Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr virus (EBV) belong to herpes virus group. This virus is transmitted by human contact and cause primary infection and may exist even for years in a latent state in healthy individuals. This virus may be reactivated by the dysregulation of the host immune system or possibly by virus mutation. Here we have firstly demonstrated the host defense of EBV infection and association of EBV with rheumatoid synovitis, and then discussed our own ideas of the possible treatment in near future. The key points of this new therapy are SAP (signaling lymphocytic-activation molecule associated protein) or SH2D1A (Src homology 2 domain-containing protein). SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain. In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome (Duncan disease), a disease characterized by an inappropriate response to EBV infection. SAP is essential for late B cell help and the development of long-term humoral immunity. New approach to the therapeutic method for EBV might be opened by the regulation of this molecule (SAP).
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PMID:[The possible curative therapy for rheumatoid arthritis--EBV infection control gene SAP and its application]. 1858 24

X-linked lympho-proliferative (XLP) is an immunodeficiency condition caused by mutation or deletion of the gene encoding the adaptor protein SAP/SH2D1A. Besides defects in T cell and NK cell function and an absence of NKT cells, XLP can also manifest as lymphomas resulting primarily from uncontrolled B cell proliferation upon acute infection by Epstein-Barr virus. While it has been demonstrated that SAP regulates the functions of T cells and NK cells through the SLAM family of immunoreceptors, its role in B cells has not been defined. Here we show that SAP forms a ternary complex with the kinase Lyn and the inhibitory IgG Fc receptor FcgammaRIIB to regulate B cell proliferation and survival. SAP binds directly and simultaneously to the Lyn SH3 domain and an Immuno-receptor Tyrosine-based Inhibitory Motif (ITIM) in FcgammaRIIB, resulting in the activation of the latter. Moreover, SAP associates with FcgammaRIIB in mouse splenic B cells and promotes its tyrosine phosphorylation. Expression of SAP in the A20 B cell line led to a marked reduction in Blnk phosphorylation, a decrease in Akt activation, and a near-complete ablation of phosphorylation of the MAP kinases Erk1/2, p38 and JNK upon colligation of FcgammaRIIB with the B cell receptor (BCR). In contrast, an XLP-causing SAP mutant was much less efficient in eliciting these effects in B cells. Furthermore, compared to A20 cells, SAP transfectants displayed a significantly reduced rate of proliferation and an increased sensitivity to activation-induced cell death. Collectively these data identify an intrinsic function for SAP in inhibitory signaling in B cells and suggests that SAP may play an important role in balancing positive versus negative immune responses.
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PMID:The X-linked lymphoproliferative syndrome gene product SAP regulates B cell function through the FcgammaRIIB receptor. 1866 72

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.
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PMID:X-linked lymphoproliferative disease (XLP): a model of impaired anti-viral, anti-tumor and humoral immune responses. 1881 45

Generation of long-term antibody-mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen-specific T and B lymphocytes. In human X-linked lymphoproliferative disease and its gene-targeted mouse model, loss-of-function mutations in signalling lymphocyte activation molecule-associated protein (SAP, encoded by SH2D1a) cause a profound defect in germinal centre formation by an as yet unknown mechanism. Here, using two-photon intravital imaging, we show that SAP deficiency selectively impairs the ability of CD4(+) T cells to stably interact with cognate B cells but not antigen-presenting dendritic cells. This selective defect results in a failure of antigen-specific B cells to receive adequate levels of contact-dependent T-cell help to expand normally, despite Sap(-/-) T cells exhibiting the known characteristics of otherwise competent helper T cells. Furthermore, the lack of stable interactions with B cells renders Sap(-/-) T cells unable to be efficiently recruited to and retained in a nascent germinal centre to sustain the germinal centre reaction. These results offer an explanation for the germinal centre defect due to SAP deficiency and provide new insights into the bi-directional communication between cognate T and B cells in vivo.
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PMID:SAP-controlled T-B cell interactions underlie germinal centre formation. 1884 57

Deletion or mutation of the SAP gene is associated with the X-linked lymphoproliferative disease (XLP) that is characterized by extreme sensitivity to Epstein-Barr virus (EBV). Primary infection of the affected individuals leads to serious, sometimes fatal infectious mononucleosis (IM) and proneness to lymphoma. Our present results revealed a proapoptotic function of SAP by which it contributes to the maintenance of T-cell homeostasis and to the elimination of potentially dangerous DNA-damaged cells. Therefore, the loss of this function could be responsible for the uncontrolled T-cell proliferation in fatal IM and for the generation of lymphomas. We show now the role of SAP in apoptosis in T and B lymphocyte-derived lines. Among the clones of T-ALL line, the ones with higher SAP levels succumbed more promptly to activation induced cell death (AICD). Importantly, introduction of SAP expression into lymphoblastoid cell lines (LCL) established from XLP patients led to elevated apoptotic response to DNA damage. Similar results were obtained in the osteosarcoma line, Saos-2. We have shown that the anti-apoptotic protein VCP (valosin-containing protein) binds to SAP, suggesting that it could be instrumental in the enhanced apoptotic response modulated by SAP.
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PMID:The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease. 1957 Sep 96

X-linked lymphoproliferative disease (XLP) is an immunodeficiency caused by defects in the adaptor molecule SAP. The manifestations of XLP generally occur following Epstein-Barr virus (EBV) infection and include fulminant mononucleosis, hypogammaglobulinemia and lymphoma. In this report, we describe two unrelated patients with fatal T-cell-mediated central nervous system vasculitis for whom repeated serologic and molecular testing for EBV was negative. In both patients, clonal T-cell populations were observed, but neither demonstrated evidence of lymphoma. Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection.
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PMID:Lymphocytic vasculitis involving the central nervous system occurs in patients with X-linked lymphoproliferative disease in the absence of Epstein-Barr virus infection. 1962 58

Deletion or mutation of the SH2D1A gene located at Xq25 is responsible for the development of the X-linked lymphoproliferative disease, XLP. Primary infection of the affected individuals with EBV leads to fulminant and often fatal infectious mononucleosis, FIM. Moreover, they run a 200 fold elevated risk for lymphoma development. Due to the critical role of the immune response for the outcome of EBV infection and the detection of EBV genomes in several malignancies, XLP studies have been mainly focused on the immunological aspects. The involvement of SAP in the apoptotic machinery provides a further aspect in the complex syndrome of XLP. Functional impairment of SAP leads to defective apoptotic responses. Activation induced apoptosis plays a pivotal role in the termination of the lymphocyte proliferation in IM. This mechanism is inefficient in XLP patients. In addition, in the absence of SAP, lymphoma development may be promoted by the illegitimate survival of lymphocytes with damaged DNA that would be normally eliminated by apoptosis.
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PMID:The apoptosis modulating role of SAP (SLAM associated protein) contributes to the symptomatology of the X linked lymphoproliferative disease. 1973 28

Chromosomal translocations that juxtapose one of the three immunoglobulin loci to the c-myc protooncogene are the hallmark of Burkitt lymphomas (BLs), whether they carry the Epstein Barr Virus (EBV) or not. Ig/myc translocations occur as accidents of normal B lymphocyte differentiation. Unless protected, the translocation carrying cells are apoptosis prone. However, the high B cell stimulatory cytokine level found in the two BL prone conditions, in chronic hyperendemic malaria and HIV infection, may rescue them. X-linked lymphoproliferative disease (XLP) is due to the lack of functional SAP protein, a consequence of mutation or deletion of the SAP gene. We and others have shown that SAP is pro-apoptotic. Here we summarize our finding that 8 of 10 EBV carrying, but none of 9 EBV negative BL lines express SAP. We suggest that the apoptosis prone Ig/myc translocation carrying EBV negative precursors of BL can only grow into lymphomas if they do not express SAP. However, their EBV positive counterparts are permissive for SAP expression, due to the anti-apoptotic function of EBNA-1.
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PMID:To the genesis of Burkitt lymphoma: regulation of apoptosis by EBNA-1 and SAP may determine the fate of Ig-myc translocation carrying B lymphocytes. 1987 94

The signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) family of adapters includes SAP, Ewing's sarcoma-associated transcript-2 (EAT-2), and EAT-2-related transducer (ERT). These Src homology-2 (SH2) domain-only molecules play critical roles in immune regulation. The prototype of the SAP family, SAP, is mutated in X-linked lymphoproliferative disease in humans. Moreover, genetically engineered mice lacking one or more SAP family members have defects in multiple immune cell types including T cells, natural killer (NK) cells, NKT cells, and B cells. Accumulating data show that SAP family adapters regulate immunity by influencing the functions of SLAM family receptors, through two distinct but cooperative mechanisms. First, SAP family adapters couple SLAM family receptors to active biochemical signals, which promote immune cell functions. Second, SAP family adapters interfere with the intrinsic ability of SLAM family receptors to trigger inhibitory signals, which could be mediated via molecules such as SH2 domain-containing 5'-inositol phosphatase-1. The latter effect of SAP family adapters does not seem to be because of direct blocking of inhibitory effector binding to SLAM family receptors. Rather, it appears to implicate alternative mechanisms such as functional competition, trans-regulation, or steric hindrance. In the absence of SAP family adapters, the inhibitory signals mediated by SLAM family receptors suppress critical activating receptors, explaining in part the pronounced phenotypes seen in SAP family adapter-deficient humans and mice. Thus, SAP family adapters are molecular switches that regulate immunity as a result of their capacity to control the type of signals and functions emanating from SLAM family receptors.
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PMID:Importance and mechanism of 'switch' function of SAP family adapters. 1990 67

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is an adaptor molecule containing a Src homology 2 (SH2) domain. SAP is expressed in T cells and natural killer (NK) cells and binds to the cytoplasmic domains of SLAM family receptors, resulting in the subsequent recruitment of Fyn. The SAP (SH2D1A) gene is located on the X chromosome and is responsible for X-linked lymphoproliferative disease, characterized by higher susceptibility to Epstein-Barr virus infection. The SAP-mediated signal is not only essential for the development of NKT cells, i.e. unconventional CD1d-restricted T cells with invariant Valpha14 T cell receptors, but also for the regulation of the function of NK cells and conventional T cells. The role of SAP-mediated signaling in the induction of autoimmune diseases has been analyzed using animal models such as lupus, hepatitis, and graft-versus-host disease and is considered important in their pathogenesis in humans. In this review we highlight the current findings on SAP-mediated signaling in hematopoietic cells and discuss its importance in autoimmune diseases and immunological disorders.
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PMID:Role of SLAM-associated protein in the pathogenesis of autoimmune diseases and immunological disorders. 2004 47


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