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A new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus

Ema

Senior Member
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4,729
Location
Midwest USA
XMEN disease: a new primary immunodeficiency affecting Mg2+regulation of immunity against Epstein-Barr virus
  1. Feng-Yen Li1,
  2. Benjamin Chaigne-Delalande1,
  3. Helen Su2,
  4. Gulbu Uzel3,
  5. Helen Matthews1, and
  6. Michael J. Lenardo1,*
+Author Affiliations

  1. * Corresponding author; email: lenardo@nih.gov

Abstract
Epstein Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named "X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease.

  • Submitted November 19, 2013.
  • Accepted February 7, 2014.
Full text at:
http://bloodjournal.hematologylibrary.org/content/early/2014/02/18/blood-2013-11-538686.abstract

ETA: I lied; the full text is behind a paywall. PM me for further info if interested.
 
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Sparrow

Senior Member
Messages
691
Location
Canada
Magnesium's link to the immune system, and in fighting Epstein-Barr in particular is very interesting. I wonder if that's part of why so many of us seem to need extra Magnesium, and why Dr. Myhill's patients found Mg injections so helpful. Thank you for sharing.
 

SOC

Senior Member
Messages
7,849
This may explain viral ME/CFS that responds to antivirals in 3 generations in my family as well as Hodgkin's Lymphoma (an EBV-associated lymphoma) also in at least 3 generations.

I think I'll be making sure we're getting our extra magnesium.

@Ema, did they say exactly what gene and what the loss-of-function mutation is, so that we might be able to look it up? I'm guessing that 23andme doesn't test for that gene, but perhaps luck will fall our way for once.
 

kaffiend

Senior Member
Messages
167
Location
California
I haven't seen this paper discussed anywhere on the forum but it looks highly relevant and is cited by the paper on this thread. I'm surprised I missed it. They used magnesium threonate.

http://www.sciencemag.org/content/341/6142/186.full

Mg2+ Regulates Cytotoxic Functions of NK and CD8 T Cells in Chronic EBV Infection Through NKG2D

Science 12 July 2013:
Vol. 341 no. 6142 pp. 186-191
DOI: 10.1126/science.1240094


The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium (Mg2+) concentrations. Individuals with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. We show that decreased intracellular free Mg2+causes defective expression of the natural killer activating receptor NKG2D in natural killer (NK) and CD8+ T cells and impairs cytolytic responses against EBV. Notably, magnesium supplementation in MAGT1-deficient patients restores intracellular free Mg2+ and NKG2D while concurrently reducing EBV-infected cells in vivo, demonstrating a link between NKG2D cytolytic activity and EBV antiviral immunity in humans. Moreover, these findings reveal a specific molecular function of free basal intracellular Mg2+ in eukaryotic cells.
 

Ema

Senior Member
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4,729
Location
Midwest USA
The article has been posted in the relevant forum (if anyone needs assistance locating it, please PM me or a moderator) and tagged with the names of those who liked it.

If it won't open, please let me know!
 

SOC

Senior Member
Messages
7,849
FWIW, I'm GG for the MAGT1 gene. The "Mendel's" are all T. When my brain is up to reading the paper :( I'll try to figure out if that is the relevant genetic abnormality or not.

@Valentijn, when you get a chance, can you look up this gene in your patient vs controls genetic data?
 
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15,786
FWIW, I'm GG for the MAGT1 gene. The "Mendel's" are all T. When my brain is up to reading the paper :( I'll try to figure out if that is the relevant genetic abnormality or not.

@Valentijn, when you get a chance, can you look up this gene in your patient vs controls genetic data?
There's only three SNPs listed for the gene, and we're all very normal compared to the controls. All the SNPs nearby are also very normal.

Presumably your GG is for rs35658443, where G has approximately 50% allele prevalence. 25% of woman will have GG and 25% will have TT, with the remaining 50% having GT. 50% of men should have G and 50% should have T.

I don't think 23andMe is testing for the nasty one.
 

SOC

Senior Member
Messages
7,849
There's only three SNPs listed for the gene, and we're all very normal compared to the controls. All the SNPs nearby are also very normal.

Presumably your GG is for rs35658443, where G has approximately 50% allele prevalence. 25% of woman will have GG and 25% will have TT, with the remaining 50% having GT. 50% of men should have G and 50% should have T.

I don't think 23andMe is testing for the nasty one.
Thanks! I'm not even sure the mutation is an allele difference in the cases they're talking about in this paper. Could be the mutation is an insertion or deletion. That's different, isn't it? :confused:

I'll try to skim the whole papers later today if my mental energy holds up. Not that I understand more than about 30% of what they'd talking about with genetics. :(
 
Messages
15,786
Thanks! I'm not even sure the mutation is an allele difference in the cases they're talking about in this paper. Could be the mutation is an insertion or deletion. That's different, isn't it? :confused:

I'll try to skim the whole papers later today if my mental energy holds up. Not that I understand more than about 30% of what they'd talking about with genetics. :(
It sounds like one is a missense mutation which results in the encoded protein (a magnesium transporter) having its assembly terminated prematurely, and the other is a large deletion. While I can't read the current article, the same group has prior articles regarding the same gene at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159560/ and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894782/ with the full text available.

The mutations they've discussed in one of those prior papers are Arg137Ter and Ivs7As. Arg137Ter is rs387906724 (not tested by 23andMe) and it looks like "A" would be the pathogenic allele. The other one is a deletion on chromosome X for positions 77,109,392 - 77,109,401. No known SNPs are listed in the area, and 23andMe doesn't test anything in that area.
 
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Sea

Senior Member
Messages
1,286
Location
NSW Australia
My CD4/CD8 ratio is 0.87 but this is reported as being within normal range (0.8 - 4.0)
I don't really know what the implications are for being on the lower end.
 

Sparrow

Senior Member
Messages
691
Location
Canada
I would guess that the specific genetic issue they're talking about is a more pronounced version, and probably something separate from what's wrong with us. And because it's on the x-chromosome, and carriers of only one copy are apparently asymptomatic, it would be very unlikely for females to be affected.

...But we have sometimes been shown to have unusually low intracellular magnesium. It seems possible that low levels might cause a similar problem to what they're describing, just on a less severe scale.
 

SOC

Senior Member
Messages
7,849
I would guess that the specific genetic issue they're talking about is a more pronounced version, and probably something separate from what's wrong with us. And because it's on the x-chromosome, and carriers of only one copy are apparently asymptomatic, it would be very unlikely for females to be affected.

...But we have sometimes been shown to have unusually low intracellular magnesium. It seems possible that low levels might cause a similar problem to what they're describing, just on a less severe scale.
Agreed. One thing to consider though, is that as medicine learns more, we are finding that people who are heterozygous for some of these severe illnesses were considered asymptomatic when in fact they are less severely affected, not without impact at all.

One example is the gene mutation that causes PKU, a severe illness for which they test newborns within hours of birth. Now they're finding that people with one copy can have hyperphenylalinemia, a milder condition, but not innocuous.

So while I'm confident we don't have the severe illness described in these papers, it's not beyond possibility that a lesser related condition could be affecting us. As you said, something causing low intracellular magnesium -- possibly a lesser form of this illness, or (more likely) a different Mg problem -- could be causing a significant number of our problems.
 
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Sparrow

Senior Member
Messages
691
Location
Canada
Agreed. One thing to consider though, is that as medicine learns more, we are finding that people who are heterozygous for some of these severe illnesses were considered asymptomatic when if fact they are less severely affected, not without impact at all.

One example is the gene mutation that causes PKU, a severe illness for which they test newborns within hours of birth. Now they're finding that people with one copy can have hyperphenylalinemia, a milder condition, but not innocuous.

So while I'm confident we don't have the severe illness described in these papers, it's not beyond possibility that a lesser related condition could be affecting us. As you said, something causing low intracellular magnesium -- possibly a lesser form of this illness, or (more likely) a different Mg problem -- could be causing a significant number of our problems.

Very true. Medicine tends to be very focused on things that are immediately fatal or obviously disabling. It takes a lot longer to see less obvious impacts, even when they're significant.