XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus

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, 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 has 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.

Figures

Figure 1

XMEN disease. (A) XMEN disease clinical features. Major features are present in almost all XMEN patients, while minor features are found only in some patients. (B) Model of the role of MAGT1 in TCR activation. In normal T cells, stimulation of the TCR triggers a Mg2+ flux through MAGT1. This transient increase of intracellular Mg2+ is required for the activation of phospholipase C γ1 (PLCγ1) required for the downstream generation of Ca2+ flux through ORAI by promoting the release of Ca2+ from the endoplasmic reticulum via inositol 1,4,5-triphosphate (IP3) and its receptor. (C) Model of role of MAGT1 in Mg2+ homeostasis and NKG2D expression. In XMEN patients, the absence of MAGT1 leads to the chronic reduction of intracellular free Mg2+, which is required to maintain the expression of NKG2D.