Interferon-γ Corrects the Respiratory Burst Defect In Vitro in Monocyte-Derived Macrophages from Glycogen Storage Disease Type 1b Patients

McCawley, Lisa J.; Korchak, Helen M.; Cutilli, Joann; Stanley, Charles A.; Baker, Lester; Douglas, Steven D.; Kilpatrick, Laurie E.

doi:10.1203/00006450-199309000-00005

Cited by 10 publications

(15 citation statements)

References 25 publications

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“…G-CSF therapy resulted in significant improvement in the levels of circulating neutrophils, which was coupled with clinical improvement with a decrease in both the rate of infection and the severity of illness. In addition to neutropenia, we previously documented depressed respiratory burst activity in neutrophils and monocytes from GSD lb patients (1 8,19,36). We next determined whether G-CSF also corrected the respiratory burst defect in GSD Ib phagocytic cells.…”

Section: Eflect Of G-csf Administration On Peripheral Blood Countsmentioning

confidence: 98%

In Vitro and In Vivo Effects of Granulocyte Colony-Stimulating Factor on Neutrophils in Glycogen Storage Disease Type IB: Granulocyte Colony-Stimulating Factor Therapy Corrects the Neutropenia and the Defects in Respiratory Burst Activity and Ca2+ Mobilization

et al. 1994

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Section: Eflect Of G-csf Administration On Peripheral Blood Countsmentioning

confidence: 98%

In Vitro and In Vivo Effects of Granulocyte Colony-Stimulating Factor on Neutrophils in Glycogen Storage Disease Type IB: Granulocyte Colony-Stimulating Factor Therapy Corrects the Neutropenia and the Defects in Respiratory Burst Activity and Ca2+ Mobilization

et al. 1994

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“…1,9,10 Moreover, monocyte/macrophage dysfunction has also been shown in patients deficient for G6PT (GSD-Ib). 12,13 Consistent with the functional codependence between G6Pase-␤ and G6PT, in G6Pase-␤ deficiency, there is also neutrophil dysfunction, but in the absence of the systemic metabolic abnormalities in GSD-Ib. 1,7,8 We have now investigated whether similar macrophage dysfunction occurs in G6pc3 Ϫ/Ϫ mice.…”

Section: Introductionmentioning

confidence: 84%

“…1 Patients with GSD-Ib, deficient in G6PT, not only manifest neutrophil dysfunction but also macrophage dysfunction. 12,13 Therefore, we hypothesized that G6pc3 Ϫ/Ϫ macrophages would also exhibit similar dysfunction and that disruption of ER cycling of G6P/glucose should lead to accumulation of G6P in the ER and prevent release of glucose back to the cytoplasm. This is then predicted to limit cytoplasmic glucose/G6P availability and to affect glycolysis and hexose monophosphate shunt, which in turn should impair additional blood glucose uptake ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Glucose-6-phosphatase-β, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality

Jun

Cheung

Lee

et al. 2012

Blood

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Glucose-6-phosphatase-␤ (G6Pase-␤ or G6PC3) deficiency, also known as severe congenital neutropenia syndrome 4, is characterized not only by neutropenia but also by impaired neutrophil energy homeostasis and functionality. We now show the syndrome is also associated with macrophage dysfunction, with murine G6pc3 ؊/؊ macrophages having impairments in their respiratory burst, chemotaxis, calcium flux, and phagocytic activities. Consistent with a glucose-6-phosphate (G6P) metabolism deficiency, G6pc3 ؊/؊ macrophages also have a lower glucose uptake and lower levels of G6P, lactate, and ATP than wild-type macrophages. Furthermore, the expression of NADPH oxidase subunits and membrane translocation of p47 phox are downregulated, and G6pc3 ؊/؊ macrophages exhibit repressed trafficking in vivo both during an inflammatory response and in pregnancy. During pregnancy, the absence of G6Pase-␤ activity also leads to impaired energy homeostasis in the uterus and reduced fertility of G6pc3 ؊/؊ mothers. Together these results show that immune deficiencies in this congenital neutropenia syndrome extend beyond neutrophil dysfunction. (Blood. 2012; 119(17):4047-4055) IntroductionGlucose-6-phosphatase-␤ (G6Pase-␤ or G6PC3) deficiency, 1-3 also known as severe congenital neutropenia syndrome type 4 (SCN4), 4 is an autosomal recessive disorder. The G6PC3 gene maps to human chromosome 17q21 and encodes the enzyme G6Pase-␤ that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. 5,6 Although a key clinical characteristic of the disease is neutropenia, it has a distinct phenotype of increased visibility of superficial veins, congenital heart defects, and urogenital malformations. [2][3][4] Recently, we have shown that, beyond the neutropenia, there is also a significant neutrophil dysfunction. 3,7,8 The neutrophil dysfunction arises from impairments in neutrophil G6P metabolism and energy homeostasis, which are directly related to the absence of G6Pase-␤ activity. 8 Between meals, when there is no external source of glucose, glucose homeostasis depends on the activity of a complex composed of 2 endoplasmic reticulum (ER) membrane proteins: glucose-6-phosphatase (G6Pase) and G6P transporter (G6PT). 1,9,10 There are 2 G6Pase activities, G6Pase-␣ and G6Pase-␤. Blood glucose homeostasis depends on the activity of a liver/kidney/intestine-restricted enzyme G6Pase-␣. 11 Mutation of this enzyme results in the metabolic disorder glycogen storage disease type Ia (GSD-Ia). 1,9 In the G6Pase-␣/G6PT complex, both proteins are functionally codependent. Therefore, mutation of G6PT also leads to a near-identical metabolic disorder, GSD-Ib. The primary difference between these 2 disorders is that in GSD-Ib there is an additional phenotype of neutrophil dysfunction. 1,9,10 This has been shown to arise as a result of the ubiquitous expression of G6PT interfering with the activity of the G6Pase-␤/G6PT complex. Indeed, G6Pase-␤ is also expressed ubiquitously, suggesting that, in tissues outside of the liver/kidney/intestine whe...

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“…We measured O 2 Ϫ generation as superoxide dismutase inhibitable cytochrome C reduction by a continuous recording spectrophotometer as described previously. 8,9,16 Patient cells were assayed in parallel with cells obtained from healthy volunteer donors. The mean activity of patient-derived cells was expressed as a percentage of the mean activity of healthy donor cells.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

“…[8][9][10]13,16 Neutrophils and monocytes were isolated from 11 of our patients at various times through the course of rhG-CSF therapy, and O 2 Ϫ generation was assessed in response to either PMA or fMLP stimulation. Of the 11 patients tested, only 2 (UPN 26 and UPN 33) did not demonstrate severe impairment of oxygen radical production prior to rhG-CSF therapy.…”

Section: Neutrophil Responsesmentioning

confidence: 99%

Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b

Calderwood

Kilpatrick

Douglas

et al. 2001

Blood

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The purpose of this study was to evaluate the efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease (GSD) type 1b. Thirteen patients with neutropenia and/or neutrophil dysfunction secondary to GSD type 1b were treated with rhG-CSF. The effects of therapy on neutrophil numbers and in vitro neutrophil function and on bone marrow cellularity and morphology were studied. The clinical status of the patients and the occurrence of adverse events associated with rhG-CSF use were monitored. Use of rhG-CSF therapy was associated with a significant increase in circulating neutrophil numbers (P < .01) and an improvement in neutrophil function as assessed in vitro. In addition, rhG-CSF therapy produced a significant increase in marrow cellularity and an increase in myeloid:erythroid (M:E) ratio, indicating stimulation of granulopoeisis. No adverse effects on marrow function were noted; in particular, no myelodysplasia or marrow exhaustion was seen. Use of rhG-CSF therapy was associated with objective and subjective improvements in infection-related morbidity. The therapy was well tolerated, although all patients developed splenomegaly, and 5 patients developed mild hypersplenism that did not require any specific treatment. rhG-CSF therapy is efficacious in the management of neutropenia and neutrophil dysfunction associated with GSD type 1b. Patients on this therapy need to be monitored for hypersplenism. Continued follow-up will be necessary to confirm long-term safety; however, no significant short-term toxicity was noted. (Blood. 2001;97:376-382)

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Interferon-γ Corrects the Respiratory Burst Defect In Vitro in Monocyte-Derived Macrophages from Glycogen Storage Disease Type 1b Patients

Cited by 10 publications

References 25 publications

In Vitro and In Vivo Effects of Granulocyte Colony-Stimulating Factor on Neutrophils in Glycogen Storage Disease Type IB: Granulocyte Colony-Stimulating Factor Therapy Corrects the Neutropenia and the Defects in Respiratory Burst Activity and Ca2+ Mobilization

In Vitro and In Vivo Effects of Granulocyte Colony-Stimulating Factor on Neutrophils in Glycogen Storage Disease Type IB: Granulocyte Colony-Stimulating Factor Therapy Corrects the Neutropenia and the Defects in Respiratory Burst Activity and Ca2+ Mobilization

Glucose-6-phosphatase-β, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality

Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b

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