X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia disease: a combined immune deficiency with magnesium defect

Abstract

Purpose of review: To describe the role of the magnesium transporter 1 (MAGT1) in the pathogenesis of 'X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia' (XMEN) disease and its clinical implications.

Recent findings: The magnesium transporter protein MAGT1 participates in the intracellular magnesium ion (Mg) homeostasis and facilitates a transient Mg influx induced by the activation of the T-cell receptor. Loss-of-function mutations in MAGT1 cause an immunodeficiency named 'XMEN syndrome', characterized by CD4 lymphopenia, chronic EBV infection, and EBV-related lymphoproliferative disorders. Patients with XMEN disease have impaired T-cell activation and decreased cytolytic function of natural killer (NK) and CD8 T cells because of decreased expression of the NK stimulatory receptor 'natural-killer group 2, member D' (NKG2D). Patients may have defective specific antibody responses secondary to T cell dysfunction, but B cells have not been shown to be directly affected by mutations in MAGT1.

Summary: XMEN disease has revealed a novel role for free intracellular magnesium in the immune system. Further understanding of the MAGT1 signaling pathway may lead to new diagnostic and therapeutic approaches.

Figure 1

Magnesium transporter 1 (MAGT1) regulates free basal magnesium concentrations and is responsible for the rapid and transient magnesium flux after T cell receptor (TCR) stimulation. In normal T cells, stimulation of the TCR triggers a transient Mg²⁺flux through MAGT1. This rapid increase of intracellular Mg²⁺is required for the activation of phospholipase Cγ1 (PLCγ1) required for the downstream generation of Ca²⁺ flux through the Ca²⁺ channel ORAI by promoting the release of Ca²⁺ from the endoplasmic reticulum (ER) via inositol 1,4,5-triphosphate (IP3) and its receptor, leading to activation of the stromal interaction molecule (STIM) and its translocation into the ER-plasma membrane junctions where they activate ORAI as shown in the TCR signaling diagram (left). The absence of MAGT1 leads to the chronic reduction of intracellular free Mg²⁺, which is required to maintain the expression of NKG2D (shown associated with adaptor molecules DAP10) and the normal cytolytic function of NK and CD8⁺ T cells as shown in the NKG2D/DAP10 diagram. Loss of MAGT1 results in defective TCR signaling and decreased expression of NKG2D. These two defects lead to failure to clear EBV infection and increased susceptibility to EBV-positive lymphomas/lymphoproliferative disease (LPD).