Epstein-Barr Virus Infections in the X-Linked Recessive Lymphoproliferative Syndrome

Purtilo, DavidT.; Bhawan, Jag; Hutt, LindseyM.; DeNicola, Lucian K.; Szymanski, Irma O.; Yang, JamesP.S.; Boto, William; Maier, Rorert; Thorley‐Lawson, David A.

doi:10.1016/s0140-6736(78)92999-9

Cited by 77 publications

(20 citation statements)

References 17 publications

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“…Epstein-Barr virus (EBV) is a human herpesvirus which is the causative agent of infectious mononucleosis, a ubiquitous but usually benign lymphoproliferative disease in man (1). In some cases, however, a genetic defect in the development of immunity to EBV leads to an uncontrolled and fatal lymphoproliferation (2). In addition, EBV also is likely to be a causative agent of nasopharyngeal carcinoma and Burkitt lymphoma, although genetic and environmental factors also are involved in the initiation of these human tumors-histocompatibility factors in the case of nasopharyngeal carcinoma and malaria in the case of Burkitt lymphoma.…”

mentioning

confidence: 99%

Cloning and mapping of BamHi endonuclease fragments of DNA from the transforming B95-8 strain of Epstein-Barr virus.

Skare¹,

Strominger²

1980

Proc. Natl. Acad. Sci. U.S.A.

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mentioning

confidence: 99%

Cloning and mapping of BamHi endonuclease fragments of DNA from the transforming B95-8 strain of Epstein-Barr virus.

Skare¹,

Strominger²

1980

Proc. Natl. Acad. Sci. U.S.A.

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“…In the absence of SAP, dysregulation of T/B-cell interactions and NK-cell functions has been proposed to result in a variable ability to control Epstein-Barr virus (EBV) infection, leading to either fatal infectious mononucleosis, or infectious mononucleosis with progression toward malignant B-cell lymphoma or acquired agammaglobulinemia. 8 However, in some patients with XLP, these manifestations can also occur in the absence of EBV infection. 9 SAP is a protein of 128 residues with a single Src homology 2 (SH2) domain binding to a consensus T.I/V.…”

Section: Introductionmentioning

confidence: 99%

SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells

Dupré

Andolfi

Tangye

et al. 2005

Blood

161

137

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IntroductionX-linked lymphoproliferative (XLP) disease is a severe immunodeficiency characterized by variable clinical phenotypes, including fatal infectious mononucleosis, malignant B-cell lymphoma, and progressive dysgammaglobulinemia. 1 The gene responsible for XLP (SH2D1A) encodes for SAP (SLAM [signaling lymphocyteactivation molecule]-associated protein), or SH2D1A, a natural killer (NK) and T-cell-specific signaling adaptor protein. [2][3][4] Mutations in the SH2D1A gene have been detected in patients with hemophagocytic lymphohistiocytosis (HLH) 5 and common variable immunodeficiency syndrome, 6,7 thereby expanding the range of clinical phenotypes associated with this genetic defect. These heterogeneous clinical manifestations might be related to viral infections, which appear to act as secondary factors triggering the severe forms of SAP-deficiency syndrome. In the absence of SAP, dysregulation of T/B-cell interactions and NK-cell functions has been proposed to result in a variable ability to control Epstein-Barr virus (EBV) infection, leading to either fatal infectious mononucleosis, or infectious mononucleosis with progression toward malignant B-cell lymphoma or acquired agammaglobulinemia. 8 However, in some patients with XLP, these manifestations can also occur in the absence of EBV infection. 9 SAP is a protein of 128 residues with a single Src homology 2 (SH2) domain binding to a consensus T.I/V.(p)Y.x.x.V/I motif on the cytoplasmic tail of surface molecules of the SLAM family, including SLAM, 2B4, CD84, Ly-9, and NTB-A. 2,10-13 These molecules form homotypic and heterotypic receptor-ligand pairs during T cell/antigen-presenting cell or NK cell/target cell contacts. SLAM is expressed on activated and memory T cells, in which it can skew cytokine production toward a T helper 1 (Th1) profile 14 and can act as a costimulatory molecule for cytotoxic activity. 15 SAP appears to be a natural inhibitor of the interaction of SLAM-family members with SH2-containing signal molecules such as the SH2-containing phosphatase 2 (SHP-2) phosphatase. 2 In T cells, SAP recruits FynT, which is required for SLAM phosphorylation. Activation of the SLAM/SAP pathway controls the phosphorylation of dok1, dok2, and SH2-containing inositol phosphatase, thereby playing a potential role in the control of interferon-␥ (IFN-␥) production. 16,17 Furthermore, SAP appears to participate in the adhesion of T cells to target cells, as well as in T-cell receptor (TCR)-mediated activation. 18,19 In SAP-deficient murine models, 20,21 infection with lymphocytic-chorio-meningitis virus is associated with higher mortality related to increased T-cell activation and IFN-␥ production, as well as to a reduction in the production of interleukin 4 (IL-4) and the generation of immunoglobulin-secreting cells. However, in this model, T-and NK-cell cytotoxic activities have not been investigated.A number of studies in patients with XLP indicate that 2B4 stimulation on NK cells induces an abnormal dominant abrogation of NK-cell lytic activity. This ...

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“…The XLP 1 syndrome is an immune deficiency condition marked by an individual's inability to control acute EpsteinBarr virus infections (1,2). It manifests itself in various phenotypes, which include fulminant infectious mononucleosis, dysgammaglobulinemia, and malignant B cell lymphomas (1)(2)(3).…”

mentioning

confidence: 99%

“…It manifests itself in various phenotypes, which include fulminant infectious mononucleosis, dysgammaglobulinemia, and malignant B cell lymphomas (1)(2)(3). Patients of XLP exhibit specific immune defects such as abnormal natural killer (NK) and T cell-mediated cytotoxicity (4 -7).…”

mentioning

confidence: 99%

Dual Functional Roles for the X-linked Lymphoproliferative Syndrome Gene Product SAP/SH2D1A in Signaling through the Signaling Lymphocyte Activation Molecule (SLAM) Family of Immune Receptors

Liu¹,

Iosef²,

Jia³

et al. 2003

Journal of Biological Chemistry

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The X-linked lymphoproliferative (XLP) syndrome gene encodes a protein named SAP or SH2D1A that is composed of a single Src homology 2 (SH2) domain. Two models have been proposed for its function in lymphocyte signaling. One postulates that it acts as an inhibitor of interactions between the phosphatase SHP-2 and the immune receptor SLAM. The other suggests that it functions as an adaptor to promote the recruitment of a kinase, FynT, to SLAM. Here, we provide evidence in support of both roles for SAP. Using an array of peptides derived from the SLAM family of receptors, we demonstrate that SAP binds with comparable affinities to the same sites in these receptors as do the SH2 domains of SHP-2 and SHIP, suggesting that these three proteins may compete against one another in binding to a given SLAM family receptor. Furthermore, in vitro and in vivo binding studies indicate that SAP is capable of binding directly to FynT, an interaction mediated by the FynT SH3 domain. In cells, FynT was shown to be indispensable for SLAM tyrosine phosphorylation, which, in turn, was drastically enhanced by SAP. Because SAP also blocked the recruitment of SHP-2 to SLAM in these cells, we propose a dual functional role for SAP in SLAM signaling by acting both as an adaptor for FynT and an inhibitor to SHP-2 binding. The physiological relevance of the dual functional role for SAP is underscored by the observation that disease-causing SAP mutants exhibited significantly reduced affinities to both FynT and SLAM.

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Epstein-Barr Virus Infections in the X-Linked Recessive Lymphoproliferative Syndrome

Cited by 77 publications

References 17 publications

Cloning and mapping of BamHi endonuclease fragments of DNA from the transforming B95-8 strain of Epstein-Barr virus.

Cloning and mapping of BamHi endonuclease fragments of DNA from the transforming B95-8 strain of Epstein-Barr virus.

SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells

Dual Functional Roles for the X-linked Lymphoproliferative Syndrome Gene Product SAP/SH2D1A in Signaling through the Signaling Lymphocyte Activation Molecule (SLAM) Family of Immune Receptors

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