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.

• Autores: Trujillo Vargas, Claudia Milena; Franco Restrepo, José Luis; Orrego Arango, Julio; Gutiérrez Hincapié, Sebastián; Matsuda Lennikov, Mami; Chauvin, Samuel D.; Zou, Juan; Biancalana, Matthew; Deeb, Sally J.; Price, Susan; Su, Helen C.; Notarangelo, Giulia; Jiang, Ping; Morawski, Aaron; Kanellopoulou, Chrysi; Binder, Kyle; Mukherjee, Ratnadeep; Anibal, James T.; Sellers, Brian; Zheng, Lixin; He, Tingyan; George, Alex B.; Pittaluga, Stefania; Powers, Astin; Kleiner, David E; Kapuria, Devika; Ghany, Marc; Hunsberger, Sally; Cohen, Jeffrey I.; Uzel, Gulbu; Bergerson, Jenna; Wolfe, Lynne; Toro, Camilo; Gahl, William; Folio, Les R; Matthews, Helen; Angelus, Pam; Chinn, Ivan K; Orange, Jordan S; Ravell, Juan C.; Patel Niraj, Chandrakant; Raymond, Kimiyo; Patiroglu, Turkan; Unal, Ekrem; Karakukcu, Musa; Day, Alexandre; Mehta, Pankaj; Masutani, Evan; De Ravin, Suk S.; Malech, Harry L.; Altan Bonnet, Grégoire; Rao V, Koneti; Mann, Matthias; Lenardo, Michael J.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2020
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/40976
• Acceso en línea: https://hdl.handle.net/10495/40976
• Palabra clave: Antigens, CD; Antígenos CD; Autoimmune Lymphoproliferative Syndrome; Síndrome Linfoproliferativo Autoinmune; CD4-CD8 Ratio; Relación CD4-CD8; Cation Transport Proteins; Proteínas de Transporte de Catión; Glycosylation; Glicosilación; Magnesium Deficiency; Deficiencia de Magnesio; X-Linked Combined Immunodeficiency Diseases; Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X; https://id.nlm.nih.gov/mesh/D015703; https://id.nlm.nih.gov/mesh/D056735; https://id.nlm.nih.gov/mesh/D016516; https://id.nlm.nih.gov/mesh/D027682; https://id.nlm.nih.gov/mesh/D006031; https://id.nlm.nih.gov/mesh/D008275; https://id.nlm.nih.gov/mesh/D053632
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/