Molecular and cellular pathogenesis of X-linked lymphoproliferative disease

Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Immunological Reviews (Impact Factor: 10.12). 03/2005; 203(1):180-99. DOI: 10.1111/j.0105-2896.2005.00230.x
Source: PubMed


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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Available from: Cindy S Ma, Apr 24, 2015
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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). "

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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.
    Full-text · Article · Nov 2010 · British Journal of Haematology
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    • "During the course of investigation, we found the proband's grandmother (III:1) had died of non-Hodgkins lymphoma at 51 years of age. Lymphoma is one of the classical presentations of XLP in males [25]. We were able to retrieve the grandmother's lymphoma tissue block and extract DNA for further testing. "
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    ABSTRACT: Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic predisposition to recurrent infections, malignancy, autoimmunity and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. Identifying the underlying genetic defect plays a critical role in patient management including diagnosis, family studies, prognostic information, prenatal diagnosis and is useful in defining new diseases. In this review we outline the clinical utility of molecular testing for these disorders using clinical cases referred to Auckland Hospital. It is written from the perspective of a laboratory offering a wide range of tests for a small developed country.
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