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)

X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.
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PMID:De novo mutation causing X-linked hyper-IgM syndrome: a family study in Taiwan. 1599 75

Hyper-IgM syndrome type 1 (HIGM1) is a primary immunodeficiency characterized by recurrent bacterial and opportunistic infections, associated with normal or high serum level of IgM and decreased serum levels of IgG, IgA and IgE due to the defect of class switch recombination. CD40LG, located in Xq26, has been reported to be mutated in male HIGM1 patients. Here, we report the second case of a female HIGM1 with the defect of CD40 ligand (CD40L) expression and of soluble serum CD40L. Clinical course and HIGM phenotype was indistinguishable from that of male HIGM1 including severe neutropenia. High-resolution chromosome banding revealed that this patient's karyotype is 46, X, t(X;14)(q26.3;q13.1), and FISH analysis demonstrated that the break point of the chromosomal translocation is within CD40LG. Using four chimeric cDNA clones obtained by 3' RACE method, the break point was identified within the intron 4 of CD40LG on X chromosome and non-coding region of chromosome 14. We also found an extremely skewed X-chromosome inactivation pattern by methylation-specific PCR. Thus, the reciprocal translocation caused the disruption of CD40LG, resulting in defective CD40L expression in the female patient with an extremely skewed X-inactivation pattern in T cells leading to the HIGM1 phenotype.
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PMID:Female hyper IgM syndrome type 1 with a chromosomal translocation disrupting CD40LG. 1631 Oct 23

We retrospectively analyzed our results of 30 patients with three distinctive primary immunodeficiency diseases (PIDs)--severe combined immunodeficiency (SCID, n = 11), Wiskott-Aldrich syndrome (WAS, n = 11) and X-linked hyper-immunoglobulin M (IgM) syndrome (XHIM, n = 8)--who underwent hematopoietic SCT (HSCT) during the past 20 years. Until 1995, all donors were HLA-haploidentical relatives with T-cell depletion (TCD) (n = 8). Since 1996, the donors have been HLA-matched related donors (MRD) (n = 8), unrelated BM (UR-BM) (n = 7) and unrelated cord blood (UR-CB) (n = 7). Twenty-seven of 30 patients had various pre-existing infections with or without organ damages before HSCT. Conditioning regimen and GVHD prophylaxis were determined according to disease, donor and pretransplant status. Although one of eight patients transplanted with TCD is alive with full engraftment, the other seven died. On the other hand, 18 of 22 patients transplanted without TCD are alive and well, including six of eight transplanted from MRD, seven of seven from UR-BM and five of seven from UR-CB. All 19 survivors did not require Ig supplementation after HSCT. These results indicate that UR-CBT as well as UR-BMT provides good results for PID comparable to MRD-SCT, and that early diagnosis, HSCT at early stage, careful supportive therapy and monitoring for various pathogens are important for the successful HSCT.
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PMID:Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. 1643 16

HyperIgM syndrome is a heterogenous immunodeficiency characterized by impaired class-switch recombination due to different molecular abnormalities. We report on two female patients affected by a novel syndrome associating HIGM, growth and pubertal disturbances, and severe lymphoid hyperplasia with eventual development into lymphomas, suggesting a DNA repair defect.
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PMID:A novel form of non-X-linked hyperigm associated with growth and pubertal disturbances and with lymphoma development. 1661 79

Hyper-immunoglobulin M (IgM) syndrome (HIGM) is a rare primary immunodeficiency characterized by elevated or normal IgM and absent or markedly decreased amounts of IgG, IgA and IgE. The X-linked form (HIGM1) is the most common type and is caused by mutations in the gene for CD40L, a T-cell surface molecule required for T-cell driven immunoglobulin class switching by B cells. In the present study we have identified a patient with X-linked hyper-IgM who failed to express CD40L on the cell surface of CD4(+) T lymphocytes. Sequence analysis of CD40L genomic DNA showed no mutations. CD40L mRNA was absent and sequence analysis of the CD40L promotor revealed a mutation at position -123 from the transcription start site. The mutation in the promotor region likely contributed to the decreased transcription as demonstrated by a luciferase reporter assay.
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PMID:Hyper-immunoglobulin M syndrome caused by a mutation in the promotor for CD40L. 1724 60

All males in two generations of a Hungarian family died of interstitial pneumonia. History and records suggested X-linked hyper-IgM syndrome (X-HIGM). DNA sequencing of a female carrier revealed a c. 654C->A transversion of the CD40L gene that predicts premature termination of CD40L synthesis. This report points to the importance of early carrier detection and genetic counseling in families with X-linked primary immunodeficiency diseases. We propose that the c.654C->A sequence variant may associate with severe X-HIGM phenotype.
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PMID:Retrospective diagnosis of X-linked hyper-IgM syndrome in a family with multiple deaths of affected males. 1729 92

X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency characterised by an inability to produce immunoglobulins of the IgG, IgA and IgE isotypes. It is caused by mutations of CD40 ligand (CD40L, CD154), expressed on T-lymphocytes. The interaction of CD40L on T-cells and its receptor CD40 on B-cells is essential for lymphocyte signalling leading to immunoglobulin class switching and B-cell maturation. To understand the structural basis for XHIGM, we utilised bioinformatics methods to analyse all the known CD40L missense mutations at both the sequence and structural level. Our results demonstrate that the 35 different missense mutations have diverse effects on CD40L structure and function, affecting structural disorder and aggregation tendencies, stability maintaining contacts and electrostatic properties. Several mutations also affect residues essential in receptor binding and trimerisation. Experimental study of effects of mutations is laborious and time-consuming and at the structural level often almost impossible. By contrast, precise and useful information about effects of mutations on protein structure and function can readily be obtained by theoretical methods. In this study, all the XHIGM causing missense mutations could be explained in terms of CD40L structure and function. Thus, the molecular basis of the syndrome could be elucidated.
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PMID:The structural basis of hyper IgM deficiency - CD40L mutations. 1730 85

We report that osteopenia is a prominent and previously unappreciated clinical feature of patients with X-linked hyper-IgM syndrome, an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L). We therefore conducted studies to determine the relationship between CD40L and osteoclastogenesis. Recognizing that activated T cells express surface receptor activator of NF-kappaB ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, we assessed the capacity of wild-type T cells and CD40L(-/-) T cells to induce osteoclastogenesis in vitro. Relative to wild-type T cells, activated CD40L(-/-) T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L(-/-) T cells had normal expression of RANKL, they were deficient in IFN-gamma production. In subsequent studies, we cultured activated CD40L(-/-) T cells in the presence of IFN-gamma, and we found that the osteoclastic capacity of CD40L(-/-) T cells could be greatly diminished. These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome.
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PMID:Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. 1736 Apr 4

Patients with phagocytic, cellular, combined and other primary immunodeficiencies exhibit immune deficits that confer increased susceptibility to fungal infections. A number of yeasts and moulds, most commonly Candida and Aspergillus but also Cryptococcus, Histoplasma, Paecilomyces, Scedosporium, Trichosporon, Penicillium and other, rarely isolated, fungal organisms, have been variably implicated in causing disease in patients with chronic granulomatous disease, severe combined immunodeficiency, chronic mucocutaneous candidiasis, hyper-IgE syndrome, myeloperoxidase deficiency, leukocyte adhesion deficiency, defects in the interferon-gamma/interleukin-12 axis, DiGeorge syndrome, X-linked hyper-IgM syndrome, Wiskott-Aldrich syndrome and common variable immunodeficiency. Differences in the spectrum of fungal pathogens as well as in the incidence and clinical presentation of the infections may be observed among patients, depending upon different immune disorders. Fungal infections in these individuals may occasionally be the presenting clinical manifestation of a primary immunodeficiency and can cause significant morbidity and potentially fatal outcome if misdiagnosed or mistreated. A high degree of suspicion is needed and establishment of diagnosis should actively be pursued using appropriate imaging, mycological and histological studies. A number of antifungal agents introduced over the last fifteen years, such as the lipid formulations of amphotericin B, the second-generation triazoles, and the echinocandins, increase the options for medical management of these infections. Surgery may also be needed in some cases, while the role of adjunctive immunotherapy has not been systematically evaluated. The low incidence of primary immunodeficiencies in the general population complicates single-center prospective or retrospective clinical studies aiming to address diagnostic or therapeutic issues pertaining to fungal infections in these patients.
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PMID:Fungal infections in primary immunodeficiencies. 1755 53

We retrospectively analyzed the transplantation outcomes of 31 patients with primary immunodeficiency diseases treated at our center (All Children's Hospital, University of South Florida) since its inception in 1986. The primary immune diseases included severe combined immunodeficiency, Wiscott-Aldrich syndrome, X-linked hyper-IgM syndrome, and chronic granulomatous disease. The age of the patient's at the time of transplant ranged from 1 month to 19 years, and conditioning regimens varied based on the patients underlying disease. In 23 patients, the graft source was bone marrow, 4 patients received umbilical cord blood grafts and 4 patients received peripheral blood stem cell grafts. Better survival rates were observed in those patients transplanted at a younger age and free of infections, demonstrating that transplantation at an early age before significant infections, autoimmune manifestation and malignant transformation have occurred is beneficial.
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PMID:Hematopoietic stem cell transplantation for pediatric patients with primary immunodeficiency diseases at All Children's Hospital/University of South Florida. 1947 60


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