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)

A 19-year-old woman with a childhood history of cavitating left upper lobe pneumonia presented with persistent weight loss, fever, cough and roentgenographic evidence of right upper lobe pneumonia resistant to antibiotic therapy. An open lung biopsy led to the diagnosis of botryomycosis. Neutrophil function studies including flow cytometric evaluation of oxidative burst, bacterial killing and evaluation of neutrophil cytosolic proteins required for oxidase activation were consistent with chronic granulomatous disease. This is the first case report of primary pulmonary botryomycosis as a clinical manifestation of CGD. Other recent cases of immunodeficiency states associated with botryomycosis are reviewed.
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PMID:Primary pulmonary botryomycosis. A manifestation of chronic granulomatous disease. 155 42

The contribution of observations in congenital deficiency disorders to our understanding of normal mechanisms can hardly be overestimated, as may in particular be seen in the complex field of mechanisms aiming at maintaining the individual integrity. After a brief summary of the natural lines of defense we demonstrate a few cases with typical deficiencies, i.e. of the integuments (ciliary dyskinesia syndrome), of the phagocytes (chronic granulomatous disease = CGD), of specific immune reactions (antibody deficiency syndrome, severe combined immunodeficiency = SCID and syndromes with associated immunodeficiencies), and finally of the complement properdin system. Classification of these Primary Immunodeficiency Syndromes (= PIDS) with exceptional research potential as proposed by an expert panel of the WHO turned out to be quite useful also for the understanding of by far more frequent secondary disorders, in particular of the recently observed acquired immunodeficiency syndrome = AIDS due to an infection with the human immunodeficiency virus (= HIV). For pediatricians in industrialized countries, however, children with frequently recurring, but trivial infections are of considerable practical importance. A clear diagnostic concept is the necessary base for the proposed treatment, counselling and help for the inflicted parents.
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PMID:[Resistance to infection. Physiology and pathology of the immune system]. 265 37

We have examined the potential of IFN-gamma to ameliorate the physiologic defect of CGD by studying its effects on CGD phagocyte superoxide generation, NADPH-oxidase kinetics, and expression of the gene for the phagocyte cytochrome b heavy chain. In vitro treatment with IFN-gamma increased the respiratory burst activity of PMN and macrophages from three patients in two kindreds with type IA (variant, X-linked). Phagocytes from type I (classic, X-linked) and types IIA and III (autosomal recessive) CGD did not respond to IFN-gamma in vitro. Preliminary studies of in vivo treatment of several of the same patients with subcutaneous IFN-gamma demonstrated similar responses. All subjects whose phagocytes had responded in vitro showed complete or partial correction of the CGD defect in superoxide generation for up to 1 month after IFN-gamma administration. One patient with type I CGD with no detectable in vitro response also showed improved phagocyte respiratory burst activity after in vivo IFN-gamma treatment. These studies establish the potential efficacy of IFN-gamma in the treatment of patients with X-linked CGD and provide an example of pharmacologic modulation of gene expression in human disease. The ease of administration and absence of toxicity suggest a place for IFN-gamma as an adjunct to more conventional antimicrobial therapy during acute infections in CGD and perhaps even other congenital and acquired immunodeficiency states.
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PMID:Cellular and molecular effects of recombinant interferon gamma in chronic granulomatous disease. 283 59

CGD is a rare inherited immunodeficiency syndrome, caused by the phagocytes' inability to produce (sufficient) reactive oxygen metabolites. This dysfunction is due to a defect in the NADPH oxidase, the enzyme responsible for the production of superoxide. It is composed of several subunits, two of which, gp91phox and p22phox, form the membrane-bound cytochrome b558, while its three cytosolic components, p47phox, p67phox and p40phox, have to translocate to the membrane upon activation. This is a tightly and intricately controlled process that involves, among others, several low-molecular weight GTP-binding proteins. Gp91phox is encoded on the X-chromosome and p22phox, p47phox and p67phox on different autosomal chromosomes, and a defect in one of these components leads to CGD. This explains the variable mode of inheritance seen in this syndrome. Clinically CGD manifests itself typically already at a very young age with recurrent and serious infections, most often caused by catalase-positive pathogens. Modern treatment options, including prophylaxis with trimethoprim-sulfamethoxazole and rIFN-gamma as well as early and aggressive anti-infection therapy, have improved the prognosis of this disease dramatically. CGD, as a very well-characterized inherited affection of the hematopoietic stem cells, is predestined to be among the first diseases to profit from the advances in cutting-edge therapeutics, such as gene therapy and in utero stem cell transplantation.
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PMID:The molecular basis of chronic granulomatous disease. 961 66

X-linked chronic granulomatous disease (X-CGD) is a primary immunodeficiency with complete absence or malfunction of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the phagocytic cells. Life-threatening infections especially with aspergillus are common despite optimal antimicrobial therapy. Bone marrow transplantation (BMT) is contraindicated during invasive aspergillosis in any disease setting. We report an 8-year-old patient with CGD who underwent HLA-genoidentical BMT during invasive multifocal aspergillus nidulans infection, nonresponsive to treatment with amphotericin-B and gamma-interferon. During the first 10 days post-BMT, the patient received granulocyte colony-stimulating factor (G-CSF)-mobilized, 25 Gy irradiated granulocytes from healthy volunteers plus G-CSF beginning on day 3 to prolong the viability of the transfused granulocytes. This was confirmed in vitro by apoptosis assays and in vivo by finding nitroblue tetrazolium (NBT)-positive granulocytes in peripheral blood 12 and 36 hours after the transfusions. Clinical and biological signs of infection began to disappear on day 7 post-BMT. Positron emission tomography with F18-fluorodeoxyglucose (FDG-PET) and computed tomography (CT) scans at 3 months post-BMT showed complete disappearance of infectious foci. At 2 years post-BMT, the patient is well with full immune reconstitution and no sign of aspergillus infection. Our results show that HLA-identical BMT may be successful during invasive, noncontrollable aspergillus infection, provided that supportive therapy is optimal.
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PMID:Successful treatment of invasive aspergillosis in chronic granulomatous disease by bone marrow transplantation, granulocyte colony-stimulating factor-mobilized granulocytes, and liposomal amphotericin-B. 976 55

For patients with well-characterized, rapidly fatal, nonmalignant immunodeficiency disorders, such as SCID, the decision to proceed with allogeneic SCT is clear-cut. For patients with many other disorders, this decision can be extremely difficult. Disorders such as LAD or CGD have a variable natural history. Each patient must be considered individually, with the risk for SCT-related morbidity and mortality carefully weighed against that of the underlying disease. Significant advances during the past 10 years have made SCT a much safer procedure. Use of nonmyeloablative conditioning regimens as a means of reducing toxicity of high-dose chemotherapy and irradiation hold great promise. Highly immunosuppressive, nonchemotherapeutic agents that inhibit graft rejection or GVHD by blocking the critical costimulatory component of the T-cell receptor-antigen interaction are beginning to emerge and may be ideal for SCT of nonmalignant diseases. Therefore, the risk-benefit equation must be reassessed each year as the severity of patients' disorders is better defined and techniques of SCT improve.
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PMID:Stem-cell transplantation for inherited immunodeficiency disorders. 1113 Oct 1

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

We have investigated the effects of itraconazole (0.1-10 micro m), an antimycotic which is often used prophylactically in primary and secondary immunodeficiency disorders, including chronic granulomatous disease, on mobilization of Ca(2+) and restoration of Ca(2+) homeostasis following activation of neutrophils with FMLP or PAF. Transmembrane fluxes of Ca(2+), as well as cytosolic concentrations of the cation were measured using a combination of spectrofluorimetric and radiometric procedures. The abruptly occurring increases in cytosolic Ca(2+) following activation of the cells with either FMLP (1 micro m) or PAF (200 nm) were unaffected by itraconazole. However, the subsequent store-operated influx of the cation was attenuated by itraconazole at concentrations of 0.25 micro m and higher. The itraconazole-mediated inhibition of uptake of Ca(2+) was not associated with detectable alterations in the intracellular concentrations of cyclic AMP, ATP or inositol triphosphate, and appeared to be compatible with antagonism of store-operated Ca(2+) channels. Although a secondary property, this anti-inflammatory activity of itraconazole, if operative in vivo, may be beneficial in conditions associated with dysregulation of neutrophil Ca(2+) handling such as CGD.
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PMID:Itraconazole antagonizes store-operated influx of calcium into chemoattractant-activated human neutrophils. 1508 88

Gene transfer into hematopoietic stem cells has been used successfully for correcting lymphoid but not myeloid immunodeficiencies. Here we report on two adults who received gene therapy after nonmyeloablative bone marrow conditioning for the treatment of X-linked chronic granulomatous disease (X-CGD), a primary immunodeficiency caused by a defect in the oxidative antimicrobial activity of phagocytes resulting from mutations in gp91(phox). We detected substantial gene transfer in both individuals' neutrophils that lead to a large number of functionally corrected phagocytes and notable clinical improvement. Large-scale retroviral integration site-distribution analysis showed activating insertions in MDS1-EVI1, PRDM16 or SETBP1 that had influenced regulation of long-term hematopoiesis by expanding gene-corrected myelopoiesis three- to four-fold in both individuals. Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD.
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PMID:Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. 1659 81

Chronic granulomatous disease is an infrequent primary immunodeficiency characterized by defective intracellular killing of ingested microorganisms thereby making patients highly susceptible to recurrent lite threatening bacterial and fungal infections. In this study, we review the medical course of an 8 yrs old girl with AR-CGD. She suffered from recurrent dermal and deep abscesses, retractable salmonellosis, disseminated BCGosis, recurrent aspergillus infection presenting as mandibular osteomyelitis and pulmonary involvement with invasion to rib and vertebral bodies. Despite of longterm IV amphotricin B, itraconazole and IFN-gamma administration, and surgical interventions (drainage and resection), she died in spite of long term antibiotic anti fungal prophylaxis and interferon-gamma administrations, invasive aspergillosis resistant to current conventional therapies is the cause of 1/2 to 1/3 of CGD deaths.
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PMID:Para Vertebral Abscess and Rib Osteomyelitis due to Aspergillous Fumigatus in a Patient with Chronic Granulomatous Disease. 1730 51


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