Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease.
СтатьяПоддержка NIH: внешняя программаResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, 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
Аннотация
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.