TY - JOUR

T1 - Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma

AU - Wang, Ni

AU - Brix, Susanne

AU - Larsen, Jeppe M.

AU - Thysen, Anna H.

AU - Rasmussen, Morten A.

AU - Workman, Christopher T.

AU - Stokholm, Jakob

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Chawes, Bo L.

N1 - Publisher Copyright: © 2021 John Wiley & Sons Ltd.

PY - 2021

Y1 - 2021

N2 - 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 (COPSAC2000) 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.

AB - 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 (COPSAC2000) 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.

KW - aberrant innate immune responses

KW - genetic risk locus

KW - paediatric asthma

U2 - 10.1111/cea.13900

DO - 10.1111/cea.13900

M3 - Journal article

C2 - 33987892

AN - SCOPUS:85106745092

VL - 51

SP - 892

EP - 901

JO - Clinical Allergy

JF - Clinical Allergy

SN - 0954-7894

IS - 7

ER -