SEA BLUE HISTIOCYTES IN THE BONE MARROW OF VARIANT CHRONIC GRANULOMATOUS DISEASE WITH RESIDUAL MONOCYTE NADPH-OXIDASE ACTIVITY

1991 ◽  
Vol 78 (2) ◽  
pp. 278-280 ◽  
Author(s):  
M. Gahr ◽  
V. Jendrossek ◽  
A. M. J. Peters ◽  
F. Tegtmeyer ◽  
K. Heyne
Keyword(s):  
Bone Marrow ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity

Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3738-3745 ◽  
Author(s):  
Mary C. Dinauer ◽  
Mary A. Gifford ◽  
Nancy Pech ◽  
Ling Lin Li ◽  
Patricia Emshwiller
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Gene Transfer ◽  
Nadph Oxidase ◽  
Host Defense ◽  
Marrow Transplantation ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Nadph Oxidase Activity

Chronic granulomatous disease (CGD) is an inherited immunodeficiency in which the absence of the phagocyte superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in recurrent bacterial and fungal infections. A murine model of X-linked CGD (X-CGD) was used to explore variables influencing reconstitution of host defense following bone marrow transplantation and retroviral-mediated gene transfer. The outcomes of experimental infection with Aspergillus fumigatus, Staphylococcus aureus, orBurkholderia cepacia were compared in wild-type, X-CGD mice, and transplanted X-CGD mice that were chimeric for either wild-type neutrophils or neutrophils with partial correction of NADPH oxidase activity after retroviral-mediated gene transfer. Host defense to these pathogens was improved in X-CGD mice even with correction of a limited number of neutrophils. However, intact protection against bacterial pathogens required relatively greater numbers of oxidant-generating phagocytes compared to protection against A fumigatus. The host response also appeared to be influenced by the relative level of cellular NADPH oxidase activity, particularly forA fumigatus. These results may have implications for developing effective approaches for gene therapy of CGD.

Deficiency of NADPH oxidase activity in chronic granulomatous disease

1977 ◽  
Vol 90 (2) ◽  
pp. 213-217 ◽  
Author(s):  
Linda C. McPhail ◽  
Lawrence R. DeChatelet ◽  
Pamela S. Shirley ◽  
Catherine Wilfert ◽  
Richard B. Johnston ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity

scholarly journals Late-Onset of Chronic Granulomatous Disease Revealed By Paecilomyces Lilacinus Cutaneous Infection

2021 ◽  
Author(s):  
Clément Lemaigre ◽  
Felipe Suarez ◽  
Jean-Philippe Martellosio ◽  
Cindy Barbarin ◽  
Kevin Brunet ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Late Onset ◽  
Asymptomatic Carrier ◽  
Clinical Manifestations ◽  
Female Carrier ◽  
Granulomatous Disease ◽  
Nadph Oxidase Activity ◽  
Inherited Immunodeficiency

Abstract Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus, Paecylomyces lilacinus as the first manifestation of CGD. Dihydrorhodamin 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis of undetermined potential (CHIP) could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

scholarly journals Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1558-1562 ◽  
Author(s):  
RC Woodman ◽  
RW Erickson ◽  
J Rae ◽  
HS Jaffe ◽  
JT Curnutte
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Interferon Gamma ◽  
Oxidase Activity ◽  
Small Subset ◽  
Variant Form ◽  
Granulomatous Disease ◽  
Recombinant Interferon ◽  
Nadph Oxidase Activity ◽  
O2 Production

Recombinant interferon-gamma (rIFN-gamma) therapy has become an effective form of prophylaxis for patients with chronic granulomatous disease (CGD). Preliminary studies with CGD suggested that rIFN-gamma treatment enhanced phagocyte oxidase activity and increased superoxide (O2-) production. We evaluated several aspects of neutrophil NADPH oxidase activity in 19 CGD patients (representing all four known types of CGD) receiving prolonged rIFN-gamma therapy (6 to 27 months). In contrast to earlier studies, we failed to detect any improvement in neutrophil NADPH oxidase activity in 18 of the 19 CGD patients as determined by (1) intact cell O2- production (continuous assay), (2) nitroblue tetrazolium (NBT) staining, (3) cytochrome b558 spectroscopy, and (4) activity levels of cytosol and membrane oxidase components using a cell-free activation system. One patient with a variant form of X-linked CGD had a transient increase in neutrophil O2- production following 3 months of rIFN-gamma therapy. However, this was not sustained, and was not associated with any change in cytochrome b levels. In some patients, rIFN-gamma therapy was associated with the appearance of a small subset of circulating monocytes (1% to 20%) that were NBT-positive. Although the functional significance of this monocyte subpopulation needs to be determined, these results suggest that one possible mechanism by which rIFN-gamma may benefit CGD patients is by partially correcting the respiratory burst defect in a subset of monocytes. We conclude that the clinical benefit of prolonged rIFN-gamma therapy in the vast majority of CGD patients is not due to enhanced neutrophil NADPH oxidase activity. The mechanism of action of rIFN-gamma in most CGD patients remains unknown.

Heightened turnover and failed maturation of monocyte-derived macrophages in murine Chronic Granulomatous Disease

Blood ◽  
2021 ◽  
Author(s):  
Sophie Louise Gibbings ◽  
Kelsey Haist ◽  
Heidi J Nick ◽  
S Courtney Frasch ◽  
Teagan H Glass ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Granulomatous Disease ◽  
Adoptive Transfer ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Nadph Oxidase Activity ◽  
Normal Behavior ◽  
Bone Marrow Chimeras ◽  
Over Time

Loss of NADPH oxidase activity leads to altered phagocyte responses and exaggerated inflammation in Chronic Granulomatous Disease (CGD). We sought to assess the effects of Nox2 absence on monocyte-derived macrophages (MoMacs) in gp91phox-/y mice during zymosan-induced peritonitis. MoMacs from CGD and wild type (WT) peritonea were characterized over time after zymosan injection. Though numbers lavaged from both genotypes were virtually identical, there were marked differences in maturation: newly recruited WT MoMacs rapidly enlarged and matured, losing Ly6C and gaining MHCII, CD206 and CD36, while CGD MoMacs remained small and were mostly Ly6C+MHCII-. RNAseq analyses showed few intrinsic differences between genotypes in newly recruited MoMacs but significant differences with time. WT MoMacs demonstrated changes in metabolism, adhesion and reparative functions, while CGD MoMacs remained inflammatory. PKH dye labeling demonstrated that while WT MoMacs were mostly recruited within the first 24h and remained in the peritoneum while maturing and enlarging, CGD monocytes streamed into the peritoneum for days with many migrating to the diaphragm where they were found in fibrin(ogen) clots surrounding clusters of neutrophils in nascent pyogranulomata. Importantly, these observations appeared to be driven by milieu: adoptive transfer of CGD MoMacs into inflamed peritonea of WT mice resulted in immunophenotypic maturation and normal behavior, whereas altered maturation/behavior of WT MoMacs resulted from transfer into inflamed peritonea of CGD mice. Additionally, Nox2-deficient MoMacs behaved similarly to their Nox2-sufficient counterparts within the largely WT milieu of mixed bone marrow chimeras. These data demonstrate persistent recruitment with fundamental failure of MoMac maturation in CGD.

Long-Term Correction of Phagocyte NADPH Oxidase Activity by Retroviral-Mediated Gene Transfer in Murine X-Linked Chronic Granulomatous Disease

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 914-922 ◽  
Author(s):  
Mary C. Dinauer ◽  
Ling Lin Li ◽  
Helga Björgvinsdóttir ◽  
Chunjin Ding ◽  
Nancy Pech
Keyword(s):  
Gene Transfer ◽  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Granulomatous Disease ◽  
Transplant Recipients ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Nadph Oxidase Activity

Chronic granulomatous disease (CGD) is an inherited deficiency of the superoxide-generating phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, resulting in recurrent, severe bacterial and fungal infections. The X-linked form of this disorder (X-CGD) results from mutations in the X-linked gene for gp91phox, the larger subunit of the oxidase flavocytochrome b558. In this study, we used a murine model of X-CGD to examine the long-term function of retroviral vectors for expression of gp91phox based on the murine stem cell virus (MSCV) backbone. NADPH oxidase activity was reconstituted in neutrophils and macrophages for up to 18 to 24 months posttransplantation of transduced X-CGD bone marrow into lethally irradiated syngeneic X-CGD mice. Southern blot analysis and secondary transplant data showed proviral integration in multilineage repopulating cells. Although relatively small amounts of recombinant gp91phox (approximately 5% to 10% of wild-type levels) were detected in neutrophils after retroviral-mediated gene transfer, superoxide-generating activity was approximately 20% to 25% of wild-type mouse neutrophils. Expression of gp91phox is normally restricted to mature phagocytes. No obvious toxicity was observed in other hematopoietic lineages in transplant recipients, and provirus-marked cells were capable of reconstituting secondary transplant recipients, who also exhibited NADPH oxidase–positive neutrophils. MSCV-based vectors for long-term expression of gp91phox may be useful for gene therapy of human CGD targeted at hematopoietic stem cells.

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