Allergen-induced activation of natural killer cells represents an early-life immune response in the development of allergic asthma - 06/12/18
, Elizabeth Whalen, PhD a, Alkis Togias, MD c, George T. O'Connor, MD d, Leonard B. Bacharier, MD e, Gordon R. Bloomberg, MD e, Meyer Kattan, MD f, Robert A. Wood, MD g, Scott Presnell, PhD a, Petra LeBeau, ScD h, Katy Jaffee, MS h, Cynthia M. Visness, PhD h, William W. Busse, MD i, James E. Gern, MD iAbstract |
Background |
Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and TH2-type inflammation; however, the early-life immune events that lead to TH2 skewing and disease development are unknown.
Objective |
We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma.
Methods |
In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years.
Results |
PBMCs from the cases showed higher levels of expression of natural killer (NK) cell–related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell–like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key TH2-type cytokines IL9, IL13, and CCL17, as well as a dendritic cell–like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell–like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma.
Conclusion |
These findings provide important mechanistic insight into an early-life immune pathway involved in TH2 polarization, leading to the development of allergic asthma.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, allergens, transcriptomics, natural killer cells, dendritic cells
Abbreviations used : DC, DM, FDR, iNKT, IRIS, KEGG, NK, TT, URECA
Plan
| Supported in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract nos. NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, HHSN272201000052I, 1UM1AI114271-01, and UM2AI117870. Additional support was provided by the National Center for Research Resources, National Institutes of Health, under grants RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, UL1TR000040, UL1TR001079, and 5UL1RR024992-02. |
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| Disclosure of potential conflict of interest: G. T. O'Connor reports National Institutes of Health (NIH) institutional grant funding, has grants or grants pending from the NIH and Janssen Pharmaceuticals, and has received personal fees from AstraZeneca related to development of medications for asthma and COPD. L. B. Bacharier reports grants from the NIH/National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study and received personal fees from Aerocrine, GlaxoSmithKline, Genentech/Novartis, Merck, Cephalon, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Vectura, and Circassia outside the submitted work. G. R. Bloomberg, P. LeBeau, and K. Jaffee report grants from the NIH/NIAID during the conduct of the study. M. Kattan reports grants from the NIH/NIAID during the conduct of the study and personal fees from Novartis Pharma outside the submitted work. R. A. Wood's institution has received NIH grant funding; has grants or grants pending from the NIH, DBV, Aimmune, Astellas, and HAL-Allergy; and reports unpaid consultancy to Stallergenes. C. M. Visness reports institutional NIH/NIAID grant funding. W. W. Busse reports grants from the NIH/NIAID during the conduct of the study and personal fees from Boston Scientific, ICON, Novartis, Glaxo SmithKline, Genentech, Roche, Boehringer Ingelheim, Sanofi Genzyme, AstraZeneca, Teva, 3M, PrEP Biopharm, Circassia, Regeneron, Peptinnovate, Knopp Bio, and Elsevier the submitted work. J. E. Gern reports grants from the NIH/NIAID during the conduct of the study and personal fees from Janssen, Regeneron, and PReP Biosciences and other funding from Boehringer Ingelheim outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 6
P. 1856-1866 - décembre 2018 Retour au numéro
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