Cause Chronic Granulomatous Disease Research Articles

A nox2/cybb zebrafish mutant with defective myeloid cell reactive oxygen species production displays normal initial neutrophil recruitment to sterile tail injuries.

Reactive oxygen species are important effectors and modifiers of the acute inflammatory response, recruiting phagocytes including neutrophils to sites of tissue injury. In turn, phagocytes such as neutrophils are both consumers and producers of reactive oxygen species. Phagocytes including neutrophils generate reactive oxygen species in an oxidative burst through the activity of a multimeric phagocytic nicotinamide adenine dinucleotide phosphate oxidase complex. Mutations in the NOX2/CYBB (previously gp91phox) nicotinamide adenine dinucleotide phosphate oxidase subunit are the commonest cause of chronic granulomatous disease, a disease characterized by infection susceptibility and an inflammatory phenotype. To model chronic granulomatous disease, we made a nox2/cybb zebrafish (Danio rerio) mutant and demonstrated it to have severely impaired myeloid cell reactive oxygen species production. Reduced early survival of nox2 mutant embryos indicated an essential requirement for nox2 during early development. In nox2/cybb zebrafish mutants, the dynamics of initial neutrophil recruitment to both mild and severe surgical tailfin wounds was normal, suggesting that excessive neutrophil recruitment at the initiation of inflammation is not the primary cause of the "sterile" inflammatory phenotype of chronic granulomatous disease patients. This nox2 zebrafish mutant adds to existing in vivo models for studying reactive oxygen species function in myeloid cells including neutrophils in development and disease.

Engineering Fe-N Doped Graphene to Mimic Biological Functions of NADPH Oxidase in Cells.

NADPH oxidase (NOX) as a transmembrane enzyme complex controls the generation of superoxide that plays important roles in immune signaling pathway. NOX inactivation may elicit immunodeficiency and cause chronic granulomatous disease (CGD). Biocompatible synthetic materials with NOX-like activities would therefore be interesting as curative and/or preventive approaches in case of NOX deficiency. Herein, we synthesized a Fe-N doped graphene (FeNGR) nanomaterial that could mimic the activity of NOX by efficiently catalyzing the conversion of NADPH into NADP+ and triggering the generation of oxygen radicals. The resulting FeNGR nanozyme had similar cellular distribution to NOX and is able to mimic the enzyme function in NOX-deficient cells by catalyzing the generation of superoxide and retrieving the immune activity, evidenced by TNF-α, IL-1β, and IL-6 production in response to Alum exposure. Overall, our study discovered a synthetic material (FeNGR) to mimic NOX and demonstrated its biological function in immune activation of NOX-deficient cells.

Nox2 deficiency in neutrophils promotes excessive and sustained inflammatory responses at local and distal sites of inflammation

Abstract NADPH oxidase 2 (Nox2) plays important roles both in protection from pathogens and in responses to inflammatory stimuli, and its functional loss is the cause of Chronic Granulomatous Disease. While earlier reports implicated macrophage Nox2 as the major contributor to inflammatory responses, we sought to determine the respective contributions of Nox2 in resident macrophages or neutrophils to early inflammatory responses induced by two different stimuli and routes of induction. We hypothesized that absence of Nox2 function in resident macrophages would drive excessive, prolonged inflammation. Intraperitoneal (i.p.) zymosan or intratracheal (i.t.) killed A. fumigatus in Nox2-deficient mice both drive a severe, sustained inflammatory response locally with continually elevated levels of neutrophils, monocytes, and macrophages and granulomata formation, whereas WT mice exhibit rapidly resolving responses. We employed a novel mixed bone marrow chimera approach in which neutrophils are predominantly Nox2-sufficient yet resident macrophages are largely Nox2-deficient. We treated these mice and WT control mixed chimeras with both i.p. zymosan and i.t. killed A. fumigatus and characterized the inflammatory response in both the lung and peritoneal cavity after either stimulus. Notably, the Nox2-deficient mixed chimeras responded similarly to WT control chimeras, including reduced neutrophil and monocyte recruitment and absence of granulomata, demonstrating that Nox2 deficiency specifically in neutrophils drives excessive inflammation in response to both i.p. zymosan and i.t. A. fumigatus. These data highlight the importance of neutrophil Nox2 in normal progression and resolution of these inflammatory responses.

Differential Transgene Silencing of Myeloid-Specific Promoters in the AAVS1 Safe Harbor Locus of Induced Pluripotent Stem Cell-Derived Myeloid Cells.

Targeted integration into a genomic safe harbor, such as the AAVS1 locus on chromosome 19, promises predictable transgene expression and reduces the risk of insertional mutagenesis in the host genome. The application of gamma-retroviral long terminal repeat (LTR)-driven vectors, which semirandomly integrate into the genome, has previously caused severe adverse events in some clinical studies due to transactivation of neighboring proto-oncogenes. Consequently, the site-specific integration of a therapeutic transgene into a genomic safe harbor locus would allow stable genetic correction with a reduced risk of insertional mutagenesis. However, recent studies revealed that transgene silencing, especially in case of weaker cell type-specific promoters, can occur in the AAVS1 locus of human pluripotent stem cells (PSCs) and can impede transgene expression during differentiation. In this study, we aimed to correct p47phox deficiency, which is the second most common cause of chronic granulomatous disease, by insertion of a therapeutic p47phox transgene into the AAVS1 locus of human induced PSCs (iPSCs) using CRISPR-Cas9. We analyzed transgene expression and functional correction from three different myeloid-specific promoters (miR223, CatG/cFes, and myeloid-related protein 8 [MRP8]). Upon myeloid differentiation of corrected iPSC clones, we observed that the miR223 and CatG/cFes promoters achieved therapeutically relevant levels of p47phox expression and nicotinamide adenine dinucleotide phosphate oxidase activity, whereas the MRP8 promoter was less efficient. Analysis of the different promoters revealed high CpG methylation of the MRP8 promoter in differentiated cells, which correlated with the transgene expression data. In summary, we identified the miR223 and CatG/cFes promoters as cell type-specific promoters that allow stable transgene expression in the AAVS1 locus of iPSC-derived myeloid cells. Our findings further indicate that promoter silencing can occur in the AAVS1 safe harbor locus in differentiated hematopoietic cells and that a comparison of different promoters is necessary to achieve optimal transgene expression for therapeutic application of iPSC-derived cells.

NOX2 mediates quiescent handling of dead cell remnants in phagocytes

The phagocyte NADPH oxidase (the NOX2 complex) generates superoxide, the precursor to reactive oxygen species (ROS). ROS possess both antimicrobial and immunoregulatory function. Inactivating mutations in alleles of the NOX2 complex cause chronic granulomatous disease (CGD), characterized by an enhanced susceptibility to infections and autoimmune diseases such as Systemic lupus erythematosus (SLE). The latter is characterized by insufficient removal of dead cells, resulting in an autoimmune response against components of the cell's nucleus when non-cleared apoptotic cells lose their membrane integrity and present autoantigenic molecules in an inflammatory context. Here we aimed to shed light on the role of the NOX2 complex in handling of secondary necrotic cells (SNECs) and associated consequences for inflammation and autoimmunity during lupus.We show that individuals with SLE and CGD display accumulation of SNECs in blood monocytes and neutrophils. In a CGD phenotypic mouse strain (Ncf1** mice) build-up of SNECs in Ly6CHI blood monocytes was connected with a delayed degradation of the phagosomal cargo and accompanied by production of inflammatory mediators. Treatment with H2O2 or activators of ROS-formation reconstituted phagosomal abundance of SNECs to normal levels. Induction of experimental lupus further induced increased antibody-dependent uptake of SNECs into neutrophils. Lupus-primed Ncf1** neutrophils took up more SNECs than wild type neutrophils, whereas SNEC-accumulation in regulatory Ly6C−/LO monocytes was lower in Ncf1**mice. We deduce that the inflammatory rerouting of immune-stimulatory necrotic material into inflammatory phagocyte subsets contributes to the connection between low ROS production by the NOX2 complex and SLE.

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.

EROS/CYBC1 mutations: Decreased NADPH oxidase function and chronic granulomatous disease

Short Summary The phagocyte respiratory burst is mediated by the phagocyte NADPH oxidase, a multi-protein subunit complex that facilitates production of reactive oxygen species and which is essential for host defence. Monogenic deficiency of individual subunits leads to chronic granulomatous disease (CGD), which is characterized by an inability to make reactive oxygen species, leading to severe opportunistic infections and auto-inflammation. However, not all cases of CGD are due to mutations in previously identified subunits. We recently showed that Eros, a novel and highly conserved ER-resident transmembrane protein, is essential for the phagocyte respiratory burst in mice because it is required for expression of gp91 phox -p22 phox heterodimer, which are the membrane bound components of the phagocyte NADPH oxidase. Eros has a human orthologue, CYBC1 / EROS . We now show that the function of CYBC1/EROS is conserved in human cells and describe a case of CGD secondary to a homozygous CYBC1/EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of CYBC1/EROS in human immunity and describes a novel cause of CGD.

NADPH oxidase activation regulates apoptotic neutrophil clearance by murine macrophages

AbstractThe phagocyte reduced NAD phosphate (NADPH) oxidase generates superoxide, the precursor to reactive oxygen species (ROS) that has both antimicrobial and immunoregulatory functions. Inactivating mutations in NADPH oxidase alleles cause chronic granulomatous disease (CGD), characterized by enhanced susceptibility to life-threatening microbial infections and inflammatory disorders; hypomorphic NADPH oxidase alleles are associated with autoimmunity. Impaired apoptotic cell (AC) clearance is implicated as an important contributing factor in chronic inflammation and autoimmunity, but the role of NADPH oxidase–derived ROS in this process is incompletely understood. Here, we demonstrate that phagocytosis of AC (efferocytosis) potently activated NADPH oxidase in mouse peritoneal exudate macrophages (PEMs). ROS generation was dependent on macrophage CD11b, Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response 88 (MyD88), and was also regulated by phosphatidylinositol 3-phosphate binding to the p40phox oxidase subunit. Maturation of efferosomes containing apoptotic neutrophils was significantly delayed in CGD PEMs, including acidification and acquisition of proteolytic activity, and was associated with slower digestion of apoptotic neutrophil proteins. Treatment of wild-type macrophages with the vacuolar-type H+ ATPase inhibitor bafilomycin also delayed proteolysis within efferosomes, showing that luminal acidification was essential for efficient digestion of efferosome proteins. Finally, cross-presentation of AC-associated antigens by CGD PEMs to CD8 T cells was increased. These studies unravel a key role for the NADPH oxidase in the disposal of ACs by inflammatory macrophages. The oxidants generated promote efferosome maturation and acidification that facilitate the degradation of ingested ACs.

A false-carrier state for the c.579G>A mutation in the NCF1 gene in Ashkenazi Jews

BackgroundMutations in the NCF1 gene that encodes p47phox, a subunit of the NADPH oxidase complex, cause chronic granulomatous disease (CGD). In Kavkazi Jews, a c.579G>A (p.Trp193Ter) mutation in NCF1 is...

Poly Lactic-co-glycolic acid nanoparticles encapsulation enhance the effectiveness of curcumin for rescuing trafficking-defective gp91phox in chronic granulomatous disease leukocytes.

Abstract Mutations in leukocyte NADPH oxidase genes lead to defective reactive oxygen species (ROS) production and cause chronic granulomatous disease (CGD) in humans. Previously we have shown that the sarco/endoplasmic reticulum calcium ATPase (SERCA) pump inhibitor, thapsigargin, rescues the endoplasmic reticulum (ER) retention of the mutant protein in a CGD patient with a gp91phox (H338Y) mutation. Curcumin, a natural constituent of Curcuma longa, is also a SERCA pump inhibitor. However, the clinical effectiveness of curcumin is not satisfactory due to its poor in vivo bioavailability and potential cytotoxicity. In this study, we investigated the effects of organelle-targeting nanoparticles on the delivery of curcumin to leukocytes for the treatment of CGD. First, we investigated the cytotoxicity of curcumin with poly (lactic-co-glycolic acid) (PLGA) nanoparticles encapsulation. Next, we investigated the therapeutic potential of PLGA encapsulated curcumin in mice expressing gp91phox (H338Y) mutant protein. Our results showed that (1) ER-targeting peptide decoration enhanced the localization of PLGA encapsulated curcumin in the ER region; (2) PLGA encapsulated curcumin induced ER calcium release, but the following extracellular calcium entry and ER stress-associated cell death was inhibited; (3) The in vivo test showed that PLGA encapsulated curcumin with ER-targeting peptide decoration enhanced leukocytes gp91phox (H338Y) mutant protein processing and the ROS production. This study showed the therapeutic potential of PLGA encapsulated curcumin for diseases with protein-trafficking defective mutations. Efficient organelle-targeting may promote the efficiency of nanoparticle-based curcumin delivery system.

Hyperinflammation in patients with chronic granulomatous disease leads to impairment of hematopoietic stem cell functions

Defects in phagocytic nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) function cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by dysfunctional microbicidal activity and chronic inflammation. We sought to study the effect of chronic inflammation on the hematopoietic compartment in patients and mice with X-linked chronic granulomatous disease (X-CGD). We used immunostaining and functional analyses to study the hematopoietic compartment in patients with CGD. An analysis of bone marrow cells from patients and mice with X-CGD revealed a dysregulated hematopoiesis characterized by increased numbers of hematopoietic progenitor cells (HPCs) at the expense of repopulating hematopoietic stem cells (HSCs). In patients with X-CGD, there was a clear reduction in the proportion of HSCs in bone marrow and peripheral blood, and they were also more rapidly exhausted after in vitro culture. In mice with X-CGD, increased cycling of HSCs, expansion of HPCs, and impaired long-term engraftment capacity were found to be associated with high concentrations of proinflammatory cytokines, including IL-1β. Treatment of wild-type mice with IL-1β induced enhanced cell-cycle entry of HSCs, expansion of HPCs, and defects in long-term engraftment, mimicking the effects observed in mice with X-CGD. Inhibition of cytokine signaling in mice with X-CGD reduced HPC numbers but had only minor effects on the repopulating ability of HSCs. Persistent chronic inflammation in patients with CGD is associated with hematopoietic proliferative stress, leading to a decrease in the functional activity of HSCs. Our observations have clinical implications for the development of successful autologous cell therapy approaches.

Copy Number Variations Due to Large Genomic Deletion in X-Linked Chronic Granulomatous Disease

Mutations in genes for any of the six subunits of NADPH oxidase cause chronic granulomatous disease (CGD), but almost 2/3 of CGD cases are caused by mutations in the X-linked CYBB gene, also known as NAD (P) H oxidase 2. Approximately 260 patients with CGD have been reported in Japan, of whom 92 were shown to have mutations of the CYBB gene and 16 to have chromosomal deletions. However, there has been very little detailed analysis of the range of the deletion or close understanding of the disease based on this. We therefore analyzed genomic rearrangements in X-linked CGD using array comparative genomic hybridization analysis, revealing the extent and the types of the deletion genes. The subjects were five Japanese X-linked CGD patients estimated to have large base deletions of 1 kb or more in the CYBB gene (four male patients, one female patient) and the mothers of four of those patients. The five Japanese patients were found to range from a patient exhibiting deletions only of the CYBB gene to a female patient exhibiting an extensive DNA deletion and the DMD and CGD phenotype manifested. Of the other three patients, two exhibited CYBB, XK, and DYNLT3 gene deletions. The remaining patient exhibited both a deletion encompassing DNA subsequent to the CYBB region following intron 2 and the DYNLT3 gene and a complex copy number variation involving the insertion of an inverted duplication of a region from the centromere side of DYNLT3 into the deleted region.

Alu-repeat-induced deletions within theNCF2gene causing p67-phox-deficient chronic granulomatous disease (CGD)

Mutations that impair expression or function of the components of the phagocyte NADPH oxidase complex cause chronic granulomatous disease (CGD), which is associated with life-threatening infections and dysregulated granulomatous inflammation. In five CGD patients from four consanguineous families of two different ethnic backgrounds, we found similar genomic homozygous deletions of 1,380 bp comprising exon 5 of NCF2, which could be traced to Alu-mediated recombination events. cDNA sequencing showed in-frame deletions of phase zero exon 5, which encodes one of the tandem repeat motifs in the tetratricopeptide (TPR4) domain of p67-phox. The resulting shortened protein (p67Delta5) had a 10-fold reduced intracellular half-life and was unable to form a functional NADPH oxidase complex. No dominant negative inhibition of oxidase activity by p67Delta5 was observed. We conclude that Alu-induced deletion of the TPR4 domain of p67-phox leads to loss of function and accelerated degradation of the protein, and thus represents a new mechanism causing p67-phox-deficient CGD.

CYBB, an NADPH-oxidase gene: restricted diversity in humans and evidence for differential long-term purifying selection on transmembrane and cytosolic domains

CYBB encodes the gp91-phox protein of the phagocytic NADPH oxidase; the innate immunity-related enzymatic complex responsible for the respiratory burst. Mutations in CYBB can cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by ineffective microbicidal activity, for which over 150 family-specific mutations have been described. It is also plausible that common SNPs in CYBB alter the expression or function of gp91-phox, determining differences in susceptibility to complex disorders such as autoimmune or infectious diseases. We have resequenced the exons, UTRs, and intronic regions of CYBB in 102 ethnically diverse individuals and genotyped nine tag-SNPs in 942 individuals from 52 worldwide populations. The 28 observed SNPs (none of which nonsynonymous) reside on 28 haplotypes that can be collapsed into five clades. CYBB shows lower diversity than other X-chromosome genes and most of the between-population genetic variance was observed among Africans and non-Africans. The African population shows the highest diversity and the lowest linkage disequilibrium (LD). Because there is extensive shared LD among non-Africans, tag-SNPs can be effectively employed in gene-centric association studies and are portable across Eurasian and Native American populations. Comparison of CYBB coding sequences among mammals evidences the action of long-term purifying selection, which is stronger on the C-terminal cytosolic domain than on the N-terminal transmembrane domain of gp91-phox.

Out Phoxing the Endothelium

The importance of the contribution from Li et al1 presented in this issue lies as much in the questions it raises as in those it answers. In setting out to prove that p47phox, a regulatory subunit of the phagocyte NADPH oxidase, is equally vital to the superoxide-generating enzyme of vascular endothelial cells, which they successfully did, they also turned up a number of unexpected observations. The latter results, whose interpretation will necessarily remain speculative for the time being, may become fertile ground for future investigations, not only of the endothelium, but also of other tissues that express variants of this enzyme complex first characterized in phagocytes. In the neutrophil, the bactericidal oxidative burst results from massive superoxide anion production by an NADPH oxidase, a complex of 5 major subunits, the membrane bound gp91phox and p22phox, and the regulatory cytosolic components p47phox, p67phox, and Rac.2 The importance of p47phox is well documented because its phosphorylation appears to be the limiting step required for assembly of the active enzyme complex.2 Furthermore, mutations in p47phox are a cause of chronic granulomatous disease, an immune deficiency resulting from impaired phagocyte activity. It is now clear that many other tissues, including all layers of the vascular wall, also produce superoxide and its derivatives.3 These reactive oxygen species are no longer regarded simply as undesirable by-products of aerobic metabolism but also as essential second messengers …

AG Dinucleotide Insertion in a Patient With Chronic Granulomatous Disease Lacking Cytosolic 67-kD Protein

The 67-kD cytosolic protein (p67-phox) is an essential component of the superoxide-generating system in phagocytes, and its defect is known to cause chronic granulomatous disease (CGD). We sequenced p67-phox cDNA from one of seven patients found in Japan and his parents. In the patient's cDNA, homozygous AG dinucleotide insertion at position 399 (or 401) was found together with three other homozygous substitutions in a coding region (A-542 to G, T-895 to C and A-983 to G) compared with the sequence reported for HL-60 cells. In cDNA from his parents, the AG insertion was found to be heterozygous. In contrast, the other three substitutions were found homozygously in his father's specimen and the latter two in his mother's specimen. The substitution of A-542 to G was heterozygous in his mother's cDNA. The AG insertion would induce a frame shift and bring about a stop codon at the position of 433. However, the other three differences would give insignificant changes for the protein function, if any, because the substitutions of A-542 to G and A-983 to G result in the conservative amino acid transitions, ie, Lys-180 to Arg and Lys-327 to Arg, and that of T-895 to C no amino acid change. Neutrophils from the patients completely lacked superoxide generating activity whereas those from his parents generated substantial amounts of superoxide anion upon stimulation. Thus, it is concluded that the AG dinucleotide insertion is responsible for the disease in this patient.

Homologous Dinucleotide (GT or TG) Deletion in Japanese Patients with Chronic Granulomatous Disease with p47-Phox Deficiency

The cytosolic 47-kDa protein designated as p47-phox (phagocyte oxidase) is one of the essential components of the superoxide-generating system in phagocytes, and its defect is known to cause chronic granulomatous disease (CGD). Five unrelated CGD patients with p47-phox deficiency were found among 82 CGD patients in Japan. We sequenced the cDNAs and the genomic DNAs corresponding to p47-phox derived from these patients. In all cases examined, the defect was identified to be a GT (or TG) dinucleotide deletion at bases 75/76 (or 74/75, respectively) in the coding sequence for the protein. The same mutation was reported previously for a total of 9 alleles from 5 CGD patients in England and in the United States. It seems, therefore, that the dinucleotide GT deletion is the common mutation in 47-phox deficient CGD due to certain structural issues.

Interferon-γ in the treatment of the chronic granulomatous diseases of childhood

The bactericidal activity of phagocytic cells depends largely on the production of highly reactive metabolites from the metabolism of oxygen. A lesion anywhere in the biochemical pathway of hydrogen peroxide production has the potential to cause chronic granulomatous disease (CGD). Recent findings have shown that CGD results from distinct abnormalities in the NADPH oxidase system, which includes the membrane-associated proteins, NADPH oxidase, cytochrome b-558, and several cytosolic proteins. Specific genetic markers have been identified for the most common biochemical variants of CGD. Pharmacologic alteration of phagocyte oxidative metabolism is now possible through the use of recombinant interferon-gamma. In vitro studies have shown that neutrophils and monocytes derived from patients with autosomal recessive cytochrome b-positive CGD respond to interferon-gamma with an enhanced respiratory burst (superoxide production) and increased bactericidal activity. Furthermore, subcutaneous interferon-gamma administration improves bactericidal activity in neutrophils and monocytes derived from patients with X-linked, cytochrome b-negative CGD, despite the lack of effect on superoxide production. This suggests that interferon-gamma also stimulates nonoxidative bactericidal pathways. Data from a multicenter clinical trial indicate sustained administration of interferon-gamma is effective in the management of CGD. In addition, related studies indicate that modern molecular and genetic technologies offer the possibility of improved management or cure for CGD.

Interferon- in the Management of Chronic Granulomatous Disease

Bactericidal activity of phagocytic cells depends largely upon their production of highly reactive compounds via the metabolism of oxygen. A lesion anywhere in the biochemical pathway of hydrogen peroxide production potentially can cause chronic granulomatous disease (CGD). Recent work has shown that CGD results from specific abnormalities in the nicotinamide-adenine dinucleotide phosphate (NADPH) system, which includes membrane-associated proteins, NADPH, cytochrome b-558, and several cytosolic proteins. Pharmacologic alteration of phagocytic oxidative metabolism can now be achieved through use of recombinant interferon-gamma (IFN-gamma). Data from a multicenter clinical trial indicate that sustained administration of IFN-gamma is effective in the management of CGD; for patients who received IFN-gamma, a 72% reduction in the relative risk of serious infection was noted in comparison with the risk for patients who received placebo. IFN-gamma reduced not only the number of serious primary infections but also the length of hospitalizations.

Genetic Defects of Phagocyte Nadph Oxidase Activity and Activation

NADPH oxidase is the key enzyme of the free radical-generating oxidative matabolism of phagocytes. Work from our and other's laboratories has recently established that the oxidase is not a single molecular entity, but it is a multicomponent system including a NADPH-binding protein, a flavoprotein, a b-type cytochrome and other unidentified factors. A working model of the molecular nature and of the activation mechanism of phagocyte NADPH oxidase is here proposed. This model is suitable for the study and the classification of the molecular pathology of the oxidase system. The various genetic defects of the NADPH oxidase, that are the cause of chronic granulomatous disease, (CGD) are here presented and discussed.