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Ca 2+ and innate immune pathways are activated and differentially expressed in childhood asthma phenotypes


Boeck, Andreas; Landgraf‐Rauf, Katja; Vogelsang, Vanessa; Siemens, Diana; Prazeres da Costa, Olivia; Klucker, Elisabeth; von Mutius, Erika; Buch, Thorsten; Mansmann, Ulrich; Schaub, Bianca (2018). Ca 2+ and innate immune pathways are activated and differentially expressed in childhood asthma phenotypes. Pediatric Allergy and Immunology, 29(8):823-833.

Abstract

Background

Asthma is the most common chronic disease in children. Underlying immunologic mechanisms—in particular of different phenotypes—are still just partly understood. The objective of the study was the identification of distinct cellular pathways in allergic asthmatics (AA) and nonallergic asthmatics (NA) vs healthy controls (HC).

Methods

Peripheral blood mononuclear cells (PBMCs) of steroid‐naïve children (n(AA/NA/HC) = 35/13/34)) from the CLARA study (n = 275) were stimulated (anti‐CD3/CD28, LpA) or kept unstimulated. Gene expression was investigated by transcriptomics and quantitative RT‐PCR. Differentially regulated pathways between phenotypes were assessed after adjustment for sex and age (KEGG pathways). Networks based on correlations of gene expression were built using force‐directed graph drawing.

Results

Allergic asthmatics vs NA and asthmatics overall vs HC showed significantly different expression of Ca2+ and innate immunity‐associated pathways. PCR analysis confirmed significantly increased Ca2+‐associated gene regulation (ORMDL3 and ATP2A3) in asthmatics vs HC, most prominent in AA. Innate immunity receptors (LY75, TLR7), relevant for virus infection, were also upregulated in AA and NA compared to HC. AA and NA could be differentiated by increased ATP2A3 and FPR2 in AA, decreased CLEC4E in AA, and increased IFIH1 expression in NA following anti‐CD3/28 stimulation vs unstimulated (fold change).

Conclusions

Ca2+ regulation and innate immunity response pattern to viruses were activated in PBMCs of asthmatics. Asthma phenotypes were differentially characterized by distinct regulation of ATP2A3 and expression of innate immune receptors (FPR2, CLEC4E, IFIH1). These genes may present promising targets for future in‐depth investigation with the long‐term goal of more phenotype‐specific therapeutic interventions in asthmatics.

Abstract

Background

Asthma is the most common chronic disease in children. Underlying immunologic mechanisms—in particular of different phenotypes—are still just partly understood. The objective of the study was the identification of distinct cellular pathways in allergic asthmatics (AA) and nonallergic asthmatics (NA) vs healthy controls (HC).

Methods

Peripheral blood mononuclear cells (PBMCs) of steroid‐naïve children (n(AA/NA/HC) = 35/13/34)) from the CLARA study (n = 275) were stimulated (anti‐CD3/CD28, LpA) or kept unstimulated. Gene expression was investigated by transcriptomics and quantitative RT‐PCR. Differentially regulated pathways between phenotypes were assessed after adjustment for sex and age (KEGG pathways). Networks based on correlations of gene expression were built using force‐directed graph drawing.

Results

Allergic asthmatics vs NA and asthmatics overall vs HC showed significantly different expression of Ca2+ and innate immunity‐associated pathways. PCR analysis confirmed significantly increased Ca2+‐associated gene regulation (ORMDL3 and ATP2A3) in asthmatics vs HC, most prominent in AA. Innate immunity receptors (LY75, TLR7), relevant for virus infection, were also upregulated in AA and NA compared to HC. AA and NA could be differentiated by increased ATP2A3 and FPR2 in AA, decreased CLEC4E in AA, and increased IFIH1 expression in NA following anti‐CD3/28 stimulation vs unstimulated (fold change).

Conclusions

Ca2+ regulation and innate immunity response pattern to viruses were activated in PBMCs of asthmatics. Asthma phenotypes were differentially characterized by distinct regulation of ATP2A3 and expression of innate immune receptors (FPR2, CLEC4E, IFIH1). These genes may present promising targets for future in‐depth investigation with the long‐term goal of more phenotype‐specific therapeutic interventions in asthmatics.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Laboratory Animal Science
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Immunology, Immunology and Allergy, Pediatrics, Perinatology, and Child Health
Language:English
Date:1 December 2018
Deposited On:17 Dec 2018 16:23
Last Modified:18 Dec 2018 08:34
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0905-6157
OA Status:Closed
Publisher DOI:https://doi.org/10.1111/pai.12971
Project Information:
  • : FunderGerman research foundation as part of the trans-regional collaborative research program TR22 “allergic immune responses of the lung,” grant
  • : Grant IDDFG SFB TR22/A22
  • : Project Title
  • : FunderGSK grant
  • : Grant IDFöFoLe Reg.Nr. 839
  • : Project Title
  • : Fundergrant DFG SFB
  • : Grant IDZ03
  • : Project Title

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