Article

Molecular and cellular pathogenesis of X-linked lymphoproliferative disease

Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Immunological Reviews (Impact Factor: 12.91). 03/2005; 203(1):180-99. DOI: 10.1111/j.0105-2896.2005.00230.x
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ABSTRACT X-linked lymphoproliferative disease (XLP) is an inherited immune defect caused by mutations in the Src homology 2 domain-containing gene 1A, which encodes the adapter protein, signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). SAP is expressed in T cells, natural killer (NK) cells, and NKT cells, where it binds to the cytoplasmic domain of the surface receptor SLAM (CD150) and the related receptors, 2B4 (CD244), CD84, Ly9 (CD229), NK-T-B-antigen, and CD2-like receptor-activating cytotoxic T cells. SAP also binds to the Src family tyrosine kinase Fyn and recruits it to SLAM, which leads to the generation of downstream phosphotyrosine signals. While the roles of the SLAM family receptors are only beginning to be understood, experiments suggest that these molecules regulate important aspects of lymphocyte function, such as proliferation, cytokine secretion, cytotoxicity, and antibody production. Thus, in XLP patients who lack functional SAP, the SLAM family receptors may not signal properly. This property likely contributes to the phenotypes of XLP, including fulminant infectious mononucleosis, lymphoma, and hypogammaglobulinemia. Further studies of SAP and the SLAM family receptors will provide insights into XLP and elucidate the signaling events regulating lymphocyte ontogeny and function.

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    • "Thirdly, NKT-cells are a rare subset of T-cells with invariant T-cell receptors (alpha/beta) that mediate antiviral and antitumour immune responses. SH2D1A is essential for NKT-cell development and XLP patients lack NKT-cells (Nichols et al, 2005). Altered SH2D1A expression, therefore , results in defective NK-and cytotoxic T-cell function and predisposes to dysgammaglobulinaemia, severe EBV infection, and lymphoma (Rezaei et al, 2011). "
    British Journal of Haematology 07/2013; DOI:10.1111/bjh.12454 · 4.96 Impact Factor
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    • "To date, over 70 SH2D1A alterations have been reported (Filipovich et al, 2010; Piirilä et al, 2006; Vihinen & Notarangelo, 2008), including missense, nonsense and deletion mutations. Most mutations result in diminished or absent SAP protein expression (Nichols et al, 2005a) and there is no apparent correlation between type of SH2D1A mutation and severity of disease (Brandau et al, 1999; Nelson & Terhorst, 2000; Sumegi et al, 2000). "
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    ABSTRACT: X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by the clinical triad of increased susceptibility to primary Epstein-Barr virus (EBV) infection, dysgammaglobulinaemia and lymphoma. Most cases are caused by germline mutations in the SH2D1A gene, which encodes the adaptor molecule Signalling Lymphocytic Activation Molecule (SLAM)-associated protein (SAP). Recently, a subset of patients with an XLP-like phenotype was found to carry mutations in XIAP, the gene encoding the X-linked inhibitor of apoptosis protein (XIAP). Studies of XLP patients and Sap-/- mice reveal that loss of SAP expression impairs immune cell activities, such as natural killer and CD8+ T cell cytotoxicity, T cell cytokine production, activation-induced cell death, germinal centre formation and natural killer T cell development. Efforts to dissect the diverse roles of SAP and XIAP are enhancing our understanding of immune cell biology and defining how genetic defects in these molecules predispose to EBV-specific as well as more general cellular and humoral immune dysfunction. These studies are also highlighting critical signalling pathways that might be amenable to pharmacological targeting to improve the treatment of XLP and other disorders associated with impaired antiviral and antitumour immunity.
    British Journal of Haematology 11/2010; 152(1):13-30. DOI:10.1111/j.1365-2141.2010.08442.x · 4.96 Impact Factor
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    • "To date, over 70 SH2D1A alterations have been reported (Filipovich et al, 2010; Piirilä et al, 2006; Vihinen & Notarangelo, 2008), including missense, nonsense and deletion mutations. Most mutations result in diminished or absent SAP protein expression (Nichols et al, 2005a) and there is no apparent correlation between type of SH2D1A mutation and severity of disease (Brandau et al, 1999; Nelson & Terhorst, 2000; Sumegi et al, 2000). "
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    ABSTRACT: A major focus of our research is to understand the molecular and cellular basis of X-linked lymphoproliferative disease (XLP), a rare and often fatal immunodeficiency caused by mutations in the SH2D1A gene, which encodes the adaptor molecule SAP. Recently, we observed that SAP is essential for the development of natural killer T (NKT) cells, a lymphocyte population that participates in protection against certain tumors, infections, and autoimmune states. In this review, we describe the approaches that we are taking to understand the role of SAP in immune cells, including NKT cells. By using SAP as the focal point of our studies, we hope to identify novel signaling pathways that could be targeted to improve the treatment for patients with XLP as well as more common disorders, such as autoimmunity and cancer.
    Immunologic Research 10/2008; 42(1-3):145-59. DOI:10.1007/s12026-008-8048-7 · 3.53 Impact Factor
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