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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcription directed by the human immunodeficiency virus type 2 long terminal repeat (HIV-2 LTR) responds to T-cell antigen receptor signaling. Agents that stimulate T-cell signaling pathways activated by the antigen receptor, such as phorbol ester, plant lectin, or anti-CD3 antibody treatment, have been shown to increase transcription directed by the HIV-2 LTR. In this study, we examine the activation of the HIV-2 LTR in T cells stimulated with the physiologic ligand of the T-cell receptor, antigenic peptide presented by a major histocompatibility molecule. HIV-2 reporter plasmids were transfected into the antigen-specific T-cell hybridoma, 2B4.11, where they responded to antigen-dependent activation. This antigen-mediated transcriptional activation of the HIV-2 enhancer required the presence of at least four regulatory elements in the HIV-2 enhancer, including two purine boxes, PuB1 and PuB2, an AP-1/CREB-like element (pets), and kappa B. This finding suggests that signals emanating from the antigen receptor act coordinately on a set of transcription factors that bind to conserved HIV-2 regulatory elements. Despite differences in the organization of potentially related enhancer elements in HIV-2 and IL-2, these enhancers exploit a similar signal transduction pathway to induce gene expression in antigen-activated T cells.
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PMID:Multiple cis-acting elements in the human immunodeficiency virus type 2 enhancer mediate the response to T-cell receptor stimulation by antigen in a T-cell hybridoma line. 814 52

X-linked lymphoproliferative disease (XLP) is a rare inherited immunodeficiency to Epstein-Barr virus (EBV). The gene responsible for XLP has recently been identified as the four-exon SH2D1A gene encoding a 128-amino-acid protein that contains an SH2-domain. Functional studies indicate the SH2D1A protein acts as a regulator of at least two signal transduction pathways initiated by the cell surface molecules SLAM and 2B4, respectively, and possibly related to the host immune response to EBV infection. We have carried out a systematic mutation study of the SH2D1A gene in our series of 19 typical and 8 atypical XLP patients by polymerase chain reaction (PCR), reverse transcription/PCR, and sequencing, and have reconstructed the haplotypes of the patients. Four out of the 13 mutations detected are previously unreported. The identification of SH2D1A mutations in carriers from all three XLP families screened and the detection of mutations in two out of eight atypical patients indicates the usefulness of a DNA-based diagnosis for XLP disease.
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PMID:SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients. 1059 19

The CD2-subset of the immunoglobulin superfamily of cell surface receptors is an emerging family of proteins involved in cellular activation. Members of this family are CD2, CD48, CD58, CD84, signaling lymphocytic activation molecule (SLAM), 2B4 and Ly-9. These proteins are expressed on different leukocyte populations and the receptors of this family, specifically CD2, 2B4 and SLAM, contribute to the activation of T cells and natural killer cells. 2B4 and SLAM associate with a protein termed SLAM-associated protein that is the genetic defect in the immunodeficiency X-linked lymphoproliferative syndrome. Impaired signaling via these receptors may contribute to this often-fatal immunodeficiency.
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PMID:The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK cells and other immune cells. 1076 23

2B4 is a surface molecule involved in activation of the natural killer (NK) cell-mediated cytotoxicity. It binds a protein termed Src homology 2 domain-containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV(+) B cell lines. Remarkably, NK cells from XLP patients could not kill EBV(+) B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4-CD48 interaction restored lysis of EBV(+) target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I(+)) EBV(+) lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4-CD48 and NK receptor-HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain-containing phosphatase 1.
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PMID:X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. 1093 22

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.
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PMID:Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. 1097 98

2B4 is a member of the CD2 subset of the immunoglobulin superfamily of cell surface receptors. Other members of this family include CD2, CD48, CD58, CD84, signaling lymphocytic activation molecule and Ly-9. Some of these molecules are activating structures expressed by natural killer cells and T cells. We have recently cloned and characterised the human homologue of 2B4 and found that the cytoplasmic domain of 2B4 can interact with SAP, a signaling adaptor protein that is mutated in the immunodeficiency X-linked lymphoproliferative disease (XLP). Additionally, the natural ligand of 2B4 has been identified as CD48. These findings have facilitated the investigation of the functional role of this receptor-ligand pair, and associated signal transduction pathways, on immune cells. In this study, it was found that the interaction between 2B4 on effector cells and CD48 on target cells induced NK-cell activation, as evidenced by increased cytotoxicity and secretion of IFN-gamma. The responses induced by ligation of 2B4 could be reduced by the co-ligation of inhibitory receptors expressed by NK cells, demonstrating that activation signals delivered via 2B4 can be regulated by the action of certain inhibitory receptors. Because the signalling pathway of 2B4 involves SAP, it is possible that 2B4-mediated NK-cell activation may be compromised in patients with XLP due to mutations in SAP. This may contribute to the phenotype and progression of this disease.
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PMID:2B4-mediated activation of human natural killer cells. 1116 99

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency, involving primarily T and natural killer (NK) cells, which in the majority of cases exacerbates following exposure to Epstein-Barr virus (EBV). Prior to EBV infection, most boys with the defective XLP gene appear to be clinically healthy EBV infection in males with the defective XLP gene leads to three main phenotypes: severe and mostly fatal infectious mononucleosis (58%), lymphoproliferative disorders mostly of B-cell origin (30%) and/or dysgammaglobulinemia (31%). Later in life, dysgammaglobulinemia and malignant lymphoma may also develop in about 53% and 56% of EBV-negative XLP males, respectively This fact suggests that EBV may only act as a potent trigger of the earliest and most serious clinical phenotype of XLP, i.e. fatal infectious mononucleosis. XLP has an unfavorable prognosis. Successful transplanta tion of hematopoietic stem cells can cure this immunodeficiency In the future, gene therapy may eventually become an additional option to prevent XLP. The gene responsible for XLP, SH2-domain containing gene 1A (SH2D1A) has recently been identified and sequenced. SH2D1A encodes a polypeptide of 128 amino acids containing a single SH2 domain. Until now, 45 different SH2D1A gene mutations have been identified in patients with XLP SH2D1A is thought to play an important role in signal transduction in T and NK cells. In vitro, SH2D1A has been shown to interact as an adaptor protein with the signaling pathways through SLAM, a T-cell co-stimulatory molecule, and 2B4, an NK-cell-activating receptor. Further functional studies of the SH2D1A protein will probably provide new insights into the pathogenesis of severe infectious mononucleosis, malignant lymphomas and immunodeficiency in patients with XLP.
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PMID:X-linked lymphoproliferative disease is caused by deficiency of a novel SH2 domain-containing signal transduction adaptor protein. 1121 3

Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.
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PMID:Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. 1124 35

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.
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PMID:X-linked lymphoproliferative disease: genetics and biochemistry. 1125 22

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.
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PMID:Distinct interactions of the X-linked lymphoproliferative syndrome gene product SAP with cytoplasmic domains of members of the CD2 receptor family. 1141 39


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