Blood Spotlight XMEN disease: a new primary immunodeficiency affecting Mg 21 regulation of immunity against Epstein-Barr virus Feng-Yen Li, 1,2 Benjamin Chaigne-Delalande, 1 Helen Su, 3 Gulbu Uzel, 4 Helen Matthews, 1 and Michael J. Lenardo 1 1 Molecular Development of the Immune System Section, Lymphocyte Molecular Genetics Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; 2 University of California-San Francisco, San Francisco, CA; 3 Immunological Diseases Unit, Laboratory of Host Defenses, and 4 Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and per- sists in 95% of adults worldwide and has the potential to cause fatal disease, espe- cially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malig- nancies 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 encod- ing magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened sus- ceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in im- mune functions and has led to novel diag- nostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mecha- nisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease. (Blood. 2014;123(14):2148-2152) Introduction Epstein-Barr virus (EBV), a B-cell–tropic gammaherpesvirus present in latent form, is widespread and affects the majority of adults and children worldwide. 1 While most infections are asymptomatic or cause nonspecific symptoms, about 75% of adolescents and young adults with primary EBV infection develop mononucleosis. 2 Moreover, hosts with acquired immunodeficiencies secondary to posttrans- plantation immunosuppression or HIV are at increased risk of developing EBV-positive B-cell lymphomas and other opportun- istic infections. Failure to control EBV along with the potential lethal sequelae associated with persistent active EBV infection, such as EBV-positive B-cell lymphomas, fulminant infectious mononucleosis, chronic active EBV infections (CAEBV), and/or hemophagocytic lymphohistiocytosis, are key pathologic hall- marks of primary immunodeficiencies (PIDs) such as X-linked lymphoproliferative disease type 1 (XLP1), interleukin-2 in- ducible tyrosine kinase (ITK) deficiency, or CD27 deficiency. 3 These PIDs illustrate key proteins in T cells and natural killer (NK) cells that are important for EBV control. We recently identified a new PID associated with chronic high-level EBV and susceptibility to EBV- positive B-cell lymphomas in a cohort of 7 patients, which has now been named “X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) disease. 4,5 Identification of the gene mutated in XMEN, MAGT1, has revealed an unexpected but essential role of free intracellular magnesium in the control of EBV by T and NK cells. 4,5 Here, we review the phenotypic and genotypic features of this disease and how its novel pathogenetic mechanism demonstrates a fundamental role of magnesium transport for immu- noregulation and provides new unconventional diagnostic and thera- peutic strategies. Clinical manifestations We initially identi fied 3 patients with XMEN disease based on persistent high EBV levels and inverted CD4:CD8 ratio. 4 Sub- sequently, we screened 61 patients for CD4 lymphopenia, chronic high EBV levels comparable to those in CAEBV patients (ranging from 1000 to 100 000), and/or EBV-associated B-cell lympho- mas. Although EBV levels detected in XMEN patients vary widely, uncontrolled EBV should be detectable, and extremely high levels of EBV in a male child should raise the index of suspicion of this disease. While we did not find any additional XMEN patients with only inverted CD4:CD8 ratios, we identified 5 additional unrelated XMEN patients with chronic EBV in- fection and persistent EBV levels in the blood (Table 1). 5 All patients also had splenomegaly. The patients were developmen- tally normal and had no signs of end organ dysfunction except for patient B.1, who presented with CAEBV disease with hepatitis, pancytopenia, and hemophagocytosis. 6 We found that, except for the youngest individuals (A.1, A.2, C.1), all postpubertal XMEN patients developed various EBV-associated B-cell lymphoproli- ferative disorders (Table 1). The most consistent clinical feature among the 7 XMEN patients characterized thus far is a persistent high level of EBV along with increased susceptibility for devel- oping EBV-positive lymphomas. 4 All human patients in this study provided written informed consent in accordance with Helsinki principles for enrollment in research protocols that were approved by the institutional review board of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH). Submitted November 18, 2013; accepted February 7, 2014. Prepublished online as Blood First Edition paper, February 18, 2014; DOI 10.1182/blood- 2013-11-538686. 2148 BLOOD, 3 APRIL 2014 x VOLUME 123, NUMBER 14 Downloaded from http://ashpublications.org/blood/article-pdf/123/14/2148/1374984/2148.pdf by guest on 28 October 2023