Chronic granulomatous disease: why an inflammatory disease?

Roxo, Pérsio; Simao, Huang

doi:10.1590/1414-431x20143735

Cited by 16 publications

(14 citation statements)

References 46 publications

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“…This role is consistent with known function for ROS in cell signaling, communication, and recruitment [25][26][27][28][29][30] . The antiinflammatory role of ROS is also in line with data seen in CGD patients who can develop pathological, excessive inflammatory responses [31][32][33] . The increased swarming size is consistent with previous reports that CGD neutrophils release increased amounts of pro-inflammatory cytokine, interleukin (IL)-8, in response to fungi, including C. albicans, and increase accumulation of LTB 4 34,35 .…”

Section: Discussionsupporting

confidence: 81%

Neutrophil swarming delays the growth of clusters of pathogenic fungi

et al. 2020

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Neutrophils employ several mechanisms to restrict fungi, including the action of enzymes such as myeloperoxidase (MPO) or NADPH oxidase, and the release of neutrophil extracellular traps (NETs). Moreover, they cooperate, forming "swarms" to attack fungi that are larger than individual neutrophils. Here, we designed an assay for studying how these mechanisms work together and contribute to neutrophil's ability to contain clusters of live Candida. We find that neutrophil swarming over Candida clusters delays germination through the action of MPO and NADPH oxidase, and restricts fungal growth through NET release within the swarm. In comparison with neutrophils from healthy subjects, those from patients with chronic granulomatous disease produce larger swarms against Candida, but their release of NETs is delayed, resulting in impaired control of fungal growth. We also show that granulocyte colony-stimulating factors (GCSF and GM-CSF) enhance swarming and neutrophil ability to restrict fungal growth, even during treatment with chemical inhibitors that disrupt neutrophil function.

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Section: Discussionsupporting

confidence: 81%

Neutrophil swarming delays the growth of clusters of pathogenic fungi

et al. 2020

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“…Reactive oxygen species have been shown to affect transcription factors such as NF-κβ ( 91 , 92 ) which mediates the induction of IL-1β and IL-8 expression. However, CGD shows that NF-κβ activation is independent of ROS and is also mediated by TNF and IL-1 ( 93 , 94 ) and so neutrophils in these individuals are still able to release these pro-inflammatory factors and uncontrolled chronic inflammation ensues ( 95 , 96 ). Pro-inflammatory mediators alone, such as leukotrienes and IL-1β, are not enough to control infection and it is likely that the overproduction thereof augments the lack of M. tuberculosis infection control in CGD patients ( 44 ).…”

Section: Neutrophils In M Tuberculosis Infection mentioning

confidence: 99%

Neutrophils: Innate Effectors of TB Resistance?

et al. 2018

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Certain individuals are able to resist Mycobacterium tuberculosis infection despite persistent and intense exposure. These persons do not exhibit adaptive immune priming as measured by tuberculin skin test (TST) and interferon-γ (IFN-γ) release assay (IGRA) responses, nor do they develop active tuberculosis (TB). Genetic investigation of individuals who are able to resist M. tuberculosis infection shows there are likely a combination of genetic variants that contribute to the phenotype. The contribution of the innate immune system and the exact cells involved in this phenotype remain incompletely elucidated. Neutrophils are prominent candidates for possible involvement as primers for microbial clearance. Significant variability is observed in neutrophil gene expression and DNA methylation. Furthermore, inter-individual variability is seen between the mycobactericidal capacities of donor neutrophils. Clearance of M. tuberculosis infection is favored by the mycobactericidal activity of neutrophils, apoptosis, effective clearance of cells by macrophages, and resolution of inflammation. In this review we will discuss the different mechanisms neutrophils utilize to clear M. tuberculosis infection. We discuss the duality between neutrophils' ability to clear infection and how increasing numbers of neutrophils contribute to active TB severity and mortality. Further investigation into the potential role of neutrophils in innate immune-mediated M. tuberculosis infection resistance is warranted since it may reveal clinically important activities for prevention as well as vaccine and treatment development.

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“…At autopsy, evidence of acute lung injury, skin ichthyosis, and the significant immune deficiency was found. Primary defects in NOX4 are postulated to contribute to all the autopsy findings [27][28][29][30][31]. Moreover, NOX4 is constitutively expressed and active in a variety of cells [32,33].…”

Section: Discussionmentioning

confidence: 99%

Tread carefully: A functional variant in the human NADPH oxidase 4 ( NOX4 ) is not disease causing

Nafisinia

Menezes

Gold

et al. 2018

Molecular Genetics and Metabolism

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In this study, we report a paediatric patient with a lethal phenotype of respiratory distress, failure to thrive, pancreatic insufficiency, liver dysfunction, hypertrophic cardiomyopathy, bone marrow suppression, humoral and cellular immune deficiency. To identify the genetic basis of this unusual clinical phenotype and potentially make available the option of future prenatal testing, whole exome sequencing (WES) was used followed by functional studies in a bid to confirm pathogenicity. The WES we identified a homozygous novel variant, AK298328; c.9_10insGAG; p.[Glu3dup], in NOX4 in the proband, and parental heterozygosity for the variant (confirmed by Sanger sequencing). NADPH Oxidase 4 NOX4 (OMIM 605261) encodes an enzyme that functions as the catalytic subunit of the NADPH oxidase complex. NOX4 acts as an oxygen sensor, catalysing the reduction of molecular oxygen, mainly to hydrogen peroxide (HO). However, although, our functional data including 60% reduction in NOX4 protein levels and a 75% reduction in the production of HO in patient fibroblast extracts compared to controls was initially considered to be the likely cause of the phenotype in our patient, the potential contribution of the NOX4 variant as the primary cause of the disease was clearly excluded based on following pieces of evidence. First, Sanger sequencing of other family members revealed that two of the grandparents were also homozygous for the NOX4 variant, one of who has fibromuscular dysplasia. Second, re-evaluation of more recent variant databases revealed a high allele frequency for this variant. Our case highlights the need to re-interrogate bioinformatics resources as they are constantly evolving, and is reminiscent of the short-chain acyl-CoA dehydrogenase deficiency (SCADD) story, where a functional defect in fatty acid oxidation has doubtful clinical ramifications.

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Chronic granulomatous disease: why an inflammatory disease?

Cited by 16 publications

References 46 publications

Neutrophil swarming delays the growth of clusters of pathogenic fungi

Neutrophil swarming delays the growth of clusters of pathogenic fungi

Neutrophils: Innate Effectors of TB Resistance?

Tread carefully: A functional variant in the human NADPH oxidase 4 ( NOX4 ) is not disease causing

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