Innate IL-23/Type 17 immune responses mediate the effect of the 17q21 locus on childhood asthma
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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.
Originalsprog | Engelsk |
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Tidsskrift | Clinical and Experimental Allergy |
Vol/bind | 51 |
Udgave nummer | 7 |
Sider (fra-til) | 892-901 |
Antal sider | 10 |
ISSN | 0954-7894 |
DOI | |
Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:
COPSAC is funded by private and public research funds all listed on www.copsac.com . The Lundbeck Foundation (Grant no R16‐A1694); The Danish Council for Strategic Research (Grant no 0603‐00280B); The Danish Ministry of Health (Grant no 903516) and The Capital Region Research Foundation have provided core support for COPSAC. No pharmaceutical companies were involved in the study. The funding agencies did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
COPSAC is funded by private and public research funds all listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Danish Council for Strategic Research (Grant no 0603-00280B); The Danish Ministry of Health (Grant no 903516) and The Capital Region Research Foundation have provided core support for COPSAC. No pharmaceutical companies were involved in the study. The funding agencies did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors wish to thank the children and parents participating in the COPSAC2000 cohort as well as the COPSAC study team. We also wish to acknowledge the expert help from technician Lisbeth Buus Rosholm, Department of Biotechnology and Biomedicine, Technical University of Denmark for analysis of cytokines.
Publisher Copyright:
© 2021 John Wiley & Sons Ltd.
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