Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma
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Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma. / 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.
I: Clinical and Experimental Allergy, Bind 51, Nr. 7, 2021, s. 892-901.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 304061966