. The innate immune response profiles were decomposed by principal component (PC) analysis, and PC1-5 were used in mediation analyses of the effect of 25 known genetic risk variants on childhood asthma until age 7.
The effects of two variants from the 17q21 locus (rs7216389, rs2305480) on asthma and exacerbation risk were significantly mediated by immune parameters induced in response to ligands mimicking intracellular colonization; bacterial DNA (CpG) and double-stranded viral RNA (poly(I:C)). The Th17 and innate lymphoid cell type 3-amplifying cytokine IL-23 was the most prominent cytokine involved.
The 17q21 effect on childhood asthma and exacerbations was partly mediated by deregulation of IL-23 in response to intracellular microbial ligands, which may suggest ineffective clearance of intracellular pathogens in the lungs.
全基因组关联研究（GWAS）已鉴定出多个与免疫功能相关的儿童哮喘风险基因座，但其潜在机制仍不清楚。
在此，我们研究了先天免疫反应紊乱是否介导已知遗传风险变异与儿童哮喘发生之间的关联。
来自哥本哈根儿童哮喘前瞻性研究（COPSAC）队列的336名6个月大婴儿的外周血单个核细胞，在体外被6种不同的先天配体（脂多糖、CpG、聚肌苷酸胞苷酸、R848、屋尘螨变应原提取物和氢氧化铝以及低水平脂多糖）刺激，然后在刺激后40小时对18种释放的细胞因子和趋化因子进行定量。通过主成分（PC）分析分解先天免疫反应谱，并将PC1-5用于对25个已知遗传风险变异对7岁前儿童哮喘影响的中介分析。
17q21基因座的两个变异（rs7216389、rs2305480）对哮喘和加重风险的影响，由模拟细胞内定植的配体诱导的免疫参数显著介导；细菌DNA（CpG）和双链病毒RNA（聚肌苷酸胞苷酸）。Th17和先天淋巴细胞3型扩增细胞因子白细胞介素-23是最主要的相关细胞因子。
17q21对儿童哮喘和加重的影响部分是由细胞内微生物配体诱导的白细胞介素-23失调介导的，这可能表明肺部细胞内病原体清除无效。
