Interleukin 7 Receptor Alpha Chain Haplotypes Vary in Their Influence on Multiple Sclerosis Susceptibility and Response to Interferon Beta

Interleukin 7 receptor alpha chain (IL-7R alpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7R alpha, and therefore reduced interference with receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7R alpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7R alpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend only), and in CD4+CD45RO+ and CD4+CD45RA+ cells. In PBMCs, IL-7R alpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P < 0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7R alpha by IFN-beta may contribute to the genetic association of IL-7R alpha with MS.