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 2

Multisystem abnormalities in XMEN disease.

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Multisystem abnormalities in XMEN disease. Platelet (A) and absolute neu...
Platelet (A) and absolute neutrophil (B) counts for an EBV-naive (red) patient and an EBV-positive (blue) patient with a normal range (gray) and patients’ age. (C) ALT and AST levels in EBV-naive (black), EBV-infected (red), and EBV-naive patients who became EBV infected (blue) with a normal range (light blue) and patients’ identities (shown on the x axis). (D) Increased hepatic echogenicity in liver ultrasound from an EBV-naive patient. (E and F) H&E-stained (HE) liver biopsy from an EBV-naive patient showing mild focal portal chronic inflammatory infiltrates (black arrow) without interface hepatitis and hepatocytes with pale cytoplasm. (G) Masson’s trichrome–stained image of liver biopsy sample from the same EBV-naive patient shows periportal fibrosis (black arrow). (H) T1-weighted MRI demonstrating severe diffuse atrophy of the cerebrum, cerebellum, brainstem, and spinal cord (yellow arrows). (I) T2 fluid-attenuated inversion recovery (FLAIR) brain MRI showing occipital leukomalacia (yellow arrow). (J) T2-weighted brain MRI demonstrating CSP (yellow arrow). (K) CT scan of paranasal sinuses showing opacification of the maxillary sinuses (yellow arrows) in a patient with bacterial sinusitis. (L) CT scan showing extensive tree-in-bud nodular infiltrates in the right lung (yellow circle) in a patient with longstanding hypogammaglobulinemia. (E–G) Scale bars: 50 μm (gray) and 100 μm (black).