Science and Research

IL-33 polymorphisms are associated with increased risk of hay fever and reduced regulatory T cells in a birth cohort

BACKGROUND: IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. METHODS: Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4(+) CD25(high) FOXP3(+) Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years. RESULTS: rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95%CI = 1.02-3.08; OR = 1.79, 95%CI = 1.04-3.11) and CD4(+) CD25(high) FOXP3(+) Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004; p(LPS) = 0.005; p(U) = 0.001; p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p(rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs. CONCLUSIONS: IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.

  • Schroder, P. C.
  • Casaca, V. I.
  • Illi, S.
  • Schieck, M.
  • Michel, S.
  • Bock, A.
  • Roduit, C.
  • Frei, R.
  • Lluis, A.
  • Genuneit, J.
  • Pfefferle, P.
  • Roponen, M.
  • Weber, J.
  • Braun-Fahrlander, C.
  • Riedler, J.
  • Lauener, R.
  • Vuitton, D. A.
  • Dalphin, J. C.
  • Pekkanen, J.
  • von Mutius, E.
  • Kabesch, M.
  • Schaub, B.
  • Pasture Study group

Keywords

  • Cells, Cultured
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Forkhead Transcription Factors/metabolism
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Germany
  • Humans
  • Interleukin-33/*genetics
  • Male
  • Polymorphism, Single Nucleotide
  • Rhinitis, Allergic, Seasonal/*genetics
  • Risk
  • Suppressor of Cytokine Signaling 3 Protein/genetics/*metabolism
  • T-Lymphocytes, Regulatory/*immunology
  • * il-33
  • *Tregs
  • *childhood
  • *hay fever
  • *polymorphisms
Publication details
DOI: 10.1111/pai.12597
Journal: Pediatr Allergy Immunol
Pages: 687-695 
Number: 7
Work Type: Original
Location: BREATH, CPC-M
Disease Area: AA
Partner / Member: KUM, LMU
Access-Number: 27171815
See publication on PubMed

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