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X-linked lymphoproliferative syndrome (XLP; Duncan's disease) is a primary immunodeficiency disease that manifests as an inability to regulate the immune response to Epstein-Barr virus (EBV) infection. Here we examine the ability of the product of the gene defective in XLP, SAP (DSHP/SH2D1A), to associate with the cytoplasmic domains of several members of the CD2 subfamily of cell surface receptors, including SLAM, 2B4, and CD84. While recruitment of SAP to SLAM occurred in a phosphorylation-independent manner, SAP was found to bind preferentially to tyrosine-phosphorylated cytoplasmic domains within 2B4 and CD84. Missense or nonsense mutations in the SAP open reading frame were identified in five of seven clinically diagnosed XLP patients from different kindreds. Four of these variants retained the ability to bind to the cytoplasmic tails of SLAM and CD84. While ectopic expression of wild-type SAP was observed to block the binding of SHP-2 to SLAM, mutant SAP derivatives that retained the ability to bind SLAM did not inhibit recruitment of SHP-2 to SLAM. In contrast, SAP binding to CD84 had no effect on the ability of CD84 to recruit SHP-2, but instead displaced SHP-1 from the cytoplasmic tail of CD84. These results suggest that mutations in the gene encoding the XLP protein SAP lead to functional defects in the protein that include receptor binding and SHP-1 and SHP-2 displacement and that SAP utilizes different mechanisms to regulate signaling through the CD2 family of receptors., (Copyright 2001 Academic Press.)

The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macrophages. Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a strong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein-Barr virus (EBV)-associated immunodeficiency resulting from defects in SH2D1A, a small SH2 domain-containing protein expressed in T lymphocytes and natural killer cells. Here it is shown that 4 of 25 male patients with HLH who were examined harbored germline SH2D1A mutations. Among these 4 patients, only 2 had family histories consistent with XLP. On the basis of these findings, it is suggested that all male patients with EBV-associated hemophagocytosis be screened for mutations in SH2D1A. Patients identified as having XLP should undergo genetic counseling, and be followed long-term for development of lymphoma and hypogammaglobulinemia.

X-linked lymphoproliferative syndrome (XLP) is an immunodeficiency characterized by life-threatening infectious mononucleosis and EBV-induced B cell lymphoma. The gene mutated in XLP encodes SLAM (signaling lymphocytic activation molecule-associated protein)-associated protein (SAP), a small SH2 domain-containing protein. SAP associates with 2B4 and SLAM, activating receptors expressed by NK and T cells, and prevents recruitment of SH2 domain-containing protein tyrosine phosphatase-2 SHP-2) to the cytoplasmic domains of these receptors. The phenotype of XLP may therefore result from perturbed signaling through SAP-associating receptors. We have addressed the functional consequence of SAP deficiency on 2B4-mediated NK cell activation. Ligating 2B4 on normal human NK cells with anti-2B4 mAb or interaction with transfectants bearing the 2B4 ligand CD48 induced NK cell cytotoxicity. In contrast, ligation of 2B4 on NK cells from a SAP-deficient XLP patient failed to initiate cytotoxicity. Despite this, CD2 or CD16-induced cytotoxicity of SAP-deficient NK cells was similar to that of normal NK cells. Thus, selective impairment of 2B4-mediated NK cell activation may contribute to the immunopathology of XLP.

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency in which affected boys show abnormal responses to Epstein-Barr virus infection. The gene defective in XLP has been identified and designated SH2D1A and encodes a protein termed SLAM-associated protein (SAP). Mutation analysis in individuals with typical XLP presentations and family histories has only detected abnormalities in approximately 60% of patients. Thus, genetic analysis alone cannot confirm a diagnosis of XLP We have developed a SAP expression assay that can be used as a diagnostic indicator of XLP We show that SAP is constitutively expressed in normal individuals, in patients with severe sepsis and in patients with other primary immunodeficiencies. In six XLP patients, four with classical and two with atypical presentations, SAP expression was absent. In the latter two, who were previously assigned as having common variable immunodeficiency (CVID), the diagnosis of XLP was initially made using the protein expression assay. In two further patients in whom no mutation could be detected by genetic analysis, lack of SAP expression strongly suggests that these individuals have XLP. We therefore suggest that XLP should be suspected in certain boys previously diagnosed as having CVID and recommend that patients are investigated both by genetic analysis of SH2D1A and by expression of SAP protein.

Primary immunodeficiencies comprise a broad group of disorders due to germline mutations in genes regulating lymphocyte development and function. One of these genes, DSHP (also known as SH2D1A, SAP), is mutated in X-linked lymphoproliferative syndrome (XLP), an inherited immunodeficiency characterized by increased susceptibility to primary Epstein-Barr virus (EBV) infection, hypogammaglobulinenia, and lymphoma. Expressed primarily in T and NK cells, DSHP consists of a single SH2 domain and short carboxyl-terminal tail. The presence of a single SH2 domain, without other functional motifs, suggests that DSHP may be a physiologic competitor of other SH2 domain-containing proteins whose binding to phosphotyrosine controls lymphocyte activation and/or function. DSHP binds to the cytoplasmic domains of CDw150 (Signaling Lymphocyte Activation Molecule, SLAM) and 2B4, and may regulate signals transmitted by these receptors in T and NK cells, respectively. Unlike other SH2 domain-containing proteins, DSHP associates with both phosphorylated and non-phosphorylated tyrosine residues, and crystallography studies have revealed novel properties of the DSHP SH2 domain. Future studies exploring the function of DSHP during lymphocyte proliferation and activation should improve our ability to diagnose and treat XLP and possibly other human diseases associated with EBV.

X-linked lymphoproliferative syndrome (XLP) is an inherited immunodeficiency characterized by increased susceptibility to Epstein-Barr virus (EBV). In affected males, primary EBV infection leads to the uncontrolled proliferation of virus-containing B cells and reactive cytotoxic T cells, often culminating in the development of high-grade lymphoma. The XLP gene has been mapped to chromosome band Xq25 through linkage analysis and the discovery of patients harboring large constitutional genomic deletions. We describe here the presence of small deletions and intragenic mutations that specifically disrupt a gene named DSHP in 6 of 10 unrelated patients with XLP. This gene encodes a predicted protein of 128 amino acids composing a single SH2 domain with extensive homology to the SH2 domain of SHIP, an inositol polyphosphate 5-phosphatase that functions as a negative regulator of lymphocyte activation. DSHP is expressed in transformed T cell lines and is induced following in vitro activation of peripheral blood T lymphocytes. Expression of DSHP is restricted in vivo to lymphoid tissues, and RNA in situ hybridization demonstrates DSHP expression in activated T and B cell regions of reactive lymph nodes and in both T and B cell neoplasms. These observations confirm the identity of DSHP as the gene responsible for XLP, and suggest a role in the regulation of lymphocyte activation and proliferation. Induction of DSHP may sustain the immune response by interfering with SHIP-mediated inhibition of lymphocyte activation, while its inactivation in XLP patients results in a selective immunodeficiency to EBV.

The X-linked lymphoproliferative syndrome (XLP) is an inherited immuno-deficiency to Epstein-Barr virus infection that has been mapped to chromosome Xq25. Molecular analysis of XLP patients from ten different families identified a small interstitial constitutional deletion in 1 patient (XLP-D). This deletion, initially defined by a single marker, DF83, known to map to interval Xq24-q26.1, is nested within a previously reported and much larger deletion in another XLP patient (XLP-739). A cosmid minilibrary was constructed from a single mega-YAC and used to establish a contig encompassing the whole XLP-D deletion and a portion of the XLP-739 deletion. Based on this contig, the size of the XLP-D deletion can be estimated at 130 kb. The identification of this minimal deletion, within which at least a portion of the XLP gene is likely to reside, should greatly facilitate efforts in isolating the gene.