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 6

Impaired glycosylation of immune proteins and CDT pattern in XMEN disease.

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Impaired glycosylation of immune proteins and CDT pattern in XMEN diseas...
(A) Flow cytometric histogram and MFI quantification relative to HCs of CD28, CD70, HLA-DR, and TCRβ in T cells from HCs (blue) and patients with XMEN (red), with an unstained control (gray, n = 6). (B) Immunoblot of CD70, HLA-DR, TCRβ, CERS2, SLC4A7, and β-tubulin in T cells from HCs and patients with XMEN with (+) or without (–) PNGase F treatment. Unglycosylated (0), partially glycosylated (1), and fully glycosylated (2) bands. (C) Immunoblot of CD28 and HSP90 in T cells from HCs (n = 2) and patients with XMEN (n = 12) with the indicated mutations. Glycosylated (1) and unglycosylated (2) CD28 bands. (D) Immunoblot of CD28 and HSP90 in T cells treated with DMSO (0) or tunicamycin for 48 hours. Glycosylated (1) and unglycosylated (2) CD28 bands. The numbers on the left for immunoblots indicate kDa standards. (E) Pie chart showing the biological function of abnormally glycosylated proteins in XMEN. (F) Mass spectrometric traces of a CDT test for HCs (blue) and patients with XMEN (red). Mass and intensity are expressed in daltons (Da) and counts per second (cps), respectively. Data are representative of 5 (B), 2 (C), and 3 (D) replicates. Data represent the mean ± SEM. *P < 0.05 and **P < 0.01, by 1-sample t test with μ = 1.