Background : IL-33 polymorphisms influences the susceptibility to asthma according to a GWAS. IL-33 can upregulate Regulatory T cells (Tregs) which are critical for healthy immune homeostasis. Aim : To investigate associations between IL-33 polymorphisms during development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. Methods : 829 children from the PASTURE/EFRAIM birth cohort were genotyped for IL-33 polymorphisms rs928413, rs1342326. In a subsample (n=99) of 4,5 years old children CD4+CD25highFOXP3+ Tregs were assessed by Flow cytometry following 24-hour-stimulation of peripheral blood mononuclear cells with PMA/Ionomycin or innate stimulus LPS or without stimuli. mRNA (ST2L, TLR4) expression and protein (sST2) levels ex vivo were measured in all 829 children by Real-Time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at age 6. Results: An increased risk for hay fever at the age of 6 years was observed for minor allele homozygotes of IL-33 polymorphisms rs928413 and rs1342326 (p=0.004; p=0.06). In parallel, CD4+CD25highFOXP3+ Tregs were decreased in minor allele homozygotes rs928413 (p=0.001) and rs1342326 (p=0.005) in unstimulated cells. mRNA Expression of ST2L, TLR4 and protein sST2 levels remained unchanged for both IL-33 polymorphisms. Conclusions: IL-33 rs928413 and rs1342326 polymorphisms were associated with increased risk for hay fever at the age of 6 years. Lower Tregs in minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.
Schröder et al. (Mon,) studied this question.