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Boeck, Andreas; Landgraf-Rauf, Katja; Vogelsang, Vanessa; Siemens, Diana; Prazeres da Costa, Olivia; Klucker, Elisabeth; Mutius, Erika von; Buch, Thorsten; Mansmann, Ulrich; Schaub, Bianca (2018): Ca2+ and innate immune pathways are activated and differentially expressed in childhood asthma phenotypes. In: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, Vol. 29, No. 8: pp. 823-833
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BACKGROUND Asthma is the most common chronic disease in children. Underlying immunological mechanisms - in particular of different phenotypes - are still just partly understood. The objective of the study is the identification of distinct cellular pathways in allergic asthmatics (AA) and non-allergic 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 AA 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. This article is protected by copyright. All rights reserved.