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Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

2019; American Society for Clinical Investigation; Volume: 130; Issue: 1 Linguagem: Inglês

10.1172/jci131116

1558-8238

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 Anibal, Brian A. Sellers, Lixin Zheng, Tingyan He, Alex George, Stefania Pittaluga, Astin S. Powers, David E. Kleiner, Devika Kapuria, Marc G. Ghany, Sally Hunsberger, Jeffrey I. Cohen, Gülbû Uzel, Jenna Bergerson, Lynne A. Wolfe, Camilo Toro, William A. Gahl, Les Folio, Helen Matthews, Pam Angelus, Iván K. Chinn, Jordan S. Orange, Claudia M. Trujillo‐Vargas, José Luis Franco, Julio César Orrego Arango, Sebastián Gutiérrez-Hincapié, Niraj Patel, Kimiyo Raymond, Türkan Patıroğlu, Ekrem Ünal, Musa Karakükçü, Alexandre G. R. Day, Pankaj Mehta, Evan Masutani, Suk See De Ravin, Harry L. Malech, Grégoire Altan‐Bonnet, V. Koneti Rao, Matthias Mann, Michael J. Lenardo,

Immune Cell Function and Interaction

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.