Archive for August, 2015

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.


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.

ACT NOW: Just Say NO to Funding Cuts for ME/CFS Research

ALERT: Senate Cuts CDC’s funding for CFS to Zero, gutting 50% of federal research funding for ME/CFS

NO Funding Cuts:  One Clear, Consistent Demand for Equal Funding

By Cort Johnson and Robert and Courtney Miller

While patients advocate for Equal Funding for ME/CFS research, the Senate Appropriations Subcommittee quietly zeroed out CDC’s budget request for CFS research.

One of the studies to be cut would be the CDC’s Clinical Assessment or Multi-site study. Dr. Peterson had this to say about that study:

“The CDC’s clinical assessment study is pivotal to patients with CFS/ME allowing CFS clinicians to analyze our ‘classic’ patients for commonalities, subset distinctions and biological markers in a collaborative manner. The last few years of this work with Dr. Unger and the CDC staff has increased our understanding and evolved the spectrum of collaboration. Many more resources are required to expand on recent scientific findings.”    Dr. Daniel Peterson, Sierra Internal Medicine and Simmaron Scientific Advisor

Patients with ME or CFS only have two choices right now: either we go forward with one clear demand for Equal Funding for federal scientific research – which means no cuts! – or we go backwards. We need your action to restore precious funds!

We should be going forward now. Institute of Medicine profiled the “urgent need for more research” in February. In June, National Institutes of Health’s Pathways to Prevention Panel said “innovative biomedical research is urgently needed….” Columbia University published groundbreaking patterns of immune abnormality. CDC just published new findings of gene variants in the immune and inflammatory pathway of patients.

500 patients and caregivers wrote the Secretary of Health and Director of NIH in May highlighting these independent reports and demanding that research into our illness be funded equally with Multiple Sclerosis or Systemic Lupus, at more than $100 million per year. Sen Zero for CDC CFS

Meanwhile, the Senate Appropriations Subcommittee quietly zeroed out the only earmarked funding for CFS in any health agency budget: they crossed $5.4 million out of CDC’s proposed budget and put “0” next to CFS.

NIH is watching this closely. NIH only spent $5 million last year on CFS research. Why should the NIH fund ME/CFS at $100+ million, when Senate appropriators can get away with removing funding for the only line item ME/CFS patients have in the federal budget?

This cut isn’t about CDC’s bad history with CFS. It’s about whether or not ME/CFS patients will protest in one voice that it is time to fund us equally.

Huge ME/CFS Study Put in Jeopardy

At the heart of the CDC’s ME/CFS program lies one of the largest ME/CFS studies ever undertaken – the Multi-site (Clinical Assessment) study created by Dr. Andy Kogelnik.

We believe this project provides a distinct and welcome turning point for CDC’s CFS program.

We have watched closely as the CDC collaborates with CFS/ME experts like Dr. Daniel Peterson, Dr. Nancy Klimas and Dr. Andy Kogelnik. For the past 3 years, seven expert doctors have been collaborating with CDC’s Dr. Unger to study patients selected and diagnosed by the doctors, collaborating on what diagnostic markers to test, under what conditions, across 7 clinics, for consistency, new data and a different future.

The study will help inform efforts to create a new definition, uncover subsets, produce new diagnostic guidelines, understand the course of the disease, and introduce to the public for the first time, treatments ME/CFS experts use to enhance the health of their patients.

Phase II of the study, underway now, will, also for the first time, ever assess large numbers of severely ill patients. The study also includes a large exercise study that will assess the effects of exercise on lactate levels, gene expression, cognition and symptoms.

This study will end if the Senate’s budget stays at 0 for the CFS program. That would be tragic.

Take Action

Please make it clear to the Senate Appropriations Subcommittee that ME/CFS patients deserve equal funding, not funding cuts. Cutting $5.3 million from CDC’s budget would cut federal research funding in half. That is going backwards for patients.

The question is for us as a community is whether we are going to allow anyone, on the heels of the IOM and P2P reports, to cut any part of the budget for ME/CFS. In order to be successful later we must take a stand now and say no to this bizarre attempt to cut the ME/CFS research budget in half. ME/CFS support organizations (including Solve ME/CFS, the IACFS/ME, the Open Medicine Foundation, Simmaron Research, Mass CFIDS/ME, New Jersey ME/CFS and Conn. CFIDS/FM) have created their own letter and other efforts are underway to get doctors and researchers to protest this untimely cut to ME/CFS research.

Take Action with this Email Template:

Please email these senate committee staff and YOUR Senators. You can copy and paste the text below or change it as you see fit:

AND your senators – find them here:


SUBJECT:       Restore Cuts to Chronic Fatigue Syndrome Funding in CDC Budget


Dear Senate Appropriations Committee:

I am very ill with Chronic Fatigue Syndrome (known as Myalgic Encephalomyelitis). We have suffered with the smallest budget at CDC and NIH for decades. I am distressed to learn that the Senate Appropriations Subcommittee has cut CDC’s budget on Chronic Fatigue Syndrome research to zero, and I need you to restore it to the same level as the House bill in the Conference Committee. (see: pg 59)

This year, two independent panels of scientists – the prestigious Institute of Medicine and National Institutes of Health’s Pathways to Prevention Panel – both reported the same urgent need: “There is an urgent need for more research to discover what causes ME/CFS, understand the mecha­nisms associated with the development and progression of the disease, and develop effective diagnos­tic markers and treatments.”

I am disabled by CFS and I deserve equal funding, not zero funding. More than 1 million Americans have CFS, costing the US economy more than $20 billion annually. CFS is as disabling as late-stage renal failure and Multiple Sclerosis. There are no FDA-approved treatments or diagnostic tests. I want my life and health back, and I need medical research to solve my disease.

Cutting CDC’s $5.3 million request reduces federal research funding for CFS by 50% at a time when we desperately need more scientific research. Please restore the CFS budget request and urge NIH to fund CFS research equally with Multiple Sclerosis.



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