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)

The molecular basis for X-linked agammaglobulinemia, hyper-IgM syndrome, and severe combined immunodeficiency was recently identified. In X-linked agammaglobulinemia the molecular defect was found to reside in the gene encoding a novel cytoplasmic tyrosine kinase (bpk, atk, or btk) expressed by B and myeloid cells. This kinase belongs to a new subfamily of tyrosine kinases that contains SH1, SH2, and SH3 domains. A defect in the murine homologue of this kinase has been shown to be responsible for X-linked immunodeficiency in mice. Currently, the role of btk in B- and myeloid cell signaling is unknown. The molecular defect in X-linked hyper-IgM syndrome has been shown to reside in the gene encoding the T-cell activation protein gp39 (CD40L, TRAP). This protein binds to its counter receptor, CD40, on B cells and has been shown to participate in T-cell-dependent B-cell help leading to B-cell proliferation and isotype switching. X-linked severe combined immunodeficiency patients were found to have defects in the gene encoding the gamma-chain of the interleukin-2 receptor. This chain of the interleukin-2 receptor is constitutively expressed by T cells and is involved in the formation of high and intermediate affinity interleukin-2 receptor complexes. These two interleukin-2 receptor complexes are responsible for mediating interleukin-2-dependent signals.
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PMID:The molecular basis of X-linked agammaglobulinemia, hyper-IgM syndrome, and severe combined immunodeficiency in humans. 937 Dec 54

Hyper-IgM syndrome represents a diverse group of immunodeficiencies characterized by normal or high serum IgM concentrations with decreased or absent IgG, IgA, and IgE. The X-linked form of hyper-IgM syndrome is caused by mutations in the CD40 ligand gene, preventing its expression on activated T cells. The CD40 ligand--CD40 interaction is critical for effective isotype switching and for initiating antigen-specific Tf cell responses. In addition to recurrent pyogenic infections, patients with the CD40L defect also have opportunistic infections. An increased proportion of circulating gamma-delta T cells, shown to be important early during primary infections, has been demonstrated in numerous infectious diseases including toxoplasmosis. Here, we report a patient with hyper-IgM syndrome and CNS toxoplasmosis, who showed a marked increase in gamma-delta T cells in his peripheral blood and who has responded well to treatment of his toxoplasmosis and to high-dose immunoglobulin replacement therapy.
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PMID:Central nervous system toxoplasmosis with an increased proportion of circulating gamma delta T cells in a patient with hyper-IgM syndrome. 971 Jul 45

X-linked hyper-IgM (XHIM) syndrome is an immunological disorder resulting from mutations in the CD154 gene. Some mutations occur in splicing sites and result in transcripts encoding wild-type and mutant proteins. These mutants lack the tumor necrosis factor homologous (TNFH) domain and consequently fail to trimerize. Given that the TNFH domain is responsible for trimerization, one may predict that the TNFH mutant can not participate in the assembly of wild-type CD154. Thus, it was puzzling why these patients exhibit XHIM phenotype, presumably resulting from a lack of functional CD154. One possibility is that the TNFH mutant exhibits a dominant negative effect over the wild-type protein. To investigate this, we coexpressed the wild-type protein and a TNFH mutant and examined the biochemical and functional properties of the resulting CD154 products. We demonstrate that despite the lack of the TNFH domain, the TNFH mutant can associate with the wild-type protein. Furthermore, such an association compromises the ability of the wild-type protein to mature onto the cell surface. These results provide a mechanism for the defect of CD154 in XHIM patients producing both wild-type and TNFH variants and suggest that besides the TNFH domain, the stalk region participates in the assembly of CD154 trimers.
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PMID:CD154 variant lacking tumor necrosis factor homologous domain inhibits cell surface expression of wild-type protein. 1107 39

X-linked hyper IgM syndrome is largely caused by defects in the CD40L (CD154). The patients have low levels of IgG and have difficulty with respiratory infections as well as opportunistic infections. The morbidity of this syndrome is high; however, early diagnosis and therapy should reduce morbidity and mortality.
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PMID:X-linked hyper IgM syndrome. 1110 2

Somatically mutated IgM(+)-only and IgM(+)IgD(+)CD27(+) B lymphocytes comprise approximately 25% of the human peripheral B cell pool. These cells phenotypically resemble class-switched B cells and have therefore been classified as postgerminal center memory B cells. X-linked hyper IgM patients have a genetic defect characterized by a mutation of the CD40L gene. These patients, who do not express a functional CD40 ligand, cannot switch Ig isotypes and do not form germinal centers and memory B cells. We report here that an IgM(+)IgD(+)CD27(+) B cell subset with somatically mutated Ig receptors is generated in these patients, implying that these cells expand and diversify their Ig receptors in the absence of classical cognate T-B collaboration. The presence of this sole subset in the absence of IgM(+)-only and switched CD27(+) memory B cells suggests that it belongs to a separate diversification pathway.
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PMID:CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. 1115 12

To determine whether CD40 ligation influences the molecular and selective mechanisms that govern the development of the human Ig light chain repertoire, analysis of the Vkappa and Vlambda repertoires of CD19+ B cells obtained from a patient with X-linked hyper IgM syndrome (XHIM) and a nonfunctional CD154 was carried out. The nonproductive Vkappa and Vlambda repertoires were largely comparable to that of the normals with respect to V gene and J segment distribution as well as CDR3 length and VLJL joint complexity. Comparison of the nonproductive and productive repertoires indicated that a limited number of VL genes were positively and negatively selected in the XHIM patient. Although mutations were observed in the XHIM VL repertoires, the frequency of mutations was significantly lower than in normals. Typical targeting of these mutations into RGYW/WRCY motifs was significantly reduced and subsequent selection of RGYW/WRCY mutations, which is normally observed, was not found. These results indicate that CD40 ligation is not required for generation of the light chain repertoire, positive selection of some Vk rearrangements, negative selection of specific VL genes, and some degree of somatic mutation. Importantly, however, targeting of mutations to RGYW/WRCY motifs and subsequent selection of these mutated motifs does not occur in the absence of CD40 ligation.
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PMID:The role of CD40-CD40 ligand (CD154) interactions in immunoglobulin light chain repertoire generation and somatic mutation. 1141 47

CD40 and CD154 (CD40 ligand) are surface molecules that are central to the cross-talk between T cells and antigen-presenting cells. This article reviews the relevance of CD40-CD154 interaction for regulation of interleukin-12/interferon-gamma production in response to Toxoplasma gondii as an example of an intracellular pathogen. The manner in which defects in CD154 signaling contribute to immunosuppression and susceptibility to opportunistic infections in patients with X-linked hyper IgM syndrome and in patients with human immunodeficiency virus infection is also discussed.
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PMID:CD154 and type-1 cytokine response: from hyper IgM syndrome to human immunodeficiency virus infection. 1186 44

X-linked Hyper IgM Syndrome (HIM) is a rare congenital immunodeficiency recently demonstrated to be caused by a mutation in the gene encoding CD40 ligand. These patients are susceptible to Pneumocystis carinii pneumonia, which implies an important role for CD40L in host defense against P. carinii. In this study we undertook to investigate whether treatment of P. carinii infected scid mice with murine recombinant CD40 ligand trimer (muCD40L) for 21 days would facilitate clearance of the organisms. We found no significant difference in organism burden in treated compared to control animals. Therefore in this model treatment with muCD40L alone is ineffective in clearing P. carinii infection.
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PMID:Recombinant CD40 ligand administration does not decrease intensity of Pneumocystis carinii infection in scid mice. 1190 38

We report here that soluble CD40 ligand (sCD40L) is released from human platelets when activated with collagen or thrombin. The sCD40L was detectable in the culture supernatants of platelets within 30 min after stimulation in vitro, and reached maximal levels in 3 h. The release was blocked by the metalloproteinase inhibitor, KB8301, indicating that the soluble CD40L is made by cleaving the membrane bound CD40L expressed on activated platelets. The sCD40L was undetectable in the supernatant of the activated platelets obtained from patients with X-linked hyper IgM syndrome (XHIM), who have defects in CD40L gene. Since sCD40L has been shown to have biologic function on the activation of vascular endothelial cells and B cells, these findings suggest that platelets play some roles in both inflammation and humoral immune response by releasing soluble CD40L.
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PMID:Characterization of soluble CD40 ligand released from human activated platelets. 1216 Feb 39

Pneumocystis carinii pneumonia (PCP) is a frequent and serious opportunistic infection in immunocompromized patients. Although the pathogenesis of PCP-mediated lung injury is poorly understood, a central involvement of host inflammatory responses has been implicated. We have found that while the loss of specific T cell costimulatory signals increases susceptibility to the spontaneous pneumocystis infection, PCP-induced pulmonary injury (and subsequent morbidity and mortality) involves other intact costimulatory pathways. Mice that are genetically deficient for the costimulatory receptor CD154 (CD154 knockout (ko) mice) spontaneously developed PCP, consistent with the increased susceptibility of X-linked hyper IgM syndrome patients (caused by CD154 gene mutations) to P. carinii infection. In these mice PCP was manifested by progressive weight loss, dyspnea and death. In contrast, CD154 ko mice also genetically lacking ICAM1 (CD154 koxICAM1 ko) or CD28 (CD154 koxCD28 ko) costimulatory receptors had later onset of weight loss and significantly prolonged survival. Although onset of infection and age-matched P. carinii organism burden were equivalent, the CD154 single knockout mice had evidence of greater pulmonary inflammation vs. the double ko's. These findings suggest that costimulation-dependent T cell-mediated inflammation plays an important role in both susceptibility to and pathogenesis of PCP, and may identify potential molecular targets for novel immunomodulatory treatment approaches.
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PMID:Evidence for the requirement of T cell costimulation in the pathogenesis of natural Pneumocystis carinii pulmonary infection. 1247 34


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