Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

Abstract

Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-a (IL-7Ra)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Ra leads to increased soluble IL-7Ra production. Given the functional interaction between sIL-7Ra, membrane-bound IL-7Ra and IL-7, we assessed IL-7, mIL-7Ra and sIL-7Ra levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Ra levels compared with 73 HCs. The levels of sIL-7Ra increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Ra could result in a higher mIL-7Ra to soluble IL-7Ra ratio. Indeed, 52 MS patients had significantly increased mIL-7Ra to sIL-7Ra ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Ra influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Ra ratio. The soluble IL-7Ra levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Ra level may influence responsiveness of IL-7Ra þ cells.

Interleukin-7 expression and its effect on natural killer cells in patients with multiple sclerosis

“…Fig. 1A), which is consistent with several previous findings (Kreft et al, 2012a; Kreft et al, 2012b). …”

“…Our result is consistent with previous findings in which slightly but significantly decreased systemic IL-7 and a higher membrane to soluble IL-7Rα ratio on CD4 + and CD8 + cells were reported (Kreft et al, 2012a; Kreft et al, 2012b). However, these findings appear in contrast with the up-regulated IL-7 plasma levels observed by Hass et al (Haas et al, 2011).…”

“…The impact of IL-7/IL-7Rα signaling on CD4 + T cells (Kreft et al, 2012a), Treg cells (Haas et al, 2011), and CD8 + T cells (Kreft et al, 2012b) in MS has been reported to demonstrate that this pathway may subsequently enhance the pathogenicity of these immune cells. The importance of this pathway for NK cell homeostasis is underlined by several studies in both healthy human and animals (Lundstrom et al, 2012; Mazzucchelli and Durum, 2007; Michaud et al, 2010a); however, its impact on NK cell function in MS has not yet been reported.…”

Decreased serum level of IL-7 in patients with active Graves’ disease

“…Similarly, lower IL-7 serum levels were observed in active inflammatory bowel disease than in remission [27]. Also studies in patients with multiple sclerosis [28] and systemic scleroderma [29] have revealed lower serum levels of IL-7 than in controls. Our observations are consistent with those of previous study regarding expression of IL-7 in tears and orbital tissues of patients with Graves' ophthalmopathy (GO).…”

Interleukin-7 receptor gene polymorphism at +1237 locus and its effect on susceptibility to opportunistic infections among HIV and AIDS patients in Limpopo Province, South Africa

“…The biological effects of IL-7 are mediated via the hematopoietic IL-7 receptor (IL-7R) complex, IL-7 receptor α chain, which binds IL-7 and thymic stromal lymphopoietin and the IL-2 receptor γ chain; it has been found to be a cofactor for V(D)J rearrangement of T-cell receptor beta during early T-cell development (Muegge et al, 1993). Recent studies have shown that polymorphisms at specific loci on the IL-7Rα were risk factors for a number of diseases, including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease, atopic dermatitis, inhalation allergy, sarcoidosis, and graft-versus-host disease (Sombekke et al, 2011;Mazzucchelli et al, 2012;Kreft et al, 2012).…”