Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1

Platt, Craig D.; Fried, Ari J.; Hoyos-Bachiloglu, Rodrigo; Usmani, G. Naheed; Schmidt, Birgitta; Whangbo, Jennifer; Chiarle, Roberto; Chou, Janet; Geha, Raif S.

doi:10.1016/j.clim.2017.08.007

Cited by 46 publications

(33 citation statements)

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“…Taken together, these data indicate that the mutation in RASGRP1 identified in the two patients is deleterious leading to the lack of RASGRP1 expression. The clinical phenotypes as well as the immunological parameters in the two patients reported here are very similar to those initially described in one patient with a RASGRP1 deficiency (Salzer et al , ) and more recently in another patient (Platt et al , ). Therefore, these results strongly support that RASGRP1 deficiency is associated with a specific susceptibility to EBV infection.…”

Section: Resultssupporting

confidence: 87%

“…CD70 is highly expressed on EBV‐infected cells and drives proliferation of CD27‐expressing T cells. More recently, null homozygous mutations in RASGRP1 were reported in two patients with combined immunodeficiency associated with pulmonary infections and persistent EBV infection including EBV‐driven Hodgkin lymphoma (Salzer et al , ; Platt et al , ). RASGRP1 codes for a diacylglycerol (DAG)‐regulated guanidine exchange factor (GEF) preferentially expressed in T and NK cells (Hogquist, ; Kortum et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

et al. 2018

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Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T‐lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein–Barr virus (EBV) infection. RASGRP1 is a T‐lymphocyte‐specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1‐deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild‐type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1‐deficient T cells also exhibited decreased CD27‐dependent proliferation toward CD70‐expressing EBV‐transformed B cells, a crucial pathway required for expansion of antigen‐specific T cells during anti‐EBV immunity. Furthermore, RASGRP1‐deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

et al. 2018

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“…RASGRP1 immunodeficiency is an autosomal‐recessive genetic disease. To date, 9 patients have been identified . All developed severe EBV infections, including B‐cell lymphoma.…”

Section: Immunodeficiencies Causing Ebv‐driven B‐lymphoproliferative mentioning

confidence: 99%

“…Like CTPS1‐deficient patients, RASGRP1‐deficient patients are also prone to other severe viral infections (including CMV and HPV), fungal infections, and bacterial infections. Moreover, 5 patients also exhibited autoimmune manifestations . RASGRP1 is a diacylglycerol‐regulated guanidine exchange factor (GEF) for the small GTPase Ras.…”

Section: Immunodeficiencies Causing Ebv‐driven B‐lymphoproliferative mentioning

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

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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

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“…RasGRP1 has also been implicated in immunodeficiencies and autoimmune diseases. Loss of RasGRP1 in patients leads to immunodeficiency, impaired cytotoxic T cell and NK T cell functions, and susceptibility to bacterial and viral infections . Mice with point mutations in Rasgrp1 have also been created in addition to genetic deletions or forced overexpression.…”

Section: Rasgrp1 and Diseasementioning

confidence: 99%

mTOR and other effector kinase signals that impact T cell function and activity

Myers

Wheeler

Roose

2019

Immunological Reviews

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T cells play important roles in autoimmune diseases and cancer. Following the cloning of the T cell receptor (TCR), the race was on to map signaling proteins that contributed to T cell activation downstream of the TCR as well as co-stimulatory molecules such as CD28. We term this "canonical TCR signaling" here. More recently, it has been appreciated that T cells need to accommodate increased metabolic needs that stem from T cell activation in order to function properly. A central role herein has emerged for mechanistic/mammalian target of rapamycin (mTOR). In this review we briefly cover canonical TCR signaling to set the stage for discussion on mTOR signaling, mRNA translation, and metabolic adaptation in T cells. We also discuss the role of mTOR in follicular helper T cells, regulatory T cells, and other T cell subsets. Our lab recently uncovered that "tonic signals", which pass through proximal TCR signaling components, are robustly and selectively transduced to mTOR to promote baseline translation of various mRNA targets. We discuss insights on (tonic) mTOR signaling in the context of T cell function in autoimmune diseases such as lupus as well as in cancer immunotherapy through CAR-T cell or checkpoint blockade approaches. K E Y W O R D Sautoimmune, cancer, mammalian target of rapamycin, signaling, T cell, tonic | 135 MYERS Et al

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Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1

Cited by 46 publications

References 10 publications

Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

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

mTOR and other effector kinase signals that impact T cell function and activity

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