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

Signalling for the B-cell immunoglobulin isotype switch requires T-cell-derived cytokines and T-B cell interaction, which operates primarily through the CD40 molecule on B cells with its ligand (CD40L) on activated T cells (reviewed in ref. 1). The CD40L is a type II membrane protein with homology to tumour necrosis factor-alpha and -beta, and has important functions in B-cell activation and differentiation. Human CD40L maps on Xq26.3-27.1 (ref. 3), the region where a primary immunodeficiency characterized by an immunoglobulin isotype switch defect (the hyper-IgM immunodeficiency syndrome, HIGM1) has been localized. The hypothesis that HIGM1 involves an abnormality of the CD40L has been tested. We report here the lack of CD40L expression in four unrelated male children with the hyper-IgM syndrome. CD40L transcripts in these patients showed either deletions or point mutations clustered within a limited region of the CD40L extracellular domain. These genetic alterations with abnormal CD40L expression provide a molecular basis for immunoglobulin isotype switch defects observed in this immunodeficiency.
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PMID:CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. 842 98

X linked immunodeficiency with hyperimmunoglobulinaemia M (HIGM1), which is characterised by agammaglobulinaemia together with excess IgM production reflecting an impairment of the immunoglobulin heavy chain class switch of B lymphocytes, has been mapped to Xq26. We report multipoint linkage data in six families with HIGM1 which show that the most likely position for the gene is close to HPRT with a maximum lod score of 4.89. The finding of recombinations between HIGM1 and both HPRT and DXS42 implies that HIGM1 is not allelic to X linked lymphoproliferative disease. These data will be useful in genetic counselling in families and will also be useful in testing candidate genes.
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PMID:Mapping of the X linked form of hyper IgM syndrome (HIGM1) 809 58

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

Lack of functional expression of CD40 ligand (CD40L) on T cells results in hyper-IgM syndrome (HIGM1), a human immunodeficiency associated with a severely impaired humoral immune response that is consistent with defects in B-cell responses. Patients also succumb to recurrent opportunistic infections such as Pneumocystis carinii and Cryptosporidial diarrhoea, suggesting that T-cell functions are also compromised in these individuals, but so far this has not been explained. We have previously shown that mice deficient for CD40L, like HIGM1 patients, show grossly abnormal humoral responses. Here we report that CD40L-deficient mice are defective in antigen-specific T-cell responses. Adoptively transferred antigen-specific CD4+ T cells lacking CD40L failed to expand upon antigen challenge of the recipients, showing that expression of CD40L on T cells is required for in vivo priming of CD4+ T cells and therefore for the initiation of specific T-cell immune responses.
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PMID:Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. 852 95

Small cell undifferentiated carcinoma (oat cell carcinoma) is a malignant epithelial neoplasm with neuroendocrine features. It can appear as a primary tumor in many organs besides the lung, including the colon. We report a case of primary small cell undifferentiated carcinoma of the left colon with omental metastases in a 23-year-old man with a history of X-linked hyper-IgM syndrome. The patient had a simultaneous primary hepatocellular carcinoma. A literature review of this rare colonic malignancy is presented together with a discussion of the possible relationship of this tumor with hepatic malignancy and immunodeficiency.
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PMID:Small cell undifferentiated carcinoma of the colon associated with hepatocellular carcinoma in an immunodeficient patient. 881

X-linked hyper-IgM syndrome (X-HIM) is an immunodeficiency caused by mutations in the gene encoding the CD40 ligand (CD40L). A database (CD40Lbase) of CD40L mutations has now been established, and the resultant information, together with other mutations reported elsewhere in the literature, is presented here.
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PMID:CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome. 896 27

X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency caused by a defective CD40 ligand. We identified mutations of the CD40 ligand gene in 13 unrelated Japanese XHIM patients. Of the four patients with missense mutations, one had a mutation within the transmembrane domain, and the three others had mutations affecting the TNF homology region of the extracellular domain. Two of the missense mutations resulted in the substitution of amino acids that are highly conserved in TNF family proteins. Three patients had nonsense mutations, all of which resulted in the truncation of the TNF homology domain of the CD40 ligand. Three patients had genomic DNA deletions of 2, 3 or 4 nucleotides, respectively. All of the deletions were flanked by direct repeat sequences, suggesting that these deletions were caused by slipped mispairing. Three patients had mutations within introns resulting in altered splicing, and multiple splicing products were found in one patient. Thus, each of the 13 Japanese patients had different mutations, 9 of them being novel mutations. These results indicate that mutations in XHIM are highly heterogeneous, although codon 140 seems to be a hot spot of the CD40 ligand gene since two additional point mutations were located at Trp 140, bringing the total numbers of mutations affecting codon 140 to six. In one XHIM family with a missense mutation, prenatal diagnosis was performed by single-strand conformation polymorphism analysis of genomic DNA of a male fetus.
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PMID:Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome. 915 Jul 29

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.
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PMID:Clinical spectrum of X-linked hyper-IgM syndrome. 1093 36

Immunodeficiencies form a distinct group of human hereditary diseases with several rare disorders. During recent years, information has been collected concerning immunodeficiency patients and mutations causing disorders. The large European (ESID) registry contains clinical data for some 7,000 patients. At present, international mutation databases have information for > 1,000 immunodeficiency patients, including X-linked chronic granulomatous disease (XCGD), Wiskott-Aldrich syndrome (WAS), and X-linked thrombocytopenia (XLT), X-linked hyper-IgM syndrome (XHIM), X-linked agammaglobulinemia (XLA), and X-linked severe combined immunodeficiency (XSCID). The databases are available on Internet. The mutation spectra of patients in these registries were compared. Mutational hotspots were found in CpG dinucleotides with a preference for selected flanking bases.
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PMID:Registries of immunodeficiency patients and mutations. 933 79

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


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