NIAID investigators have identified a genetic mutation that may account for X-linked magnesium deficiency with Epstein-Barr virus (EBV) infection and neoplasia, or XMEN, a rare primary immune deficiency disease (PIDD) characterized by very low numbers of circulating CD4 T cells and uncontrolled, persistent EBV infections. The identification of this particular disease also answers a decades-old question about the specific roles that magnesium has for normal cell functions. This finding is reported online in the July 27 issue of Nature.
PIDDs are caused by inherited genetic mutations that affect one or more parts of the immune system. Though rare, these disorders are chronic and debilitating, associated with a high frequency of severe bacterial and viral infections and, sometimes, cancers. There are currently more than 150 different known forms of PIDDs, and advances in genetic research are enabling investigators to identify and characterize more. Researchers are intensely interested in understanding rare genetic disorders both to help suffering families and also to learn more about how the immune system works in healthy people.
A condition where people present with very low numbers of circulating CD4+ T cells without HIV infection is known as idiopathic CD4 lymphocytopenia (ICL), which has been suspected to be a PIDD. ICL causes susceptibility to bacterial, viral, and fungal infections. Most people with ICL present with cryptococcal or nontuberculosis mycobacterial infections, but some develop chronic EBV infections, which can make them more susceptible to cancer. People with ICL are treated with medications to clear the body of harmful microbes. For some, a bone marrow transplant may restore normal immune function, but it can be difficult to determine who would benefit from this type of treatment.
Identifying the genetic mutation that causes ICL for patients susceptible to EBV infections could help investigators find better ways to treat the condition.
In this study, investigators led by Michael Lenardo, M.D., chief of the Molecular Development of the Immune System Section in NIAID's Laboratory of Immunology, examined the immune cells of two young brothers and a third, unrelated male patient with ICL and persistent EBV infection. None of the patients had HIV, so HIV could not explain their low CD4+ T-cell counts. The study team also determined that the three patients did not have X-linked lymphoproliferative disease, a known PIDD characterized by overwhelming infections with EBV.
In the case of the two brothers the investigators examined the possibility that the genetic mutation was due to an abnormal gene on their mother's X chromosome. Using a type of analysis called exome sequencing, which detects mutations in regions of genes that make proteins (exons), the study team found that one of the mother's two X chromosomes carried a mutation in a gene that makes a protein called magnesium transporter 1 (MagT1), which normally moves magnesium into T cells. Without a functioning transporter protein, magnesium does not enter the cells very efficiently, so the cells do not function as they should.
Because the mother has two X chromosomes—one healthy and one with the MagT1 mutation—she had normal CD4+ T cell counts. But the boys only have one X chromosome and inherited the one carrying the mutated gene. When their T cells, along with T cells from the third boy, were observed in a lab setting, the cells did not take up magnesium easily and had impaired activation, compared to T cells from healthy people. Dr. Lenardo's team observed, however, that giving the T cells high doses of magnesium activated the cells.
This study shows that magnesium is necessary for cellular signaling. Study findings also reveal an entirely new reason why it is important to have adequate magnesium in the diet, which can come from eating dark, leafy greens, whole grains, and nuts. Although a role for magnesium in T-cell development had been previously demonstrated, the team found that magnesium in cells conveys important messages telling T cells how to function.
More importantly, Dr. Lenardo's team provided a more accurate diagnosis for the patients. With a diagnosis of XMEN disease, the NIAID team can give better treatment recommendations to the two brothers and other similarly affected families. The family of the third patient, who sadly has since died of cancer, also received a more accurate diagnosis for the unknown disease he had battled for years.
The results of this study indicate that targeting MagT1 may be a possible therapy for certain forms of ICL. In preliminary studies, Dr. Lenardo's team also has observed that giving the T cells high doses of magnesium improved their activation. This observation suggests that it may be possible to alleviate XMEN disease by giving patients magnesium. Although high doses of magnesium can be toxic and should only be given by a healthcare professional, magnesium supplementation could be a relatively simple fix for an otherwise devastating disease.
Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis J, Matthews HF, Douek D, Cohen J, Uzel G, Su HC, Lenardo MJ. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011 July 27 [Online ahead of print].
Primary Immune Deficiency Diseases
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Magnesium Supplements May Reduce Viral Infection in “XMEN” Patients
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Last Reviewed July 06, 2011