Derivation and functional analysis of patient-specific induced pluripotent stem cells as an in vitro model of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of phagocytes in which NADPH oxidase is defective in generating reactive oxygen species. In this study, we reprogrammed three normal unrelated patient's fibroblasts (p47(phox) and gp91(phox) ) to pluripotency by lentiviral transduction with defined pluripotency factors. These induced pluripotent stem cells (iPSC) share the morphological features of human embryonic stem cells, express the key pluripotency factors, and possess high telomerase activity.

Advances in the diagnosis and treatment of chronic granulomatous disease.

Purpose Of Review: Chronic granulomatous disease (CGD), characterized 50 years ago as a primary immunodeficiency disorder of phagocytic cells (resulting in failure to kill a defined spectrum of bacteria and fungi and in concomitant chronic granulomatous inflammation) now comprises five genetic defects impairing one of the five subunits of phagocyte NADPH oxidase (Phox). Phox normally generates reactive oxygen species (ROS) engaged in intracellular and extracellular host defence and resolving accompanying inflammatory processes. 'Fatal' granulomatous disease has now changed into a chronic inflammatory condition with a median survival of 35 years and is now of interest to both paediatricians and internists.

Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent infections and deregulated inflammatory responses. CGD is caused by mutations in subunits of the NADPH oxidase, an enzyme that generates reactive oxygen species in phagocytes. To elucidate the contribution of the proinflammatory protease caspase-1 to aberrant inflammatory reactions in CGD, we analyzed cells isolated from patients with defects in the phagocyte oxidase subunits p22phox, p47phox or gp91phox.

Indications for hemopoietic stem cell transplantation.

A complete list of definite, as well as possible, indications for hemopoietic stem cell transplantation in primary immunodeficiency is provided. Included are: severe combined immunodeficiency, profound T cell defects, autoimmune and autoinflammatory syndromes, innate immune defects, hemophagocytic disorders, and other conditions. Some causes and limitations are included.

Hematopoietic stem cell transplantation for chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is caused by the lack of 1 of 5 subunits of the superoxide-producing nicotinamide adenine dinucleotide phosphate oxidase of neutrophils, macrophages, and eosinophils. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for CGD and can be offered to selected patients. Improved outcome with supportive care and high clinical variability in the disease course, however, make selection of eligible patients for HSCT difficult.

Actinomyces in chronic granulomatous disease: an emerging and unanticipated pathogen.

Background: Chronic granulomatous disease (CGD) is a rare inherited disease of the phagocyte NADPH oxidase system that causes defective production of toxic oxygen metabolites, impaired bacterial and fungal killing, and recurrent life-threatening infections, mostly by catalase-producing organisms. We report for the first time, to our knowledge, chronic infections with Actinomyces species in 10 patients with CGD. Actinomycosis is a chronic granulomatous condition that commonly manifests as cervicofacial, pulmonary, or abdominal disease, caused by slowly progressive infection with oral and gastrointestinal commensal Actinomyces species.

Restoration of NET formation by gene therapy in CGD controls aspergillosis.

Chronic granulomatous disease (CGD) patients have impaired nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function, resulting in poor antimicrobial activity of neutrophils, including the inability to generate neutrophil extracellular traps (NETs). Invasive aspergillosis is the leading cause of death in patients with CGD; it is unclear how neutrophils control Aspergillus species in healthy persons. The aim of this study was to determine whether gene therapy restores NET formation in CGD by complementation of NADPH oxidase function, and whether NETs have antimicrobial activity against Aspergillus nidulans.

First successful bone marrow transplantation for X-linked chronic granulomatous disease by using preimplantation female gender typing and HLA matching.

Allogeneic hematopoietic stem cell transplantation from an human leukocyte antigen (HLA)-identical donor is currently the only proven curative treatment for chronic granulomatous disease. Hematopoietic stem cell transplantation with alternative donors is associated with higher morbidity and mortality. Therefore, we performed in vitro fertilization and preimplantation HLA matching combined with female sexing for hematopoietic stem cell transplantation in chronic granulomatous disease.

Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome.

Background: Hyper-IgE syndrome (HIES) is a rare, autosomal-dominant immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous signal transducer and activator of transcription 3 (STAT3) mutations cause autosomal-dominant HIES.

Objective: To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of patients with HIES.

Modern management of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and in defective degradation of inflammatory mediators with concomitant granuloma formation. Current prophylaxis with trimethoprim-sulfamethoxazole, itraconazole and in selected cases additional interferon gamma is efficient, but imperfect. A significant recent progress towards new antibiotic (e.

Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation.

X-linked osteopetrosis, anhydrotic ectodermal dysplasia, and immunodeficiency (XL-O-EDA-ID) is a disorder that is caused by hypomorphic mutations in the nuclear factor kappaB essential modulator (NEMO). These mutations lead to an impaired NF-kappaB activation. In vitro analyses and studies in animal models show that inhibition of NF-kappaB leads to a decrease of cytokine production and T-cell proliferation.

Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium.

Toll-like receptors (TLRs) are involved in mediating cell activation on stimulation with microbial constituents. We investigated the role for TLRs in synovial fibroblast (SF) activation in rheumatoid arthritis (RA). We analyzed whether stimulation with interleukin-1 beta and tumor necrosis factor-alpha, cytokines present in RA synovium, influences expression of TLR genes in SFs.

Treatment of chronic granulomatous disease with myeloablative conditioning and an unmodified hemopoietic allograft: a survey of the European experience, 1985-2000.

Treatment of chronic granulomatous disease (CGD) with myeloablative bone marrow transplantation is considered risky. This study investigated complications and survival according to different risk factors present at transplantation. The outcomes of 27 transplantations for CGD, from 1985 to 2000, reported to the European Bone Marrow Transplant Registry for primary immunodeficiencies were assessed.

Gene therapy of hematopoietic stem cells: strategies for improvement.

Gene therapy of hematopoietic stem cells (HSC) is limited by low frequency of the target cells, their quiescent nature, poor engraftment of treated HSC, and lack of a selective growth advantage of genetically modified cells. Lentiviral vectors combined with positive selection strategies using conditional cell-growth switches should allow for improvement.