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J Allergy Clin Immunol. 2018 Dec;142(6):1856-1866. doi: 10.1016/j.jaci.2018.02.019. Epub 2018 Mar 5.

Allergen-induced activation of natural killer cells represents an early-life immune response in the development of allergic asthma.

Author information

1
Benaroya Research Institute Systems Immunology Division, Seattle, Wash; Department of Medicine, University of Washington, Seattle, Wash. Electronic address: maltman@benaroyaresearch.org.
2
Benaroya Research Institute Systems Immunology Division, Seattle, Wash.
3
National Institute of Allergy and Infectious Diseases, Bethesda, Md.
4
Boston University School of Medicine, Boston, Mass.
5
Washington University School of Medicine, St Louis, Mo.
6
Columbia University College of Physicians and Surgeons, New York, NY.
7
Johns Hopkins University School of Medicine, Baltimore, Md.
8
Rho, Chapel Hill, NC.
9
University of Wisconsin School of Medicine and Public Health, Madison, Wis.

Abstract

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.

KEYWORDS:

Asthma; allergens; dendritic cells; natural killer cells; transcriptomics

PMID:
29518416
PMCID:
PMC6123299
DOI:
10.1016/j.jaci.2018.02.019

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