Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

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 W 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 Gr Day; Pankaj Mehta; Evan Masutani; Suk S De Ravin; Harry L Malech; Grégoire Altan-Bonnet; V Koneti Rao; Matthias Mann; Michael J Lenardo

doi:10.1172/jci131116

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

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 W Binder, Ratnadeep Mukherjee, James T Anibal, Brian Sellers, Lixin Zheng, Tingyan He, Alex B George, Stefania PittalugaAstin 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 Gr Day, Pankaj Mehta, Evan Masutani, Suk S De Ravin, Harry L Malech, Grégoire Altan-Bonnet, V Koneti Rao, Matthias Mann, Michael J Lenardo

21 Citations (Scopus)

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. EBVassociated 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+HLADR+ 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.

Original language	English
Journal	The Journal of Clinical Investigation
ISSN	0021-9738
DOIs	https://doi.org/10.1172/jci131116
Publication status	Published - 2 Jan 2020
Externally published	Yes

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Ravell, J. C., Matsuda-Lennikov, M., Chauvin, S. D., Zou, J., Biancalana, M., Deeb, S. J., Price, S., Su, H. C., Notarangelo, G., Jiang, P., Morawski, A., Kanellopoulou, C., Binder, K. W., Mukherjee, R., Anibal, J. T., Sellers, B., Zheng, L., He, T., George, A. B., ... Lenardo, M. J. (2020). Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease. The Journal of Clinical Investigation. https://doi.org/10.1172/jci131116

Ravell, 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, KW, 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, JL, Orrego-Arango, J, Gutiérrez-Hincapié, S, Patel, NC, Raymond, K, Patiroglu, T, Unal, E, Karakukcu, M, Day, AG, Mehta, P, Masutani, E, De Ravin, SS, Malech, HL, Altan-Bonnet, G, Rao, VK, Mann, M & Lenardo, MJ 2020, 'Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease', The Journal of Clinical Investigation. https://doi.org/10.1172/jci131116

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title = "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. EBVassociated 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+HLADR+ 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.",

author = "Ravell, {Juan C} and Mami Matsuda-Lennikov and Chauvin, {Samuel D} and Juan Zou and Matthew Biancalana and Deeb, {Sally J} and Susan Price and Su, {Helen C} and Giulia Notarangelo and Ping Jiang and Aaron Morawski and Chrysi Kanellopoulou and Binder, {Kyle W} and Ratnadeep Mukherjee and Anibal, {James T} and Brian Sellers and Lixin Zheng and Tingyan He and George, {Alex B} and Stefania Pittaluga and Astin Powers and Kleiner, {David E} and Devika Kapuria and Marc Ghany and Sally Hunsberger and Cohen, {Jeffrey I} and Gulbu Uzel and Jenna Bergerson and Lynne Wolfe and Camilo Toro and William Gahl and Folio, {Les R} and Helen Matthews and Pam Angelus and Chinn, {Ivan K} and Orange, {Jordan S} and Trujillo-Vargas, {Claudia M} and Franco, {Jose Luis} and Julio Orrego-Arango and Sebastian Guti{\'e}rrez-Hincapi{\'e} and Patel, {Niraj Chandrakant} and Kimiyo Raymond and Turkan Patiroglu and Ekrem Unal and Musa Karakukcu and Day, {Alexandre Gr} and Pankaj Mehta and Evan Masutani and {De Ravin}, {Suk S} and Malech, {Harry L} and Gr{\'e}goire Altan-Bonnet and Rao, {V Koneti} and Matthias Mann and Lenardo, {Michael J}",

year = "2020",

month = jan,

day = "2",

doi = "10.1172/jci131116",

language = "English",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

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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 - 2020/1/2

Y1 - 2020/1/2

N2 - 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. EBVassociated 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+HLADR+ 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.

AB - 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. EBVassociated 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+HLADR+ 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.

U2 - 10.1172/jci131116

DO - 10.1172/jci131116

M3 - Journal article

C2 - 31714901

SN - 0021-9738

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

ER -

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Abstract

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