Hartmann FJ, Khademi M, Aram J, Ammann S, Kockum I, Constantinescu C, Gran B, Piehl F, Olsson T, Codarri L, Becher B. Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells. Nat Commun. 2014 Oct 3;5:5056. doi: 10.1038/ncomms6056.
Genome-wide association studies implicate dysregulation of immune mechanisms in the pathogenesis of multiple sclerosis (MS). Particularly, polymorphisms in genes involved in T helper (TH) cell differentiation are associated with risk of developing MS. However, the underlying mechanism by which these risk alleles influence MS susceptibility has remained elusive. Initiation of neuroinflammation in animal models of MS has been shown to be dependent on TH cell-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). We here report association of GM-CSF expression by human TH cells with MS disease severity. GM-CSF is strongly induced by interleukin 2 (IL-2). We show that an MS-associated polymorphism in the IL-2 receptor alpha (IL2RA) gene specifically increases the frequency of GM-CSF-producing TH cells. The IL2RA polymorphism regulates IL-2 responsiveness of naive TH cells and their propensity to develop into GM-CSF-producing memory TH cells. These findings mechanistically link an immunologically relevant genetic risk factor with a functional feature of TH cells in MS.
The interleukin 2 receptor has a genetic variant that is linked to susceptibility to MS. This has been associated with resulting in an increase of GM-CSF (This makes macrophages and granulocytes (eosinophils, basophils and neutrophils precursors grow). This can influence dendritic cell function (a type of antigen presenting cell that stimulates T cell function. The genetic variant controlled how T cells respond to the T cell growth factor IL-2 and how they develop into GM-CSf producing memory cells, which may contain the subset of cells causing disease. It was found that some of the MS treatments can lower these cell types in the blood, this could be a reason why they work.