To the editor:
We would like to comment on the recent paper by Bianchi and coworkers.1 Patients diagnosed with chronic granulomatous disease (CGD) suffer from recurrent and life-threatening infections. Analysis of clinical data from 429 European CGD patients recently confirmed that Aspergillus is a major threat, causing mostly pneumonia but also brain abscesses.Dress Cocktail winter Collection J Crew Boutique ICXHqzwzR
Reconstitution of an intact X-linked gene encoding gp91Factory J Crew Casual Dress Store Boutique winter phox is a remarkable accomplishment and a promising new therapy for X-CGD. In their Blood paper, Bianchi et al correlate the reconstituted nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in this patient with protection against Aspergillus infection, as a result of reconstituted neutrophil extracellular trap (NET) formation. NETs are composed of chromatin decorated with granular proteins and bind Gram-positive and -negative bacteria, as well as fungi, in a nonspecific way. Recently, ex vivo NET formation was shown to depend on superoxide production by activated NADPH oxidase.winter Leisure J Store Crew Factory Khaki Shorts BwwCqnHdx The only empirical data provided by Bianchi and coauthors to underscore the crucial role of NET formation against Aspergillus infection are ex vivo observations showing a microbicidal effect of NETs against Aspergillus species.
Treating the ex vivo findings as proof of a causal link between (reconstituted) NET formation and protection against Aspergillus may be a step too far and may not be essential. NETs do not have any specificity in microbicidal activity, whereas CGD patients show a selective susceptibility only to certain microbes.
Moreover, Aspergillus infection has recently been studied in a CGD mouse model, and activity of indoleamine 2,3-dioxygenase (IDO) was shown to be crucial for the survival of Aspergillus infection.4 IDO converts L-tryptophan into L-kynurenine but requires superoxide as a cofactor for its activity. Secreted L-kynurenine subsequently acts as an anti-inflammatory agent by mechanisms that are incompletely understood but have been shown to induce cell death in proinflammatory γδ T-cell subsets producing interleukin-17.4 Romani et al thus concluded that hyperinflammation caused a lethal outcome for CGD mice upon challenge with Aspergillus, rather than a defective clearance itself, as was previously suggested in CGD patients with an overwhelming pulmonary aspergillosis.Shorts Boutique Shorts Shorts Shorts THML Boutique Boutique THML THML THML Boutique THML Boutique qZUxCHnwg This seems plausible in view of a large body of evidence showing that CGD patients often display exaggerated immune responses against immunologic challenges,6 and granulomas have been shown to develop in the absence of any detectable pathogen, even after wound sterilization or after injection of heat-inactivated pathogens.7
Romani and coworkers underscore their conclusion by demonstrating that CGD mice, which all died upon Aspergillus challenge, survive this infection when treated with the IDO product L-kynurenine in combination with interferon-γ. In turn, wild-type mice, which normally survive this challenge, no longer overcome Aspergillus infection when treated with the IDO inhibitor 1-methyl tryptophan.8 Although the specificity of the challenge and the background of the CGD mouse strain are also subject for debate, the abovementioned relevant findings were not discussed or referred to in the Bianchi paper. It might be possible that reconstitution of other superoxide-dependent steps, such as direct effects or indirectly via IDO activity, rather than the restoration of the capability of NET formation, will protect CGD patients from Aspergillus infection.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Quinten Remijsen, KU Leuven campus Kortrijk, IRC, Laboratory of Biochemistry, E Sabbelaan 53, 8500 Kortrijk, Belgium; e-mail:.
- © 2009 by The American Society of Hematology
Potential Articles of Interest
- Response: Protecting against Aspergillus infection in CGD
- Tryptophan/kynurenine metabolism in human leukocytes is independent of superoxide and is fully maintained in chronic granulomatous disease.
- Restoration of NET formation by gene therapy in CGD controls aspergillosis.
- Chronic granulomatous disease due to granulocytes with abnormal NADPH oxidase activity and deficient cytochrome-b
- Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease
- Management of Disorders of Neutrophil Function: Chronic Granulomatous Disease
- Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection
- Chronic granulomatous disease
- Feiji Recipe Reverses Lung Cancer Immune Escape by Inhibiting the Expression of IDO
- Reactive Oxygen Intermediates Appear Key in CGD