Atopic dermatitis and skin disease
IL10 polymorphisms influence neonatal immune responses, atopic dermatitis, and wheeze at age 3 years

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Background

IL10 encodes for IL-10, an important anti-inflammatory cytokine with pleiotropic effects. It is crucial for development of immune tolerance, downregulates expression of TH1 cytokines, and is relevant for T-cell regulation. Several IL10 single nucleotide polymorphisms (SNPs) were associated with inflammatory diseases, such as atopic diseases, which might have their onset during early immune maturation.

Objective

We hypothesized that IL10 SNPs are associated with decreased regulatory T (Treg) cell numbers, TH2-skewed immune responses, and decreased IFN-γ levels in cord blood parallel with increased proinflammatory markers, subsequently leading to increased atopic diseases until 3 years.

Methods

Eight genetic IL10 variants, represented by 4 linkage disequilibrium blocks (R2 > 0.80) and 2 distal promoter SNPs, were genotyped in cord blood mononuclear cells of 200 healthy neonates. Cord blood mononuclear cells were cultured unstimulated or after stimulation with lipid A, peptidoglycan, PHA, house dust mite (Der p 1), or Der p 1 plus lipid A. mRNA expression of Treg cell–associated genes (forkhead box protein P3 [FOXP3], glucocorticoid-induced TNF receptor [GITR], lymphocyte activation gene 3 [LAG3]), TH1/TH2 cytokines, TNF-α, and GM-CSF were assessed. Atopic and respiratory outcomes (atopic dermatitis [AD] and wheeze) were assessed by means of questionnaire at age 3 years.

Results

Carriers of 3 IL10 SNP blocks and both distal promoter SNPs showed reduced expression of Treg cell markers, reduced IL-5 levels, proinflammatory TNF-α and GM-CSF, and partially increased IFN-γ levels. The same SNPs presented as determinant for AD, wheeze, or symptoms of AD, wheeze, or both at age 3 years.

Conclusions

Polymorphisms in IL10 influenced Treg cell marker expression and TH1/TH2 and proinflammatory cytokine secretion early in life. This was relevant for further development of immune-mediated diseases, such as AD and wheeze, in early childhood.

Section snippets

Study population

Umbilical cord blood (n = 200; 72 samples from atopic mothers and 128 samples from nonatopic mothers) was obtained from neonates born in the Munich metropolitan area of Germany. Subjects were recruited from July 2005 to September 2007 during the last trimester of pregnancy (for details, see the Methods section in this article's Online Repository at www.jacionline.org). Our previous studies showed that maternal atopy negatively affects Treg cell quantity and function in cord blood.19, 20

Results

We assessed the genotype of 8 genetic variations in the IL10 gene (Table I) with a genotyping success rate of greater than 90%. On the basis of LD analyses, 4 major LD blocks were identified (Fig 1), each represented by a tagging SNP. Two tagging SNPs (rs1800890 and rs1878672) slightly deviated from HWE; however, they showed similar allele frequencies in comparison to the HapMap reference population Centre d'Etude du Polymorphisme Humain. In the following we focused on reporting immunologic

Discussion

In this study the effect of genetic variation in the IL10 gene on secretion of TH1/TH2 lineage and proinflammatory cytokines and expression of Treg cells was assessed in cord blood. Additionally, the potential role of IL10 SNPs on the development of immune-mediated diseases, such as AD or wheeze, until the age of 3 years was investigated. We detected a distinct pattern of T-cell lineage fate in carriers of IL10 polymorphisms in cord blood because they were primarily associated with decreased

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    Supported by Bavarian Research Association PIZ-140-08 (to B.S.) and the German Research Foundation as part of the transregional collaborative research program TR22 “allergic immune responses of the lung,” grant DFG SFB TR22/A22 (to D.R. and B.S.). Further funding was provided by the Comprehensive Pulmonary Centre (CPC for B.S.) and by the German Ministry of Education and Research (BMBF) as part of the National Genome Research Network (NGFN), with grant NGFN 01GS0810 (to L.A.P. and M.K.). Genotyping was performed in collaboration with the Genome Analysis Centre of the Helmholtz Centre Munich.

    Disclosure of potential conflict of interest: E. von Mutius is a consultant for Novartis, GlaxoSmithKline, ALK-Abelló, and Protectimmun; has received speakers' fees from InfectoPharm; has been supported by Airsonnett AB; is a member of the expert panel for the UK Research Excellence Framework; and is an Associate Editor of the Journal of Allergy and Clinical Immunology. M. Kabesch has financial interests in Roxall, GlaxoSmithKline, Novartis, Sanofi Aventis, Allergopharma, and AstraZeneca GmbH and has been supported by Deutsche Forschungsgemeinschaft (DFG), the BMBF, and the European Union (EU). B. Schaub has been supported by DFG and the EU. The rest of the authors declare that they have no relevant conflicts of interest.

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