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Innate IL‐23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma
Author(s) -
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.
Publication year - 2021
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.13900
Subject(s) - immunology , innate immune system , immune system , innate lymphoid cell , asthma , biology , genome wide association study , cytokine , chemokine , cpg site , dna methylation , genetics , single nucleotide polymorphism , genotype , gene , gene expression
Background 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. Objective Here, we examined whether perturbed innate immune responses mediate the association between known genetic risk variants and development of childhood asthma. Methods Peripheral blood mononuclear cells from 336 six‐month‐old infants from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC 2000 ) 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. Results 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. Conclusion 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.