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

X-linked lymphoproliferative disorder (XLP) was first described almost 30 years ago; remarkably, the three major manifestations of XLP, fulminant infectious mononucleosis (FIM), lymphoma, and dysgammaglobulinemia, are all described in the report of the initial kindred. Subsequent establishment of an XLP registry has led to recognition of more unusual phenotypes in affected males; concurrently, much progress has been made in caring for boys with XLP, including treatment for the three major phenotypes, and curative bone marrow transplantation (BMT). The immunologic and genetic mechanisms resulting in XLP have also been intensively studied. Several years ago, the gene defective in XLP was identified as SAP (SLAM-associated protein), and recent data suggest that SAP plays a broad role in immune signaling. Here, we review the clinical manifestations and therapy of XLP, and briefly summarize recent research into the structure and function of SAP.
 ...
PMID:X-linked lymphoproliferative disease: genetic lesions and clinical consequences. 1216 1

Mutations or deletions in the SH2D1A (src homology 2 domain protein 1A) gene result in a severe immunodeficiency called X-linked lymphoproliferative (XLP) disease. XLP is primarily characterized by a defective immune response against the Epstein-Barr virus (EBV), resulting in an unusually severe and often fatal clinical course following EBV infection. The second major cause of death is the development of B cell lymphomas, both in EBV-infected and EBV-negative patients. To study whether the clinical manifestation of XLP gene defects and/or polymorphisms extends beyond the classically recognized phenotype, we analyzed patients for the presence of SH2D1A gene alterations who presented with fatal or nonfatal, yet unusually severe or chronic EBV infections, and other possibly EBV-associated diseases, such as Hodgkin's lymphomas or nonendemic Burkitt's lymphomas and Burkitt-type leukemias. We identified mutations of the SH2D1A gene only in the majority of patients presenting with fatal mononucleosis or an XLP family history, but not in any of the other patients studied. The only alteration determined was a polymorphism in the 5' region of the SH2D1A gene both in patient groups as well as in controls.
 ...
PMID:Analysis of SH2D1A mutations in patients with severe Epstein-Barr virus infections, Burkitt's lymphoma, and Hodgkin's lymphoma. 1222 1

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by extreme vulnerability to Epstein-Barr virus (EBV) infection, resulting in fatal infectious mononucleosis, dysgammaglobulinemia and malignant lymphoma. Recently, mutations in the SH2D1A gene, which encodes SLAM-associated protein (SAP), have been found to cause XLP. Although the molecular events behind XLP are largely unknown, there is evidence that affected males exhibited some immunohematological abnormalities, such as hypogammaglobulinemia or lymphoma, even prior to EBV infection. Because of the poor prognosis in XLP, an early diagnosis to patients and families is clinically of great importance. A glutathione-S-transferase-SAP fusion protein was used to immunize rats and generate mAb against human SAP to investigate its pathogenic role in XLP and develop a flow cytometric assay for detection of XLP. By flow cytometric and Western immunoblot analyses using an established anti-SAP mAb, termed KST-3, we determined that SAP was expressed intensely in thymocytes, but at lower levels in peripheral T cells and NK cells. In contrast, expression of SAP was negligible in B cells, monocytes or granulocytes. We found that SAP expression in T cells increased upon in vivo as well as in vitro activation. In two XLP survivors with SH2D1A mutations, a flow cytometric evaluation of activated T cells using KST-3 could demonstrate SAP deficiency as a diagnostic indicator of XLP. Through this approach, we identified three novel XLP families with SH2D1A mutations in Japan. A flow cytometric assessment of SAP expressed in activated T cells would lead to easy detection of XLP patients.
 ...
PMID:Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection. 1235 86

Epstein-Barr virus (EBV) is implicated in a variety of human diseases, some of which have fatal outcomes. Some EBV related diseases are considered to be candidates for the treatment of hematopoietic stem cell transplantation (HSCT). X-linked lymphoproliferative (XLP) syndrome is one of the representative diseases in which more than half of affected males die of infectious mononucleosis (IM) within a few weeks of primary infection, whereas the minority who survive have an increased risk of acquired hypogammaglobulinemia and lymphoma. Patients with XLP usually die by the age 40. Similarly, the majority of patients with chronic active EBV infection develop hemophagocytic syndrome, organ failure, opportunistic infection, and/or lymphoma and die within 5-10 years from onset. Recently, HSCT has provided successful outcomes in these patients. In this review, progress in the new therapeutic strategy is summarized, focusing on EBV-associated T/NK-cell lymphoproliferative disease (LPD), which is one of the heterogeneous EBV-associated disorder.
 ...
PMID:Allogeneic hematopoietic stem cell transplantation for Epstein-Barr virus-associated T/NK-cell lymphoproliferative disease. 1246 65

Epstein-Barr virus (EBV) is the major triggering factor producing hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH). In this review, diagnostic problems, clinical and histopathological features, and treatment strategies of EBV-HLH have been described. In patients with EBV-HLH, the EBV-infected T cells or natural killer (NK) cells are mostly mono- or oligo-clonally proliferating, where hypercytokinemia plays a major role and causes hemophagocytosis, cellular damage and dysfunction of various organs. Although the majority of EBV-HLH cases develop in apparently immunocompetent children and adolescents, it also occurs in association with infectious mononucleosis, chronic active EBV infection, familial HLH, X-linked lymphoproliferative disease, lymphoproliferative disease like peripheral T-cell lymphoma and NK cell leukemia. In terms of treatment, special therapeutic measures are required to control the cytokine storm generated by EBV and to suppress proliferating EBV-genome-containing cells, because the clinical courses are often fulminant and result in a poor outcome.
 ...
PMID:Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. 1246 66

The Src homology 2 domain protein 1A (SH2D1A) is a small, 128-amino acid protein consisting of a single SH2 domain; it is probably involved in signal regulation. It is expressed in activated T and natural killer (NK) cells, but not in B lymphocytes. It was discovered in studies on the rare hereditary condition X-linked lymphoproliferative disease (XLP). Individuals with this condition either lack or carry an altered protein. The serious symptoms (fatal mononucleosis) present almost exclusively at the first encounter with Epstein-Barr virus (EBV). The absence of SH2D1A in B cells, which are the targets of EBV, has to be reconciled with this clinical situation. In an earlier search for B lymphocytes expressing SH2D1A, we detected it in EBV-carrying type I Burkitt's lymphoma (BL) lines. We now show SH2D1A in 5 EBV-negative classical Hodgkin's disease (HD)-derived cell lines. Two lines belong to the T lineage and 3 to the B lineage. One B-HD line, which originated from nodular lymphocyte-predominant Hodgkin's lymphoma and differed in phenotype, was SH2D1A-negative. This finding is in accordance with the previously reported abundant SH2D1A mRNA in Hodgkin and Reed-Sternberg (HRS) cells. We thus found SH2D1A expression in lines of malignant origin assigned to the B lineage. Its presence in HRS cells may lead us closer to an understanding of the pathophysiology of the serious syndrome connected with EBV infection in XLP patients, because HRS-like cells have been detected in the lymphoid tissue of patients with infectious mononucleosis. It is likely therefore that in addition to the demonstrated functional defect of T and NK cells imposed by the SH2D1A mutation, the behavior of certain EBV-infected B lymphocytes is also modified.
 ...
PMID:Expression of SH2D1A in five classical Hodgkin's disease-derived cell lines. 1259 24

Mutations in SH2D1A, a gene that codifies for the regulatory protein SAP, result in uncontrolled activation of the SLAM (signaling lymphocyte-activation molecule) pathway. This X-linked immunodeficiency becomes evident when the patients are infected with Epstein Barr virus (EBV) and develop a fulminant form of infectious mononucleosis leading to a lymphoproliferative syndrome that is often fatal (X-linked lymphoproliferative syndrome, XLP). In those who survive, hypogammaglobulinemia and oncohematologic diseases are frequently observed. In this revision, the immuno-regulatory mechanisms involved in XLP immunopathology and the role of different effector cells (CD8 T lymphocytes, NK cells) are discussed.
 ...
PMID:[X-linked lymphoproliferative syndrome, EBV virus infection and defects in cytotoxicity lymphocyte regulation]. 1267 66

Most Epstein-Barr virus (EBV) infections in infants and children are asymptomatic, while infection of adolescents or adults often results in infectious mononucleosis. The symptoms of infectious mononucleosis are primarily due to the T-cell proliferative response to EBV-infected B cells; thus, antiviral therapy does not affect the clinical course of disease. Failure of the cellular immune response to control EBV-induced B-cell proliferation can result in severe disease. Patients with the X-linked lymphoproliferative disease (XLPD) have a mutation in the SAP gene and EBV infection often leads to fatal infectious mononucleosis. Transplant recipients may develop lymphoproliferative disease, which often responds to treatment that enhances the immune response against EBV-infected B cells. About 50% of Hodgkin's and 20% of Burkitt's lymphomas in the United States contain EBV DNA. While chemotherapy and/or radiation therapy are mainstays of treatment, clinical trials are being developed using cytotoxic T cells directed against EBV proteins in these tumors.
 ...
PMID:Benign and malignant Epstein-Barr virus-associated B-cell lymphoproliferative diseases. 1270 88

Detailed longitudinal studies of patients with X-linked lymphoproliferative disease (XLP) may increase our understanding of the immunologic defects that contribute to the development of lymphoma and hypogammaglobulinemia in XLP. We describe progressive changes observed in immunoglobulin concentrations, lymphocyte subsets, and Epstein-Barr virus (EBV) loads occurring in a 2-year period in a newly infected, but otherwise healthy, carrier (patient 9). We compare these findings with those observed in the patient's brother, who had hypogammaglobulinemia and XLP (patient 4). Immunoglobulin G (IgG), IgM, and IgA concentrations increased in patient 9 during acute EBV infection, but thereafter they decreased steadily to concentrations consistent with hypogammaglobulinemia, reaching a plateau 5 months after infection. In both patients, CD19+ B-lymphocyte rates remained lower than 3%, with a contraction of the B-cell memory compartment (CD27+ CD19+/CD19+) to 20% (normal range, 32%-56%). T-lymphocyte subpopulations showed a reduction in CD4+ T-cell counts and a permanent CD8+ T-cell expansion. Interestingly, CXCR3 memory TH1 cells were expanded and CCR4+ TH2 lymphocytes were reduced, suggesting that abnormal skewing of memory T-cell subsets might contribute to reduced antibody synthesis. Despite an expanded number of CD3+CD8+ lymphocytes, increased EBV loads occurred in both patients without overt clinical symptoms of mononucleosis, lymphoproliferative disease, or lymphoma.
 ...
PMID:Loss of circulating CD27+ memory B cells and CCR4+ T cells occurring in association with elevated EBV loads in XLP patients surviving primary EBV infection. 1460 60

Hypogammaglobulinemia is a common symptom in different immunodeficiencies. It is, however, not usually associated with Epstein-Barr virus (EBV) infections. The X-linked lymphoproliferative disease (XLP) on the other hand shows immunological changes in response to the EBV. Here we report three previously healthy boys, all of which developed persistent hypogammaglobulinemia following severe acute infectious mononucleosis. All three patients revealed T-cell abnormalities including inverted CD4/CD8 and increased CD8(+) T-cell numbers. The number of IFN-gamma-producing T cells were markedly increased in the two patients studied so far. In addition, patient 2 showed mainly T cells, instead of B cells, to be infected with the EBV. Apart from an uncle of patient 3, who died of malignant lymphoma, family history was unremarkable in all cases. All three patients exhibited mutations in the SH2D1A gene, establishing the diagnosis of XLP. Protein expression was found on immunoblot analysis in one patient with a missense mutation. Development of persistent hypogammaglobulinemia after severe primary EBV infection seems to be a specific diagnostic sign for XLP even in males with unremarkable family history.
 ...
PMID:Persistent hypogammaglobulinemia following mononucleosis in boys is highly suggestive of X-linked lymphoproliferative disease--report of three cases. 1535 10


<< Previous 1 2 3 4 5 6 7 Next >>