New Roles of Magnesium as a Regulatory Ion in Immune Responses and Cell Behavior

National Institute Of Allergy And Infectious Diseases

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Abstract

The MAGT1 transporter is critically involved in the selective regulation of intracellular free Mg2+ levels in mammalian cells. The molecular functions of free Mg2+ in eukaryotic cells have not been fully established. We found that patients with genetic deficiencies in MAGT1 have high levels of Epstein-Barr virus (EBV) and a predisposition to lymphoma. Because of a key role of MAGT1 in N-linked glycosylation that we have studied for the last few years, we have updated our hypothesis. In previously studying lymphocytes from these patients, we found that a deficiency of MAGT1 caused decreased basal intracellular free Mg2+ leading to defective expression of the natural killer activating receptor NKG2D in NK and CD8+ T cells. Without NKG2D, cytolytic responses against EBV are diminished, thereby revealing the first specific molecular function of intracellular basal free Mg2+ in eukaryotic cells. Intracellular free Mg2+ and NKG2D expression and function can be rescued in vitro by incubating patient cells and elevated levels of Mg2+. Moreover, NKG2D expression and cytolytic function can be improved and EBV-infected cells reduced in vivo, in MAGT1-deficient patients by magnesium administration. Thus, our data indicate an important molecular function for free basal Mg2+ in immunity and demonstrate a requirement for NKG2D cytolytic function in an essential EBV antiviral response in humans. We tested this hypothesis with a clinical trial. Mg2+ supplementation was considered an attractive therapy for XMEN disease because it is a readily available over-the-counter supplement and could distribute throughout the body and potentially rescue extra-hematopoietic manifestations. However, the initial data were uncontrolled and limited and a placebo-controlled, double-blind study was essential to make a definitive recommendation regarding Mg2+ supplementation. Unfortunately, in this clinical trial, we found that Mg2+ supplementation had no beneficial effect on the primary endpoints in either EBV-positive or EBV-negative patients. The only EBV-positive patient who completed the trial did not achieve a significant reduction in the number of EBV+ infected B cells or EBV viral load. None of the patients who completed part 1 or part 2 of the trial showed a twofold increase in NKG2D on CD8+ T or NK cells. Except for asymptomatic elevations in liver enzymes with both oral and intravenous Mg2+ administration in one EBV-nave XMEN patient, both oral and intravenous Mg2+ were generally well tolerated. It remains unclear if the hepatic enzyme elevations were induced by Mg2+ or were transient elevations seen with the mild liver disease found in XMEN patients. Thus, while the trial shows that Mg2+ supplementation is a safe intervention, evidence for effectiveness is lacking.