Large Deletion of MAGT1 Gene in a Patient with Classic Kaposi Sarcoma, CD4 Lymphopenia, and EBV Infection

Brigida, Immacolata; Chiriaco, Maria; Cesare, Silvia Di; Cittaro, Davide; Matteo, Gigliola Di; Giannelli, Stefania; Lazarevic, Dejan; Zoccolillo, Matteo; Stupka, Elia; Jenkner, Alessandro; Francalanci, Paola; Livadiotti, Susanna; Morawski, Aaron; Ravell, Juan C; Lenardo, Michael J.; Cancrini, Caterina; Aiuti, Alessandro; Finocchi, Andrea

doi:10.1007/s10875-016-0341-y

Cited by 41 publications

(32 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We reviewed the records of 23 patients from 17 unrelated families (A, B, and D-R) with LOF MAGT1 mutations. We observed that XMEN is a multisystem disease that is more complex than previously appreciated (3,(23)(24)(25)(26). (Figure 1, A and B, Table 1, and Supplemental Table 1; supplemental material available online with this article; https:// doi.org/10.1172/JCI131116DS1).…”

Section: Resultsmentioning

confidence: 88%

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Ravell¹,

Matsuda-Lennikov²,

Chauvin³

et al. 2019

Journal of Clinical Investigation

Self Cite

121

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 88%

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Ravell¹,

Matsuda-Lennikov²,

Chauvin³

et al. 2019

Journal of Clinical Investigation

Self Cite

121

View full text Add to dashboard Cite

“…XMEN disease (for X‐linked immunodeficiency, magnesium defect, Epstein‐Barr virus infection and neoplasia syndrome ‐ also referred to as magnesium transporter protein 1 [MAGT1] deficiency) is caused by hemizygous mutations in the MAGT1 gene . MAGT1 is an integral membrane protein ubiquitously expressed that is implicated in the preservation of intracellular free Mg 2+ pools .…”

Section: Immunodeficiencies Causing Ebv‐driven B‐lymphoproliferativementioning

confidence: 99%

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Latour

Fischer

2019

Immunological Reviews

113

View full text Add to dashboard Cite

Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

show abstract

“…Furthermore, two additional primary immunodeficiencies that compromise T cell receptor signaling present with CD4 + T cell lymphopenia and uncontrolled EBV infection, as observed under FK506 treatment of EBV-infected humanized mice. One immunodeficiency affects cytosolic Mg 2+ levels, required for PLCγ1 activation, via mutations in the magnesium transporter 1 (MAGT1) in patients with X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) [47][48][49][50][51]. The other immunodeficiency is caused by mutations in the guanine nucleotide exchange factor RasGRP1, downstream of PLCγ1 signaling [52,53].…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

et al. 2020

View full text Add to dashboard Cite

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication after organ transplantation frequently associated with the Epstein-Barr virus (EBV). Immunosuppressive treatment is thought to allow the expansion of EBV-infected B cells, which often express all eight oncogenic EBV latent proteins. Here, we assessed whether HLA-A2 transgenic humanized NSG mice treated with the immunosuppressant FK506 could be used to model EBV-PTLD. We found that FK506 treatment of EBV-infected mice led to an elevated viral burden, more frequent tumor formation and diminished EBV-induced T cell responses, indicative of reduced EBV-specific immune control. EBV latency III and lymphoproliferationassociated cellular transcripts were up-regulated in B cells from immunosuppressed animals, akin to the viral and host gene expression pattern found in EBV-PTLD. Utilizing an unbiased gene expression profiling approach, we identified genes differentially expressed in B cells of EBV-infected animals with and without FK506 treatment. Upon investigating the most promising candidates, we validated sCD30 as a marker of uncontrolled EBV proliferation in both humanized mice and in pediatric patients with EBV-PTLD. High levels of sCD30 have been previously associated with EBV-PTLD in patients. As such, we believe that humanized mice can indeed model aspects of EBV-PTLD development and may prove useful for the safety assessment of immunomodulatory therapies.

show abstract

Large Deletion of MAGT1 Gene in a Patient with Classic Kaposi Sarcoma, CD4 Lymphopenia, and EBV Infection

Cited by 41 publications

References 5 publications

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

Contact Info

Product

Resources

About