Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants.
The receptor for the homeostatic T cell cytokine interleukin-7 (IL-7Ralpha) has recently shown genetic association to multiple sclerosis (MS). To investigate the functional contribution of IL-7Ralpha polymorphisms to the pathogenesis of MS, we correlated the IL-7Ralpha haplotypes with different T cell parameters in a group of MS patients and healthy controls. We show that carriers of one of the four IL-7Ralpha haplotypes (Hap4) show a higher expression of IL-7Ralpha (CD127) on their CD4(+) T cells, compared with noncarriers (P=0.04). Moreover, Hap4 carriers possess higher frequencies of recent thymic emigrants (RTEs, CD31(+)) in both the regulatory T cell (Treg; P=0.007) and conventional T cell (Tconv) population (P=0.0001). This effect is most pronounced within the MS population (Treg, P=0.0077; Tconv, P=0.0007), whereas in healthy controls significance was only reached for Tconv (P=0.043; Treg, P=0.11). Because previous studies showed a decreased RTE-Treg frequency in MS patients compared to healthy subjects, we here conclude that this decrease is localized within the MS population of non-Hap4 carriers. In conclusion, our findings suggest that IL-7Ralpha polymorphisms can influence T cell development and homeostasis, and thereby contribute to the altered immune regulation associated with disease development in patients with MS.
Broux
B
B
Biomedical Research Institute, Hasselt University and School of Life Sciences, transnationale Universiteit Limburg, Diepenbeek, Belgium.
Hellings
N
N
Venken
K
K
Rummens
J-L
JL
Hensen
K
K
Van Wijmeersch
B
B
Stinissen
P
P
D016022:Case-Control Studies; D006239:Haplotypes; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000473:pathology*
D053699:Interleukin-7 Receptor alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1