Understanding MS genetics, Interleukin7 receptor

#MSresearch #MSblog unravelling biology behind genetics

Epub: Lundström et al. Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A. 2013 Apr.

Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Mouse models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.

Interleukin 7 receptor is one of the 50 or more MS susceptibility genes. Interleukin 7 is a white blood cell growth factor that acts by signalling through IL-7 receptor. This molecule can be shed from the cell surface and this soluble IL-7 receptor can circulate in blood and mop up IL-7 such that it can compete for the IL-7R on cells. In this context the soluble form slows down exhaustion of the IL-7 so perhaps it is released from the soluble IL-7R to maintain effective IL-7 stimulation that can drive the immune system to potentiate the effect of autoimmunity. This also occurs were the MS associated gene can enhance the availability of IL-7 and keeps it around to stimulate immune cells and gives a nice explanation of how this gene variant could be a bad idea for MS, but a good idea for other conditions,which will serve to help keep the gene variant in the human gene pool.

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