Monday, October 27, 2014

Control of EBV is so elemental

Genetic mutations provide a window into inner workings of the biological systems. 

Here is one example. This paper, Magnesium and NKG2D, was published in journal Science in summer of 2013. It came from Michael Lenardo's lab at NIAID.

I have noticed that recently his lab's focus shifted in more clinical direction, like understanding molecular mechanisms behind natural mutations affecting immune system in humans.

In this paper, his lab provided further analysis of patients (total of 7 patients) with mutation in Magnesium transporter 1, called XMEN disease. These patient show inability to control EBV infection and can develop lymphomas.

Initial study, (Second messenger role for Mg2+), published in 2011 in journal Nature showed that deficiency in Magnesium transporter 1 (MagT1) affected T cell activation. It was quite new idea since we were thought that Ca2+ was necessary for T cell activation.

Here, the authors made observation that cytotoxic activity of CD8 T cells and NK cells from XMEN patients were reduced.

Interestingly, supplementation of culture medium with magnesium could partially (for CD8 T cells) or fully (for NK) restore cytotoxic activity against target cells. 

Since activation of CD8 T cells was not restored by magnesium supplementation, increase in cytotoxicity was probably related to increase in efficiency in releasing cytotoxic granules from already differentiated effector T cells. 

Luckily for the authors, they were able to pinpoint surface molecule that was involved in Magnesium-dependent improvement in cytotoxicity. It turned out to be NKG2D, a well known molecule in NK cell activity. XMEN patients had dramatically reduced level of surface NKG2D expression on NK cells. The authors showed that increase in cytotoxicity with magnesium supplementation was correlated with up-regulation of NKG2D (on both NK and CTL), since this effect was abolished in presence of blocking NKG2D-Fc molecule in CTL assay.

Finally, in vivo supplementation of XMEN patients with magnesium could improve their ability to control EBV.      

This proof of concept (POC) studies are the most straightforward to understand and easy to incorporate into patient's treatment guides. In this situation the authors could perform well established assays to verify the hypothesis. However, mutations can happen in proteins with no known functions and no known functional assays. In there any way to rapidly identify protein function and design the assay?

David Usharauli


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