Interleukin-7 receptor α-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes.

ABSTRACT

BACKGROUND: Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. METHODS: We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). RESULTS: We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. CONCLUSIONS: Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells.