Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease
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Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease. / Ravell, Juan C; 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 W; 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; Trujillo-Vargas, Claudia M; Franco, Jose Luis; Orrego-Arango, Julio; Gutiérrez-Hincapié, Sebastian; Patel, Niraj Chandrakant; Raymond, Kimiyo; Patiroglu, Turkan; Unal, Ekrem; Karakukcu, Musa; Day, Alexandre Gr; Mehta, Pankaj; Masutani, Evan; De Ravin, Suk S; Malech, Harry L; Altan-Bonnet, Grégoire; Rao, V Koneti; Mann, Matthias; Lenardo, Michael J.
In: The Journal of Clinical Investigation, 05.11.2019.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease
AU - Ravell, Juan C
AU - Matsuda-Lennikov, Mami
AU - Chauvin, Samuel D
AU - Zou, Juan
AU - Biancalana, Matthew
AU - Deeb, Sally J
AU - Price, Susan
AU - Su, Helen C
AU - Notarangelo, Giulia
AU - Jiang, Ping
AU - Morawski, Aaron
AU - Kanellopoulou, Chrysi
AU - Binder, Kyle W
AU - Mukherjee, Ratnadeep
AU - Anibal, James T
AU - Sellers, Brian
AU - Zheng, Lixin
AU - He, Tingyan
AU - George, Alex B
AU - Pittaluga, Stefania
AU - Powers, Astin
AU - Kleiner, David E
AU - Kapuria, Devika
AU - Ghany, Marc
AU - Hunsberger, Sally
AU - Cohen, Jeffrey I
AU - Uzel, Gulbu
AU - Bergerson, Jenna
AU - Wolfe, Lynne
AU - Toro, Camilo
AU - Gahl, William
AU - Folio, Les R
AU - Matthews, Helen
AU - Angelus, Pam
AU - Chinn, Ivan K
AU - Orange, Jordan S
AU - Trujillo-Vargas, Claudia M
AU - Franco, Jose Luis
AU - Orrego-Arango, Julio
AU - Gutiérrez-Hincapié, Sebastian
AU - Patel, Niraj Chandrakant
AU - Raymond, Kimiyo
AU - Patiroglu, Turkan
AU - Unal, Ekrem
AU - Karakukcu, Musa
AU - Day, Alexandre Gr
AU - Mehta, Pankaj
AU - Masutani, Evan
AU - De Ravin, Suk S
AU - Malech, Harry L
AU - Altan-Bonnet, Grégoire
AU - Rao, V Koneti
AU - Mann, Matthias
AU - Lenardo, Michael J
PY - 2019/11/5
Y1 - 2019/11/5
N2 - X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) disease is caused by deficiency of the magnesium transporter 1 gene (MAGT1). We studied 23 XMEN patients, 8 of whom were EBV-naïve. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum, and increased CD4-CD8-B220-TCRalpha/beta+ T (abDNT) cells, 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 investigated XMEN patients and autoimmune lymphoproliferative syndrome (ALPS) patients by deep immunophenotyping (32 immune markers) using Time of Flight Mass Cytometry (CyTOF). Our analysis revealed that the abundance of two populations of naïve 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 normal 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.
AB - X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) disease is caused by deficiency of the magnesium transporter 1 gene (MAGT1). We studied 23 XMEN patients, 8 of whom were EBV-naïve. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum, and increased CD4-CD8-B220-TCRalpha/beta+ T (abDNT) cells, 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 investigated XMEN patients and autoimmune lymphoproliferative syndrome (ALPS) patients by deep immunophenotyping (32 immune markers) using Time of Flight Mass Cytometry (CyTOF). Our analysis revealed that the abundance of two populations of naïve 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 normal 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.
U2 - 10.1172/JCI131116
DO - 10.1172/JCI131116
M3 - Journal article
C2 - 31714901
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
ER -
ID: 230896116