Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.

TitleDefective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsRavell, JC, Matsuda-Lennikov, M, Chauvin, SD, Zou, J, Biancalana, M, Deeb, SJ, Price, S, Su, HC, Notarangelo, G, Jiang, P, Morawski, A, Kanellopoulou, C, Binder, K, Mukherjee, R, Anibal, JT, Sellers, B, Zheng, L, He, T, George, AB, Pittaluga, S, Powers, A, Kleiner, DE, Kapuria, D, Ghany, M, Hunsberger, S, Cohen, JI, Uzel, G, Bergerson, J, Wolfe, L, Toro, C, Gahl, W, Folio, LR, Matthews, H, Angelus, P, Chinn, IK, Orange, JS, Trujillo-Vargas, CM, Franco, JLuis, Orrego-Arango, J, Gutiérrez-Hincapié, S, Patel, NChandrakan, Raymond, K, Patiroglu, T, Unal, E, Karakukcu, M, Day, AGr, Mehta, P, Masutani, E, De Ravin, SS, Malech, HL, Altan-Bonnet, G, V Rao, K, Mann, M, Lenardo, MJ
JournalJ Clin Invest
Volume130
Issue1
Pagination507-522
Date Published2020 Jan 02
ISSN1558-8238
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.

DOI10.1172/JCI131116
Alternate JournalJ. Clin. Invest.
PubMed ID31714901
PubMed Central IDPMC6934229
Grant ListR01 AI120989 / AI / NIAID NIH HHS / United States
R35 GM119461 / GM / NIGMS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States