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)

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

A 5-week-old female infant with vertical HIV-1 exposure, progressive cough, and failure to thrive was given a diagnosis of bilateral diffuse nodular lung lesions. The child was without fever, leukocytosis, anemia, peripheral adenopathy, or hepatosplenomegaly, and the results of repeated blood tests for HIV-1 DNA were negative. A needle biopsy of the lungs revealed granulomatous inflammation and giant cells, with fungal organisms suggestive of Aspergillus species. A nitroblue tetrazolium dye test performed on the patient's blood specimen demonstrated absence of dye reduction, suggesting a diagnosis of chronic granulomatous disease. Further analysis revealed that the child had a deficiency of the p47(phox) component of the nicotinamide adenine dinucleotide phosphate oxidase system. Thus this child with vertical HIV-1 exposure and diffuse pulmonary nodules actually had an autosomal recessive form of chronic granulomatous disease. This case study clearly demonstrates that children with suspected HIV-1 infection might also need evaluation for primary immunodeficiency and that the clinical immunology laboratory is a powerful adjunct in coming to a correct diagnosis.
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PMID:A 5-week-old HIV-1-exposed girl with failure to thrive and diffuse nodular pulmonary infiltrates. 1510 Jun 65

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome caused by a profound defect in the oxygen metabolic burst machinery. Activity of NADPH oxidase is absent or profoundly diminished, as at least one of its components (gp91(phox), p22(phox), p47(phox) and p67(phox)) is lacking or non-functional. This review explains the molecular basis of NADPH oxidase dysfunction by the effects of mutations in genes coding for particular oxidase components. Among the four types of CGD, the most common is X-linked CGD (approximately 65%), with defects in the CYBB gene encoding gp91(phox). A wide spectrum of mutations has been described in the CYBB gene with no predominant genotype. The second most common subtype of CGD caused by NCF1 mutation accounts for 30% of CGD patients and is inherited in an autosomal recessive manner, with predominance of a homozygotous deltaGT deletion in the genotype. The other two CGD subtypes having an autosomal recessive pattern together account for no more than 10% of CGD cases. A strategy for the molecular diagnostics in CGD patients is proposed and principles of genetic counseling are discussed here.
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PMID:Genetic and biochemical background of chronic granulomatous disease. 1517 25

We describe 2 cases of autosomal recessive chronic granulomatous disease (CGD) in 2 sisters presenting with a picture consistent with inflammatory bowel disease. The index case is a 10-year-old girl with a history of refractory Crohn's colitis treated with aggressive immunosuppressive therapy whose course subsequently was complicated by central nervous system aspergillosis. Additional evaluation showed a diagnosis of CGD, an underlying immunodeficiency in which phagocytes fail to produce microbicidal reactive oxygen intermediates because of inherited defects in the reduced form of nicotinamide-adenine phosphate dinucleotide (NADPH) oxidase. The diagnosis of a typically X-linked inherited disease in our female patient suggested that she had 1 of the 3 less common autosomal recessive forms of the disease. This was confirmed by studies showing the absence of the p47(phox) subunit of NADPH oxidase in her neutrophils and the presence of a homozygous dinucleotide deletion in the neutrophil cytosolic factor 1 gene that encodes p47(phox). Additional analyses of members of the patient's immediate family showed the same homozygous mutation in 2 siblings, 1 of whom also developed chronic colitis consistent with a diagnosis of Crohn's disease. These 2 cases emphasize the importance of high clinical suspicion for an alternative diagnosis of immune deficiency in the setting of presumed inflammatory bowel disease and opportunistic infection.
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PMID:Chronic granulomatous disease caused by a deficiency in p47(phox) mimicking Crohn's disease. 1529 Jun 62

Even a minor degree of haploinsufficiency could eventually reduce the frequency of an autosomal immunodeficiency disease. Searching for such a condition, we have re-examined the phenotype of mice +/- for the NCF1 gene encoding p47(phox) and humans +/- for NCF1 and NCF2 using a procedure that allowed the respiratory burst of granulocytes and macrophages to be measured simultaneously. The mice showed significant haploinsufficiency in granulocytes but not in macrophages (i.e. conditional haploinsufficiency). Our human data were obtained from blister cells, and were too scattered to allow a firm conclusion. In view of recent re-evaluation of the role of the respiratory burst these findings are compatible with the view that haploinsufficiency occurs particularly among rate-limiting genes that operate in regulatory/signaling pathways.
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PMID:Conditional haploinsufficiency of NCF1 (encoding p47(phox)), a signaling gene with a heterozygous phenotype potentially subject to natural selection. 1562 77

Chronic granulomatous disease (CGD) is an innate immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. In the course of 21 years, 38 Israeli CGD patients were diagnosed with 17 gene mutations, seven of which were new. Clinical, functional, and molecular studies were accomplished. Although X-linked recessive (XLR)-CGD is worldwide the most common genotype of the disease (~70%), in our study only 11 patients (29%) suffered from XLR-CGD. In Israel, the higher incidence of the autosomal recessive (AR) form of CGD (63%) may be related to consanguineous marriages. In three patients (8%), all four proteins of the NADPH oxidase were present. Severe clinical expression was found both in the XLR and AR forms, but in general a milder disease was evident in AR-CGD, particularly in patients with p47(phox) deficiency. Despite early and aggressive therapy, a mortality rate of 26% was noted. Given that bone-marrow transplantation was successful in five of seven patients, it is recommended to perform it as early as possible before tissue damage is irreversible.
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PMID:Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients. 1870 96

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by early onset of recurrent and severe infections. The molecular defects causing CGD are heterogeneous and lead to absence, low expression, or malfunctioning of one of the phagocyte NADPH oxidase components. It is known that mutations leading to CGD reside within the genes encoding four essential components of the oxidase designated as gp91-phox (phagocyte oxidase), p22-phox, p47-phox and p67-phox. gp91- together with p22-phox form the membrane cytochrome b(558) and play an essential role in the transfer of electrons following assembly of the active oxidase with the cytoplasmic p47- and p67-phox components. In hematopoietic cells, CYBB expression (the gene encoding gp91-phox) is limited to the granulocyte and monocyte/macrophage lineages during the process of terminal differentiation. CYBB is responsive to a number of inflammatory cytokines, especially interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). Cytokines have been also studied for activation of phagocytes respiratory burst. IFN-gamma stimulates superoxide release and is a prophylactic agent for CGD. It has been shown in vitro and in vivo to correct at least in part alterations of the oxidative metabolism, and to improve their microbicidal function. It has demonstrated clinical benefit in the majority of patients with CGD, reducing the relative risk of severe infections in 70%. In this study, we review mechanisms showing that IFN-gamma improves the splicing efficiency of CYBB gene transcripts in a particular group of CGD patients. The present article is an informative review of recent patents related to the use of interferon gamma therapy in chronic granulomatous disease.
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PMID:The use of interferon-gamma therapy in chronic granulomatous disease. 1899 4

The Nef protein of the human immunodeficiency virus type 1 (HIV-1) plays a crucial role in AIDS pathogenesis by modifying host cell signaling pathways. We investigated the effects of Nef on the NADPH oxidase complex, a key enzyme involved in the generation of reactive oxygen species during the respiratory burst in human monocyte/macrophages. We have recently shown that the inducible expression of HIV-1 Nef in human macrophages cell line modulates in bi-phasic mode the superoxide anion release by NADPH oxidase, inducing a fast increase of the superoxide production, followed by a delayed strong inhibition mediated by Nef-induced soluble factor(s). Our study is focused on the molecular mechanisms involved in Nef-mediated activation of NADPH oxidase and superoxide anion release. Using U937 cells stably transfected with different Nef alleles, we found that both Nef membrane localization and intact SH3-binding domain are needed to induce superoxide release. The lack of effect during treatment with a specific MAPK pathway inhibitor, PD98059, demonstrated that Nef-induced superoxide release is independent of Erk1/2 phosphorylation. Furthermore, Nef induced the phosphorylation and then the translocation of the cytosolic subunit of NADPH oxidase complex p47(phox) to the plasma membrane. Adding the inhibitor PP2 prevented this process, evidencing the involvement of the Src family kinases on Nef-mediated NADPH oxidase activation. In addition, LY294002, a specific inhibitor of phosphoinositide 3-kinase (PI3K) inhibited both the Nef-induced p47(phox) phosphorylation and the superoxide anion release. These data indicate that Nef regulates the NADPH oxidase activity through the activation of the Src kinases and PI3K.
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PMID:HIV-1 Nef induces p47(phox) phosphorylation leading to a rapid superoxide anion release from the U937 human monoblastic cell line. 1913 May 4

Chronic granulomatous disease (CGD) is an immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase complex and is usually diagnosed in early childhood. CGD patients suffer from severe, recurrent infections with bacteria, fungi and yeasts. We report a 25-year-old female with protracted fever because of a Staphylococcus aureus liver abscess, which did not resolve until breakthrough into the stomach. Despite her age, CGD was considered on diagnosis on the basis of the clinical symptoms. Analysis of the NADPH-oxidase activity confirmed CGD as the underlying condition. Western blotting revealed the absence of p47(phox) and subsequent sequencing of the p47(phox)-encoding gene, neutrophil cytosolic factor (NCF1), identified a deletion of 837C in the maternal NCF1 allele. The paternal allele contained a stopcodon because of a conversion between NCF1 and one of its PsiNCF1 pseudogenes. The patient had one novel mutation, c.837delC, and one conversion in NCF1, resulting in the complete absence of the p47(phox) component of the NADPH-oxidase complex. This p47(phox)-deficient CGD patient had the highest age at diagnosis reported thus far.
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PMID:A novel mutation in NCF1 in an adult CGD patient with a liver abscess as first presentation. 1932 91

The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O(2)( )). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-kappaB essential modulator (NEMO or IkappaB kinase gamma) deficiency. We observed impaired O(2)( ) generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47(phox) and subnormal translocation of p47(phox), p67(phox), Rac2, and gp91(phox)/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O(2)( ) in response to LPS-primed fMLP and translocated less p67(phox) than normal PMN, although p47(phox) and Rac2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency.
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PMID:Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. 1972 66


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