Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease
Juan C. Ravell, … , Matthias Mann, Michael J. Lenardo
Juan C. Ravell, … , Matthias Mann, Michael J. Lenardo
Published November 5, 2019
Citation Information: J Clin Invest. 2020;130(1):507-522. https://doi.org/10.1172/JCI131116.
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Research Article Immunology

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Abstract

X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4–CD8–B220–TCRαβ+ T cells (αβDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27–CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27–CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10–CD38–) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.

Authors

Juan C. Ravell, Mami Matsuda-Lennikov, Samuel D. Chauvin, Juan Zou, Matthew Biancalana, Sally J. Deeb, Susan Price, Helen C. Su, Giulia Notarangelo, Ping Jiang, Aaron Morawski, Chrysi Kanellopoulou, Kyle Binder, Ratnadeep Mukherjee, James T. Anibal, Brian Sellers, Lixin Zheng, Tingyan He, Alex B. George, Stefania Pittaluga, Astin Powers, David E. Kleiner, Devika Kapuria, Marc Ghany, Sally Hunsberger, Jeffrey I. Cohen, Gulbu Uzel, Jenna Bergerson, Lynne Wolfe, Camilo Toro, William Gahl, Les R. Folio, Helen Matthews, Pam Angelus, Ivan K. Chinn, Jordan S. Orange, Claudia M. Trujillo-Vargas, Jose Luis Franco, Julio Orrego-Arango, Sebastian Gutiérrez-Hincapié, Niraj Chandrakant Patel, Kimiyo Raymond, Turkan Patiroglu, Ekrem Unal, Musa Karakukcu, Alexandre G.R. Day, Pankaj Mehta, Evan Masutani, Suk S. De Ravin, Harry L. Malech, Grégoire Altan-Bonnet, V. Koneti Rao, Matthias Mann, Michael J. Lenardo

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Figure 3

Lymphoproliferation in XMEN disease.

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Lymphoproliferation in XMEN disease. (A) CT scan of chest, abdomen, and ...
(A) CT scan of chest, abdomen, and pelvis depicting bilateral axillary, mesenteric, and inguinal LAD in an EBV-infected patient (yellow arrows). (B) Contrast-enhanced CT scan of the chest showing axillary LAD (yellow arrow) in an EBV-naive patient. (C) Contrast-enhanced CT scan of the abdomen depicting splenomegaly (red arrow) and mesenteric LAD (yellow arrows) in an EBV-infected patient. (D) FDG-PET scan of a patient with XMEN and EBV-positive LPD showing hypermetabolic splenomegaly and bilateral axillary LAD (yellow arrows). (E) HE stain of cervical LN biopsy from an EBV-naive patient showing reactive lymphoid hyperplasia with Castleman-like changes (black arrows) and negative EBER ISH staining. (F) Image of biopsy sample from a large mediastinal mass showing lymphoid tissue obliterating normal LN architecture and negative EBER staining. (G) H&E-stained sections of an inguinal LN biopsy from an EBV-positive patient showing reactive lymphoid hyperplasia and positive EBER staining. (H) HE, EBER, CD20, and CD30 staining of cervical LN biopsy tissue from a patient with EBV LPD. (I) Percentage relative to CD3+ DNTs, αβDNTs, and B220+ αβDNTs from age-matched HCs (n = 10), EBV-naive patients (EBV–, n = 6), EBV-infected patients (EBV+, n = 10), and ALPS patients (n = 3). Data are expressed as the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by ordinary 1-way ANOVA with Tukey’s multiple comparisons test (α = 0.05). (J) Percentage of T cell death after treatment with different concentrations of the agonistic anti-FAS antibody APO-1.3 or anti-CD3 antibody for HCs, patients with ALPS (ALPS-1 and ALPS-2), and patients with XMEN (A.3, Q.1, and H.1). Results are representative of all XMEN patients tested (n = 13) in 3 independent experiments. (E–H) Scale bars: 50 μm (gray), 100 μm (black), and 200 μm (white).