The Epstein-Barr Virus, Magnesium and ME/CFS Connection (?)

Magnesium may be the most commonly used supplement in chronic fatigue syndrome and fibromyalgia.  Some people think a smoldering Epstein-Barr Virus infection may be common in ME/CFS.  In something of a shocker, recent research into EBV and magnesium suggests that low magnesium and EBV infections may sometimes go hand in hand.Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D. Benjamin Chaigne-Delalande,1* Feng-Yen Li,1,2* Geraldine M. O’Connor,3 Marshall J. Lukacs,1 Ping Jiang,1 Lixin Zheng,1 Amber Shatzer,4 Matthew Biancalana,1 Stefania Pittaluga, et. al, Michael J. Lenardo1† 12 JULY 2013 VOL 341 SCIENCEThe authors had recently characterized a primary immunodeficiency disease in people with chronic Epstein-Barr virus infection called XMEN.XMEN disease is a rare genetic disease mostly appearing in men that is caused by mutations in the MAGTI magnesium transporter gene. People with XMEN disease suffer from increased infections including upper respiratory infections, sinusitis, otitis media, viral pneumonia, diarrhea, epiglottitis, and pertussis.They also typically have high levels of Epstein-Barr virus infection and are at increased risk of coming down with EBV associated lymphoma.The link to lymphoma and the recurrent infections were explained when they discovered that increased magnesium levels are required for natural killer (NK) and T-cell activation.XMEN disease is not chronic  fatigue syndrome and vice versa, but the two diseases may share four intriguing  factors: EBV reactivation, poorly functioning NK and T-cells, the need for magnesium supplementation and possibly increased risk of lymphoma.

The Magnesium - Immune System Connection

The vast majority (95%) of the magnesium in our body is bound in our cells but it's the 5% that's unbound that makes the difference in our immune response.  The XMEN patients studied - some of whom had developed lymphoma - had normal levels of bound magnesium in their cells but reduced levels of unbound magnesium.Interestingly, all experienced repeated minor viral infections and had elevated levels of active EBV in their blood.  Tests indicated that their immune systems knew the virus was there - it was producing normal levels of the  EBV specific memory T-cells - but their NK and cytotoxic T-cells - the cells tasked with killing EBV - were having trouble killing it.The question was why. First they looked at the receptors on the NK and T-cells that activate them in the presence of EBV infected cells.   If the receptors are not present or are damaged the cells are effectively blind to EBV.They  found reduced levels of the NKG2D receptors needed to turn NK and T cells into killing machines. They knew the genetics of the XMEN patients prevented them from taking up magnesium properly.  When they pumped their NK and T-cells full of magnesium (by culturing them in magnesium sulfate) the NKG2D receptors started working again. The cytotoxic T cell killing  problem was partially resolved and the NK cell killing problem was fully resolved.They also found, importantly, that reducing magnesium levels abolishes NKG2D activation in normal T-cells; i.e. proper magnesium levels are needed for T-cell functioning. (Other receptors on NK and T-cells were not affected by magnesium levels - only these specific receptors.)Next the researchers tested their hypothesis on humans. Upon being provided oral magnesium gluconate small but significant increases in free magnesium and a "modest restoration" in NKG2D levels were seen in an XMEN patient. A decline in the number of his B-cells harboring EBV suggested that his NK and perhaps T-cells were, indeed, more effectively targeting EBV infected  B-cells.When the patient went off the magnesium supplementation the situation reversed itself.Further testing indicated that infusions of magnesium sulfate and oral supplementation of magnesium threonate were more effective.This was an early study (which did make it into Science) but it suggests that something as simple as magnesium supplementation may reduce the rate of infections and possibly the risk of lymphoma in XMEN patients.EBV infections don't necessarily lead to or are even associated with these problems: only one type of EBV patient was shown to have them in this study.  People with chronic active EBV infections (CAEBV) or something called X-linked lymphoproliferative disease (XLP) did not have reduced basal free levels of Mg2+ or problems with magnesium transport.

The ME/CFS Connection (???)

ME/CFS and FM  are not XMEN disease. They're not rare and active EBV is not commonly found. Nor does magnesium supplementation, as common as it is, lead to a cure as it might for XMEN disease.Because neither the MAGTI transporters or the NKG2D receptors found to play a role in XMEN disease have been assessed in ME/CFS, we have no idea if these transporters are functioning correctly in ME/CFS or FM.Research into rare, genetic diseases, however, often gives us insight into more common disorders. That could be the case with ME/CFS.EBV triggered infectious mononucleosis, after all is common in ME/CFS, natural killer and T-cells are dysfunctional, magnesium supplementation is rampant, and some ME/CFS patients do very well on antivirals targeting EBV. Recurrent (upper respiratory) infections can be found in some ME/CFS patients as well and increased rates of lymphoma have been found in early studies. (Could the increased rates of lymphoma found ME/CFS due to undiagnosed XMEN disease?).  Some researchers and doctors believe a special kind of EBV reactivation often occurs in ME/CFS.Further studies in this area could impact ME/CFS or FM in several ways. They could elucidate problems with magnesium transportation and they could uncover other ways to fight EBV.Indeed, the National Institutes of Allergy and Infectious Diseases (NIAID believes that further research into magnesium associated EBV reactivation could help patients with chronic EBV disorders.

Because chronic EBV infections afflict patients of other disorders, this information may be useful for designing general therapies against EBV. National Institute of Allergy and Infectious Disorders

Whether or not  ME/CFS falls into chronic EBV infected group largely depends on who you're talking to.  An EBV ME/CFS researcher was, however, recently given a major NIH grant to study EBV infection and the Simmaron Research Foundation is engaged in similar research (see below).

The Future

We are going to learn a lot more how about how magnesium is transported into and out of cells, though.  Lenardo and Chaigne-Delalande are currently examining how other magnesium transporters work.  That's good news for diseases like ME/CFS and fibromyalgia in which magnesium supplementation is common. They'll also continue to examine magnesium's role in chronic EBV infection.(One question not examined in the study was whether EBV be somehow damaging magnesium transporters in order to turn off NK and T cell activity…)

More Epstein-Barr Virus News

The smoldering EBV infection hypothesis for ME/CFS recently got a boost when Ohio State University professor Dr. Vance Williams got a major NIH grant to study it. Williams earlier studies indicated that unusual EBV proteins rarely seen in humans can produce many of the symptoms found ME/CFS. Williams multi-year, multi-million dollar NIH study will further investigate the effects these proteins are having in this disease. The Simmaron Research Foundation's NIH study examining the extent of autoimmunity and non-Hodgkin's Lymphoma in people with ME/CFS and their family members will focus on similar ground. This study will determine whether antibodies to the same EBV proteins Williams uncovered in ME/CFS are present. Finding antibodies to these unusual proteins would a) implicate EBV as a key player in ME/CFS and b) strongly suggest ME/CFS is an autoimmune disorder.Please support the Simmaron Research Foundation as it scientifically redefines how ME/CFS is understood and treated.