Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular bases of the X-linked immunodeficiency diseases remain largely undetermined. Two of the genes involved in these diseases have been isolated, namely the genes for X-linked chronic granulomatous disease and properdin deficiency, and substantial progress has now been made in identifying the genes which are defective in the other five diseases, Wiskott-Aldrich syndrome, X-linked severe combined immunodeficiency, X-linked agammaglobulinaemia, X-linked hyper-IgM and X-linked lymphoproliferative syndrome. We review here the nature of the diseases, progress made in identifying and isolating the genes involved and the prospects for improved prenatal detection, carrier status determination and treatment of these life-threatening conditions.
 ...
PMID:The molecular basis of X-linked immunodeficiency disease. 152 25

Lymphocytes of female carriers of X-linked severe combined immunodeficiency (XSCID; McKusick 300400; HGM genetic locus designation SCIDX1) exhibit nonrandom X chromosome inactivation. This phenomenon reflects a tissue-specific selective disadvantage for lymphocyte progenitors with an XSCID mutation on the active X chromosome and presumably is analogous to the process that inhibits T-cell development in affected boys with a single XSCID-bearing X chromosome. We investigated the specificity of T-cell X chromosome inactivation pattern as an indicator of immunodeficiency carrier status, as follows: X-inactivation ratios determined in a control group of noncarrier women exhibited a wide range, 20%-86% of T-cells with the paternal X active. Maximum-likelihood analysis of these data suggested that, in humans, mature T-cells are derived from a small pool of only about 10 randomly inactivated stem cells. Despite the wide variability in normal X-inactivation ratios, X inactivation in XSCID carriers appeared far more markedly skewed. Therefore a maximum-likelihood odds-ratio test was developed and proved to be successful in predicting the carrier status of women in XSCID pedigrees. This test has made it possible to identify XSCID carriers among mothers of boys with the heterogeneous syndrome of sporadic severe combined immunodeficiency.
 ...
PMID:Maximum-likelihood analysis of human T-cell X chromosome inactivation patterns: normal women versus carriers of X-linked severe combined immunodeficiency. 155 Jan 18

Six human immunodeficiency diseases have been associated with the X chromosome by family studies. Genetic mapping with restriction fragment length polymorphisms (RFLPs) has permitted assignment of these diseases to specific loci on the X chromosome. Each of the disease entities maps to a single locus, confirming that the diagnostic criteria describe single diseases. X-linked chronic granulomatous disease and Wiskott-Aldrich syndrome map to loci on the short arm of the X chromosome; X-linked severe combined immunodeficiency, X-linked agammaglobulinemia, X-linked immunodeficiency with hyper-IgM, and X-linked lymphoproliferative syndrome map to loci on the long arm. Lyon's hypothesis predicts that these X-linked immunodeficiencies may be detectable in carriers of the diseases as a result of X chromosome inactivation of the normal disease gene. Four of the immunodeficiency diseases, X-linked agammaglobulinemia, X-linked severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and X-linked chronic granulomatous disease, affect cellular development so that carriers have a monomorphic population of immunocytes. The specific immunocyte development affected in carriers varies according to the disease. Genetic mapping of the diseases, with a collection of informative RFLPs, provides a tool that permits probability-based prenatal diagnosis. Carrier detection complements the RFLP-based genetic mapping, serving to confirm X-linkage in carriers.
 ...
PMID:X chromosome linked immunodeficiency. 198 31

Carrier detection of three of the X-linked primary immunodeficiency diseases (X-linked agammaglobulinemia, X-linked severe combined immunodeficiency disease, and the Wiskott-Aldrich syndrome) is possible by analyzing patterns of X-chromosome inactivation in those cells affected by the disorder. Normal women have balanced patterns of X-chromosome inactivation; that is, in a given population of cells, approximately half of their active X chromosomes are of paternal origin and half of their active X chromosomes are of maternal origin. In contrast, female carriers of these X-linked immunodeficiency disorders have an unbalanced pattern of X-chromosome inactivation in those cell lineages that are affected by the disorder; that is, all the active X chromosomes in affected cell lineages are the X chromosomes that carry the normal allele. Two techniques are available for X-chromosome inactivation analysis. One technique depends on methylation differences between the active and inactive X chromosome, and the other technique uses somatic cell hybrids that selectively retain the active X chromosome. In either case, carrier detection can be performed in individuals from families in which only one member of the family has been affected, since neither of these methods depends on linkage analysis.
 ...
PMID:Carrier detection of the X-linked primary immunodeficiency diseases using X-chromosome inactivation analysis. 219 94

The interleukin 2 receptor gamma chain (IL-2R gamma) is a component of the receptors for IL-2, IL-4, IL-7, and IL-15. Mutations in IL-2R gamma in man appear responsible for the X chromosome-linked immunodeficiency SCIDX1, characterized by a defect in T-cell and natural killer (NK)-cell differentiation with the presence of poorly functioning B cells. To explore at which level IL-2R gamma affects lymphoid development in vivo, we have analyzed mice derived from embryonic stem (ES) cells with mutant IL-2R gamma loci generated by Cre/loxP-mediated recombination. In the peripheral blood of chimeric animals, lymphoid cells derived from IL-2R gamma- ES cells were not detected, although control ES cells carrying an IL-2R gamma gene with embedded loxP sites gave rise to T-, B-, and NK-cell lineages. Germline IL-2R gamma-deficient male animals, however, developed some mature splenic B and T cells, although the absolute number of lymphocytes was almost 10-fold reduced. In contrast, there was a complete disappearance of NK cells (over 350-fold reduction). Development of gut-associated intraepithelial lymphocytes was also severely diminished, and Peyer's patches were not detected. In vitro mitogenic responses of thymocytes, IL-4-directed immunoglobulin class switch of splenocytes, and NK activity were defective. Thus, IL-2R gamma facilitates mainstream B- and T-cell generation and function and also appears to be essential for NK-cell development.
 ...
PMID:Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. 783 Dec 94

Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma c) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status of X chromosome inactivation in blood leukocytes from obligate carriers of XCID was determined from the polymorphic, short tandem repeats (CAG), in the androgen receptor gene, which also contains a methylation-sensitive HpaII site. As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes. In addition, X chromosome inactivation in PMNs was variable. Findings from this analysis prompted sequencing of the gamma c gene in this pedigree. A missense mutation in the region coding for the cytoplasmic portion of the gamma c gene was found in three affected males but not in a normal brother. Therefore, this point mutation in the gamma c gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.
 ...
PMID:Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency. 788 65

X chromosome-linked severe combined immunodeficiency disease (SCIDX1) is characterized by the absence of T-cell and natural killer cell development and results from molecular mutations of the interleukin 2 receptor (IL-2R) gamma chain. The IL-2R gamma chain is a common component of the IL-2, IL-4, and IL-7 receptor systems, which may explain the severe immunophenotype in SCIDX1. We have previously described an atypical SCIDX1 syndrome demonstrating poorly functioning peripheral T cells, which we hypothesized to represent a variant allele at the SCIDX1 locus. We now demonstrate that a splice site mutation in the IL-2R gamma gene is responsible for this atypical SCIDX1. Aberrant RNA splicing resulted in the generation of two IL-2R gamma transcripts: an abundant, nonfunctional isoform containing a small intronic insertion and a second functional isoform with a single amino acid substitution present in limited amounts. Radiolabeled IL-2 binding studies revealed a 5-fold decreased level of expression of functional high-affinity IL-2Rs, which correlated with the quantity of full-length IL-2R gamma transcripts. Further analysis of the T-cell antigen receptor beta-chain repertoire of the patient's T cells demonstrated oligoclonality in multiple V beta families, thus strongly suggesting that the defect in the IL-2R gamma chain generated a limited number of peripheral T-cell clones. This atypical SCIDX1 patient demonstrates that certain IL-2R gamma chain abnormalities can also result in partial immunodeficiency phenotypes, potentially through differential effects on the IL-2, IL-4, or IL-7 receptor systems.
 ...
PMID:Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells. 793 90

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor beta.(IL-2R beta) and common gamma (gamma c) chains. Mutations of gamma c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain gamma c), and IL-9 (whose receptor is shown here to contain gamma c) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R beta and gamma c, respectively; IL-2 induced Jak3-IL-2R beta and increased Jak3-gamma c associations. Truncations of gamma c, and a gamma c, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased gamma c-Jak3 association. Thus, gamma c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.
 ...
PMID:Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. 797 58

In the 40 years since Ogden Bruton discovered agammaglobulinemia, more than 50 additional immunodeficiency syndromes have been described. Until recently, there was little insight into the fundamental problems underlying a majority of these conditions. Recently, however, the molecular bases of three X-linked immunodeficiency disorders have been reported. These include X-linked immunodeficiency with hyper IgM, X-linked agammaglobulinemia, and X-linked severe combined immunodeficiency. These remarkable accomplishments have been made possible through a combination of new knowledge of molecular signaling mechanisms between and within cells of the immune system and greatly improved approaches to disease loci mapping within the human genome. Improvements in the therapy of immunodeficiency diseases have been impressive, and the development of generally safe and effective intravenous immunoglobulin preparations and T cell depletion techniques that permit the use of non-HLA-identical bone marrow donors have been the most important advances over the past 14 years. The identification and cloning of the genes for several of the primary immunodeficiency diseases have obvious implications for potential future somatic cell gene therapy for these patients. The rapidity of these advances suggests that soon there will be many more to come.
 ...
PMID:Breakthroughs in the understanding and therapy of primary immunodeficiency. 804 66

The differential methylation of a CpG island 2.5 kb distant from a hypervariable region at the DXS255 locus provides the basis for a Southern blotting X chromosome inactivation analysis system. The technique enables carrier detection in about 90% of females at risk from pedigrees with Wiskott-Aldrich syndrome, X-linked severe combined immunodeficiency or X-linked agammaglobulinemia.
Immunodeficiency 1993
PMID:Carrier detection in X-linked immunodeficiencies. II: An X inactivation assay based on differential methylation of a line-1 repeat at the DXS255 locus. 816 3


1 2 3 4 5 Next >>