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

August 22, 2015

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 SCIENCE

The authors had recently characterized a primary immunodeficiency disease in people with chronic Epstein-Barr virus infection called XMEN.

XMEN disease

XMEN is a rare genetic disease that combines low magnesium levels and Epstein-Barr virus infection. Could it help explain ME/CFS?

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.

magnesium

Low levels of free magnesium turned off NK and T-cells – and allowed EBV to take up residence in the cell.

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.

Several features in ME/CFS and XMEN disease overlap...

Several features in ME/CFS and XMEN disease overlap…

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.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS 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.

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22 Comments

  • Cort Johnson

    August 22, 2015 at 2:26 pm - Reply

    I didn’t think of undiagnosed XMEN disease in ME/CFS but that’s surely a possibility particularly with the lymphoma patients…

  • Eilidh Hewitt

    August 22, 2015 at 3:07 pm - Reply

    This is a very interesting subject to me
    I have mentioned my family history before on Health Rising, that four uf us (mother and three children) all fell ill in th 1980s with severe ME and EBV was heavilly implicated with us all. Although my husband was initially ill with the same sort of viral infections that we all had, he did not develope ME, but he has just died on 6th April of lymphoma on. We have all wonder a lot if his illness was connected in some way with our susceptibility to ME

  • Heidi

    August 22, 2015 at 6:41 pm - Reply

    I’m so glad to hear Simmaron Research is pursuing the EBV as a possible cause of MECFS. Many researchers discarded that theory many years ago and, unfortunately, have been searching for a virus which has been right in front of them the whole time. If ebv can cause Burkitt’s lympoma, xmen disease, and possibly MS, it is can very likely be the cause of mecfs. With the great research that is happening, it gives me hope for a cure, or at least the discovery of the cause of the disease.

    • Cort Johnson

      August 22, 2015 at 6:48 pm - Reply

      I think EBV must figure in there – at least with some patients. The results of their study will be fascinating…:)

  • Aidan Walsh

    August 22, 2015 at 9:54 pm - Reply

    Not sure if my Fathers Bowel Cancer tumor could have been related or not to Lymphoma I have had very high activation to EBV plus years back my CD4/CD8 count dropped below 400 I think 391…I am helped by Magnesium Pure Oil…This test for

    XMEN is this widely available? I just had complete Immunological work up my CD4 CD8 was normal but I do take Magnesium daily it definitely helps with all my pain…I know Ehlers Danlos Syndrome has Genetic links I wonder how EBV plays a role in

    that as well…Dr Rodney Grahame from London was quoted as saying 95% of patients with CFS/Fibro have ‘undiagnosed’ Ehlers Danlos type(s) he is one brilliant Doctor very well respected in Connective Tissue disorders Cllagen Proteins…

  • Marcia Morrison

    August 23, 2015 at 6:21 pm - Reply

    Thanks for this write-up, very interesting.

    • Cort Johnson

      August 23, 2015 at 7:38 pm - Reply

      Thanks Marcia – I thought it was very interesting too :)

      I really appreciate Simmaron’s support in allowing me to do these blogs.

  • cintia

    August 23, 2015 at 6:51 pm - Reply

    I am the typical case: got Mononucleosis at 15. Never recovered. 29 years old now and my fatigue is not fluctuating at but only worsening with time…

    • Cort Johnson

      August 23, 2015 at 7:39 pm - Reply

      You’re going to find an upcoming report on a Simmaron event I just attended interesting. That will be probably be up in a week or so

      • cintia

        August 23, 2015 at 7:46 pm - Reply

        will wait for it!! :)
        thanks for the reply!

  • Jill C

    August 24, 2015 at 12:35 pm - Reply

    I got EBV in 2006 at age 38, and have had high titers and chronic EBV symptoms since. I am female, and have had a long history of ear infections and strep throat, and sinus infections as a teen. I had a tonsillectomy in 2012 which drastically and quickly improved my health so much, that I got pregnant after an 18 year stretch of infertility (along with many other health improvements). That year, I felt better than I had in my entire adult life, even through a cesarean and subsequent septicemia. I remember being in the hospital with septicemia and thinking, “I STILL feel better than I did five years ago.”
    Two months later, I was misdiagnosed with thrush because of breastfeeding pain, and prescribed Diflucan. Taking Diflucan re-ruined my health. Plus some extra fun stuff like digestive difficulties. I’ve mostly recovered from that, but am back to having CEBV symptoms. I’m sure I have other stuff going on, but I can’t find anyone who even thinks CEBV is a problem! I missed out on my diagnosis in 2007 because my doctor didn’t even call me. The last doctor I saw in the spring said the diagnosis was “unimportant” and told me to lose weight.
    So how do I find the right kind of help? I’ve already spent thousands this year on a promising doctor who turned out not to think my health issues were important.

  • Tina

    August 25, 2015 at 1:33 am - Reply

    Thank you, Cort, for sharing this! Do you know how much oral magnesium gluconate was give to the patentskin in the study?

  • Marie

    August 25, 2015 at 2:29 pm - Reply

    I was recently diagnosed with EBV for the 4th time. Was diagnosed with CFS and Fibro 10 years ago. I’ve had some improvements in symptoms with Valcyte. Been on the Pridgen Protocol for 3 months, no improvement…yet.

  • Marie

    August 26, 2015 at 8:17 pm - Reply

    I’ve recently been diagnosed with EBV for the fourth time since I was in my early 20s. I was diagnosed with CFS and Fibromyalgia 10 years ago. Eight years ago I went on Valcyte for 6 months and got partial relief from some symptoms.Two years ago, I started LDN and noticed that my immune system seemed to normalize. I started getting colds for the first time in 10 years. The down side is that EBV started replicating again. So, I’m trying the Pridgen Protocol, although not seeing any benefits yet. It seems that the EBV connection is an issue for many of us. Glad to see it’s being reconsidered.

  • TiehSsieh

    September 15, 2015 at 4:13 pm - Reply

    German specialist for Epstein-Barr Virus

  • Penny

    September 21, 2015 at 6:09 am - Reply

    I was diagnosed in 1991 with CFS and Fibro. My EBV has been high thru most of the illness, so I am also happy to see it be reconsidered. Thank-you Cort for providing such helpful information.

  • Dee

    June 5, 2016 at 7:47 pm - Reply

    I have been diagnosed with CEBV, as well as FM & Myasthenia Gravis (MG). In my mid 40’s,I was in crisis for 2 years with MG before anyone knew what I had. I lost my speech, could not eat or drink, & breathing was severely impaired. I mistakenly allowed thymectomy – removal of my thymus gland.

    While I am not in crisis these days, I am still affected & wear out quite easily. We are advised to avoid all magnesium products, which I really don’t follow that advice.

    I stumbled across your site here & through the comments saw others mentioning EXMEN disease. I have never heard of this until then. This led me to look into that, being curious as to what it was.

    I am very concerned about this finding: “Laboratory manifestations[edit] XMEN patients generally have chronically high levels of EBV with increased EBV-infected cells, diminished thymic output of CD4+ cells, reduced CD4:CD8 ratio, moderately high B cell counts, and mild neutropenia.”

    I hope this doesn’t predispose me to leukemia?

  • Barbara

    August 9, 2016 at 3:36 pm - Reply

    Following.

  • Caroline

    September 3, 2016 at 10:14 pm - Reply

    I got EBV in August of 2014, and I’ve been suffering ever since. I am chronically fatigued. I’ve had Shingles now four times. I have chronic hives and rash. I am still working but I am careful to sleep as much as I can. I usually sleep 10 to 12 hours each night and I rest on the weekend. I have given up drinking any alcohol and I have changed my diet to organic foods…no dairy and no gluten. I wish I could say my health was back to baseline, but it is not. When stress arises, I find myself ill. I am now just recovering from shingles again. It’s one day at a time once your immune system has been severely damaged by EBV. I don’t think many physicians are well versed in this topic. I’m still looking for a provider who with expertise in this area. I also take famvir every day which helps to some degree….my PCP put me on this for HSV1 supression…but I think it also helps with the fatigue related to EBV.

    • Caroline

      September 3, 2016 at 10:31 pm - Reply

      I think that there is some scientific data to support use of valacyclovir and famvir in EBV…but my doctor prescribed this for HSV1 suppression.

    • Cindy

      March 26, 2017 at 4:19 pm - Reply

      Have you tried colloidal silver? I hear it works with the correct dosage. Get MesoSilver brand…all others are worthless. I have just ordered it for myself. Let’s hope it works. I have had chronic fatique/fibro for years which I think was started by EBV – I also had shingles, chronic infections, wide spread aches and pains.

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