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

Several congenital immunodeficiency diseases can exhibit X-linked inheritance, including agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, and X-linked hyper-IgM syndrome. To date, the gene defects causing each of these X-linked immunodeficiencies have not been identified, and the pathogenic mechanisms whereby mutations in these genes result in immunodeficiency are obscure. Although rare, all are associated with severe infections from early life and high morbidity and mortality. Regional localization of each of these gene defects on the X chromosome has made possible carrier detection and prenatal diagnosis by linkage with polymorphic X chromosome markers in pedigrees demonstrating clear X-linked recessive inheritance. However, without a positive family history, it may not be possible to distinguish clinically between X-linked and autosomal forms. As a partial solution to this problem, it has now been established that female carriers of X-linked agammaglobulinemia, X-severe combined immunodeficiency, and Wiskott-Aldrich syndrome can be identified by the pattern of X chromosome inactivation in cell lineages targeted by each gene defect. As more families are offered the opportunity to use carrier detection and prenatal diagnosis, their decisions will reflect not only their personal experience with affected children with immunodeficiency, but also the clinical advances in bone marrow transplantation and immunomodulation.
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PMID:Prenatal diagnosis and genetic analysis of X-linked immunodeficiency disorders. 843 72

X-linked lymphoproliferative syndrome is an inherited immunodeficiency for which the responsible gene is currently unknown. Several megabase-sized deleted regions mapping to Xq25 have been identified in XLP patients, and more recently a 130-kb deletion has been reported (Lamartine et al., 1996; Lanyi et al., 1996). To establish a physical map of this deleted region and to identify the XLP gene, two cosmid contigs were established (Lamartine et al., 1996). However, the physical map of this region is still uncompleted and controversial and three points remain unsolved: (1) the centromeric-telomeric orientation of the whole region, (2) the relative orientation of the two contigs, and (3) the size of the gap between the two contigs. To provide a definitive answer to these questions, high-resolution mapping by fluorescence in situ hybridization on combed DNA and molecular approaches were combined to establish the physical map of the XLP region over 600 kb. Our results identified a gap of 150 kb between the two contigs, established the relative orientation of one contig to the other, and determine the centromeric-telomeric orientation of the whole region. Our results show that the order of the marker over this region is: cen.1D10T7-DF83-DXS982.tel.
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PMID:High-resolution mapping of the X-linked lymphoproliferative syndrome region by FISH on combed DNA. 973 Jun 14

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.
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PMID:Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. 981 75

The gene defect responsible for X-linked lymphoproliferative syndrome, SH2D1A (SH2-domain-containing gene 1A), was recently cloned. This gene encodes a small protein of 128 amino acids containing a single SH2 domain, which is thought to play an important role in signal transduction in activated T cells. The definition of SH2D1A protein function will provide insight into the pathogenesis of fatal Epstein-Barr virus infection, lymphomas, Hodgkins disease, immunodeficiency, aplastic anemia and lymphohistiocytic disorders that characterize the syndrome.
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PMID:The abnormal gene in X-linked lymphoproliferative syndrome. 1044 42

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

Tables 1 and 2 highlight the enormous advances that have been made in the definition of the molecular defects underlying primary immunodeficiencies in the past decade. The identification of SAP as the gene defective in XLP now completes the molecular bases of all the recognised X linked syndromes. Of the autosomally inherited syndromes, only the genes for DiGeorge syndrome, hyper-IgE, and perhaps most importantly, common variable immunodeficiency remain to be elucidated. The major clinical benefits of this information have primarily been in offering more accurate and rapid molecular diagnoses. The ability to make a molecular diagnosis also increases the options for earlier definitive treatments such as bone marrow transplantation and somatic gene therapy. Finally, as illustrated by the studies on the functions of WASP and the gamma c/JAK-3 pathway, identification of the gene defect is the first step to understanding the molecular pathogenesis of the immunological abnormalities.
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PMID:Immunogenetics: changing the face of immunodeficiency. 1076 59

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

X-linked lymphoproliferative syndrome (XLP, also known as Duncan's disease) is characterised by an extreme sensitivity to Epstein Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal mononucleosis, acquired hyogammaglobulinemia and malignant lymphoma. The gene responsible for XLP has recently been identified by a positional cloning and a functional cloning approach and encodes a small cytoplasmic protein involved in signal transduction of T and NK cells. The identification of the XLP gene will permit direct diagnosis of XLP in families with a single affected male. Recent progress in immunobiology and genetics of this primary immunodeficiency disease are presented.
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PMID:[X-linked lymphoproliferative syndrome (XLP syndrome): from clinic to gene]. 1110 49

The Internet contains scientific information in increasing amounts. It is possible to obtain the latest information, and Web services can easily be maintained and updated. We have set up three Internet services on immunodeficiencies. Immunodeficiency-related mutation infor mation is available in immunodeficiency mutation databases (IDbases). Currently 14 registries are distributed, including information about Bloom syndrome (BLMbase), X-linked agammaglobulinemia (BTKbase), X-linked and autosomal recessive chronic granulomatous diseases (CYBBbase for X-linked CGD, CYBAbase for p22(phox) deficiency, NCF1base for p47(phox) deficiency, NCF2base for p67(phox) deficiency), CD3gamma and CD3epsilon deficiencies (CD3Gbase, CD3Ebase), X-linked hyper-IgM syndrome (CD40Lbase), T-B+ severe combined immunodeficiency (JAK3base), V(D)J recombination defects (RAG1base, RAG2base), X-linked lymphoproliferative syndrome (SH2D1Abase), and ZAP-70 deficiency (ZAP70base). Information on laboratories analysing the genetic defects is collected to IDdiagnostics registry. Due to the rareness of immunodeficiencies there are very few laboratories performing genetic diagnostics. Such laboratories are listed in IDdiagnostics and physicians can use the registry to find a suitable laboratory for their diagnostic needs. Immunodeficiency Resource (IDR) is a comprehensive integrated knowledge base for all the information on immunode ficiencies, including clinical, biochemical, genetic, structural and computational data and analyses. All three services are available at http: //www.uta.fi/imt/bioinfo/.
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PMID:Novel immunodeficiency data servers. 1121 2

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


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