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Updated: May 6, 2026
Bioluminescence Imaging of NADPH Oxidase Activity in Different Animal Models
Published on: October 22, 2012
Residual NADPH oxidase and survival in chronic granulomatous disease
Douglas B Kuhns1, W Gregory Alvord, Theo Heller
1Clinical Services Program, SAIC-Frederick, Frederick, Maryland, USA.
Background:
Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22(phox), p40(phox), p47(phox), p67(phox) (autosomal chronic granulomatous disease), or gp91(phox) (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease.
Methods:
We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations.
Results:
Survival of patients with chronic granulomatous disease was strongly associated with residual ROI production as a continuous variable, independently of the specific gene affected. Patients with mutations in p47(phox) and most missense mutations in gp91(phox) (with the exception of missense mutations in the nucleotide-binding and heme-binding domains) had more residual ROI production than patients with nonsense, frameshift, splice, or deletion mutations in gp91(phox). After adolescence, mortality curves diverged according to the extent of residual ROI production.
Conclusions:
Patients with chronic granulomatous disease and modest residual production of ROI have significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. The production of residual ROI is predicted by the specific NADPH oxidase mutation, regardless of the specific gene affected, and it is a predictor of survival in patients with chronic granulomatous disease. (Funded by the National Institutes of Health.).
Insights
Residual reactive oxygen intermediate (ROI) production in chronic granulomatous disease (CGD) patients is linked to survival. Modest ROI production indicates less severe illness and better long-term outcomes for CGD patients.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Chronic granulomatous disease (CGD) is characterized by impaired phagocyte-derived superoxide and reactive oxygen intermediate (ROI) production.
- CGD results from mutations in genes encoding NADPH oxidase components (p22(phox), p40(phox), p47(phox), p67(phox), gp91(phox)), leading to variable ROI deficiency.
- Residual ROI production in CGD patients is hypothesized to correlate with clinical outcomes.
Purpose of the Study:
- To investigate the association between residual ROI production and the severity of illness and survival in patients with CGD.
- To determine if the extent of residual ROI production can predict long-term survival in CGD.
Main Methods:
- Assessed illness and mortality risks in 287 CGD patients from 244 kindreds.
- Quantified residual ROI production using superoxide-dependent ferricytochrome c reduction and dihydrorhodamine oxidation assays.
- Identified causal mutations by sequencing affected genes and detected NADPH oxidase component protein expression via immunoblotting.
Main Results:
- Survival in CGD patients strongly correlated with residual ROI production as a continuous variable, irrespective of the affected gene.
- Patients with p47(phox) mutations and most gp91(phox) missense mutations exhibited higher residual ROI production compared to those with nonsense, frameshift, splice, or deletion mutations in gp91(phox).
- Mortality curves diverged after adolescence based on the level of residual ROI production.
Conclusions:
- Modest residual ROI production in CGD patients is associated with significantly less severe disease and improved long-term survival.
- The specific NADPH oxidase mutation predicts residual ROI production, which serves as a key predictor of survival in CGD patients.
