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Editor's Choice

Editor's Choice Pediatric Allergy and Immunology IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort Manifestation of childhood asthma and allergies is influenced by genetic susceptibility and environmental exposure. In this study, we have shown that IL-33 polymorphisms influence the susceptibility to hay fever. IL-33 is a pro-inflammatory cytokine, which is known to contribute to the development of hay fever. Also, it can induce Th2 immunity via dendritic cell activation. Immunologically, it increases Tregs, which keep healthy immune homeostasis in balance. In this study, Schro €der et al. (1) have investigated the associations between IL-33 polymorphisms during the development of childhood atopic diseases and the underlying mechanisms including immune regulation of Tregs. The study was performed in a subgroup of 4.5-year-old children from the large international PASTURE/EFRAIM birth cohort in a rural environment (total n = 1133 children), where genotyping of IL-33 polymorphisms (rs928413, rs1342326), Treg, and mRNA data were available. In-depth health outcomes (hay fever, asthma) were assessed by questionnaires at age 6 years. + high + Both IL-33 SNPs were positively associated with hay fever and CD4 CD25 FOXP3 -Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes. SOCS3-mRNA expression was increased in minor allele homozygotes and heterozygotes compared to major allele homozygotes for both IL-33 polymorphisms and negatively correlated to Tregs. These novel data indicate that IL-33 polymorphisms (rs928413 and rs1342326) are associated with an increased risk for hay fever with age 6 years. The special facet of the study includes assessment of in-depth immune regulation showing that cells, which are responsible for immune balance, namely Tregs, were decreased and SOCS3, a suppressor of cytokine signalling 3 was increased. These findings point to an imbalance of immune regulation potentially resulting in exuberant allergic inflammation. Thus, this study Paul Christoph Schröder suggests the critical importance to implement immune markers to elucidate the underlying mechanisms of allergy development in large epidemiological cohort studies in childhood. Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays Protein biomarker discovery has the potential to aid in disease diagnosis, clarify our understanding of disease mechanisms and/or point towards new approaches to therapy. Using antibody array for 444 proteins in plasma samples from children at age 3 as a proteomic approach to biomarker exploration for childhood asthma, Xu et al. (2) identified initially four protein candidates and two of these were validated by ELISA assays. These two proteins are erythropoietin (EPO), found to be in lower levels, and soluble GP130 (sGP130), in higher levels in asthmatic compared to non-asthmatic children. Although these two proteins may not strike the reader as obviously related to asthma, the literature offers suggestions of their involvement, especially with studies of innate immunity and Treg cells, these entities having also recently become more implicated as contributing to asthma. In addition to its known role in erythropoiesis, EPO has been shown to act (through a distinct receptor) as an inhibitor of the inflammatory response especially in the context of TNFa increases and when used therapeutically in an animal model of asthma EPO, the reduced airway inflammatory changes appear to be lessened through an increase in M2 macrophages which in turn promote Treg cells thought to suppress inflammation. Very recently, altered innate immune responses following certain environmental exposures have been suggested as a route for protection from asthma. These studies thus provide a context for the data of Xu et al. which provide the first evidence that endogenous EPO levels in asthma may be abnormally low at least at the very early age of 3 years. A role in asthma or plasma levels of sGP130 is much less clear. Such associations, although, may invoke future mechanistic studies, a major aim of this type of hypothesis-generating approach to understanding disease mechanisms. Haili Xu No simple answers for the Finnish and Russian Karelian allergy contrast: methylation of CD14 gene The prevalence of asthma and allergy has consistently been higher in developed countries than in developing countries, and similarly higher in urban compared to rural areas. This disproportion in prevalence has not been adequately explained by genetic factors and their interactions with environmental factors. Epigenetic mechanisms that underlie the link between the host genome and the environment may hold the key to understanding the Finnish and Russian allergy contrast. The study conducted by Khoo et al. (3) hypothesized that DNA methylation in CD14 gene may play a role in the global differences in allergy prevalence. They studied the association between total serum IgE and methylation levels of three promoter CpG sites of CD14 in 500 Finnish and Russian Karelian children. These two populations are genetically similar with a shared ancestry but show a significant disparity in their prevalence of asthma and allergy. Methylation levels in two of the CpG sites were significantly higher in the Finnish compared to Russian children. This is consistent with the higher prevalence of asthma and allergy observed in the Finnish children as higher methylation in the promoter would lead to lower levels of CD14, resulting in increased risk for allergy and asthma. However, regression analysis showed that the methylation variation of CD14 did not explain the asthma/allergy contrast between these two populations. To the best of the authors’ knowledge, this is the first study to investigate the associations between the methylation levels at the promoter of CD14 and total IgE in Western vs Eastern environments. The lack of a clear contribution of CD14 methylation variation to the asthma/allergy gradient between the Finnish and Russian Siew-Kim Khoo Karelian children emphasizes the complexity of the genetic/epigenetic mechanisms underlying the so-called allergy epidemic of the modern world. References 1. Schroder € PC, Casaca VI, Illi S, et al. IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort. Pediatr Allergy Immunol 2016: 27: 686–694. 2. Xu H, Radabaugh T, Zhenqiang L, et al. Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays. Pediatr Allergy Immunol 2016: 27: 695–700. 3. Khoo S-K, M€akel€a M, Chandler D, et al. No simple answers for the Finnish and Russian Karelian allergy contrast: methylation of CD14 gene. Pediatr Allergy Immunol 2016: 27: 720–726. This logo highlights the Editor’s Choice articles in the table of contents and the first page of each of the articles. 665 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Pediatric Allergy and Immunology Wiley

Editor's Choice

Pediatric Allergy and Immunology , Volume 27 (7) – Nov 1, 2016

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References (3)

Publisher
Wiley
Copyright
Copyright © 2016 John Wiley & Sons A/S
ISSN
0905-6157
eISSN
1399-3038
DOI
10.1111/pai.12663
Publisher site
See Article on Publisher Site

Abstract

Pediatric Allergy and Immunology IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort Manifestation of childhood asthma and allergies is influenced by genetic susceptibility and environmental exposure. In this study, we have shown that IL-33 polymorphisms influence the susceptibility to hay fever. IL-33 is a pro-inflammatory cytokine, which is known to contribute to the development of hay fever. Also, it can induce Th2 immunity via dendritic cell activation. Immunologically, it increases Tregs, which keep healthy immune homeostasis in balance. In this study, Schro €der et al. (1) have investigated the associations between IL-33 polymorphisms during the development of childhood atopic diseases and the underlying mechanisms including immune regulation of Tregs. The study was performed in a subgroup of 4.5-year-old children from the large international PASTURE/EFRAIM birth cohort in a rural environment (total n = 1133 children), where genotyping of IL-33 polymorphisms (rs928413, rs1342326), Treg, and mRNA data were available. In-depth health outcomes (hay fever, asthma) were assessed by questionnaires at age 6 years. + high + Both IL-33 SNPs were positively associated with hay fever and CD4 CD25 FOXP3 -Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes. SOCS3-mRNA expression was increased in minor allele homozygotes and heterozygotes compared to major allele homozygotes for both IL-33 polymorphisms and negatively correlated to Tregs. These novel data indicate that IL-33 polymorphisms (rs928413 and rs1342326) are associated with an increased risk for hay fever with age 6 years. The special facet of the study includes assessment of in-depth immune regulation showing that cells, which are responsible for immune balance, namely Tregs, were decreased and SOCS3, a suppressor of cytokine signalling 3 was increased. These findings point to an imbalance of immune regulation potentially resulting in exuberant allergic inflammation. Thus, this study Paul Christoph Schröder suggests the critical importance to implement immune markers to elucidate the underlying mechanisms of allergy development in large epidemiological cohort studies in childhood. Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays Protein biomarker discovery has the potential to aid in disease diagnosis, clarify our understanding of disease mechanisms and/or point towards new approaches to therapy. Using antibody array for 444 proteins in plasma samples from children at age 3 as a proteomic approach to biomarker exploration for childhood asthma, Xu et al. (2) identified initially four protein candidates and two of these were validated by ELISA assays. These two proteins are erythropoietin (EPO), found to be in lower levels, and soluble GP130 (sGP130), in higher levels in asthmatic compared to non-asthmatic children. Although these two proteins may not strike the reader as obviously related to asthma, the literature offers suggestions of their involvement, especially with studies of innate immunity and Treg cells, these entities having also recently become more implicated as contributing to asthma. In addition to its known role in erythropoiesis, EPO has been shown to act (through a distinct receptor) as an inhibitor of the inflammatory response especially in the context of TNFa increases and when used therapeutically in an animal model of asthma EPO, the reduced airway inflammatory changes appear to be lessened through an increase in M2 macrophages which in turn promote Treg cells thought to suppress inflammation. Very recently, altered innate immune responses following certain environmental exposures have been suggested as a route for protection from asthma. These studies thus provide a context for the data of Xu et al. which provide the first evidence that endogenous EPO levels in asthma may be abnormally low at least at the very early age of 3 years. A role in asthma or plasma levels of sGP130 is much less clear. Such associations, although, may invoke future mechanistic studies, a major aim of this type of hypothesis-generating approach to understanding disease mechanisms. Haili Xu No simple answers for the Finnish and Russian Karelian allergy contrast: methylation of CD14 gene The prevalence of asthma and allergy has consistently been higher in developed countries than in developing countries, and similarly higher in urban compared to rural areas. This disproportion in prevalence has not been adequately explained by genetic factors and their interactions with environmental factors. Epigenetic mechanisms that underlie the link between the host genome and the environment may hold the key to understanding the Finnish and Russian allergy contrast. The study conducted by Khoo et al. (3) hypothesized that DNA methylation in CD14 gene may play a role in the global differences in allergy prevalence. They studied the association between total serum IgE and methylation levels of three promoter CpG sites of CD14 in 500 Finnish and Russian Karelian children. These two populations are genetically similar with a shared ancestry but show a significant disparity in their prevalence of asthma and allergy. Methylation levels in two of the CpG sites were significantly higher in the Finnish compared to Russian children. This is consistent with the higher prevalence of asthma and allergy observed in the Finnish children as higher methylation in the promoter would lead to lower levels of CD14, resulting in increased risk for allergy and asthma. However, regression analysis showed that the methylation variation of CD14 did not explain the asthma/allergy contrast between these two populations. To the best of the authors’ knowledge, this is the first study to investigate the associations between the methylation levels at the promoter of CD14 and total IgE in Western vs Eastern environments. The lack of a clear contribution of CD14 methylation variation to the asthma/allergy gradient between the Finnish and Russian Siew-Kim Khoo Karelian children emphasizes the complexity of the genetic/epigenetic mechanisms underlying the so-called allergy epidemic of the modern world. References 1. Schroder € PC, Casaca VI, Illi S, et al. IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort. Pediatr Allergy Immunol 2016: 27: 686–694. 2. Xu H, Radabaugh T, Zhenqiang L, et al. Exploration of early-life candidate biomarkers for childhood asthma using antibody arrays. Pediatr Allergy Immunol 2016: 27: 695–700. 3. Khoo S-K, M€akel€a M, Chandler D, et al. No simple answers for the Finnish and Russian Karelian allergy contrast: methylation of CD14 gene. Pediatr Allergy Immunol 2016: 27: 720–726. This logo highlights the Editor’s Choice articles in the table of contents and the first page of each of the articles. 665

Journal

Pediatric Allergy and ImmunologyWiley

Published: Nov 1, 2016

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