Understanding MS genetics, Interleukin7 receptor

U
#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.

About the author

MouseDoctor

Add comment

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives