title: Survival, but not maturation, is affected in neutrophil progenitors from GSD-1b patients.
abstract: Glycogen storage disease type 1b (GSD 1b) is caused by mutations in the Glucose-6-phosphate transporter and is characterized by impaired glucose homeostasis. In addition, GSD-1b is associated with chronic neutropenia resulting in recurrent infections and inflammatory bowel disease. It is unclear whether the neutropenia is solely due to enhanced apoptosis of mature neutrophils or whether aberrant neutrophil development may also contribute. Here we demonstrate that hematopoietic progenitors from GSD-1b patients are not impaired in their capacity to develop into mature neutrophils. However, optimal survival of neutrophil progenitors from GSD-1b patients requires high glucose levels (> 200 mg dl(-1)), suggesting that even under normoglycemic conditions these cells are more prone to apoptosis. Furthermore, analysis of cytokine levels in peripheral blood suggests an inflammatory state with an inverse correlation between the level of inflammation and the number of neutrophils. Finally, in some patients, with low numbers of peripheral blood neutrophils, high numbers of neutrophils were observed in the intestine. Together, these results suggest that the neutropenia observed in GSD-1b patients is not caused by impaired maturation, but may be caused by both increased levels of apoptosis and egress of neutrophils from the blood to the inflamed tissues.
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Liesbeth P
authors.initials: LP
authors.lastname: Verhagen
authors.forename: G Peter A
authors.initials: GP
authors.lastname: Smit
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Berent J
authors.initials: BJ
authors.lastname: Prakken
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Miranda
authors.initials: M
authors.lastname: Buitenhuis
mesh_terms: D000293:Adolescent; D000818:Animals; D017920:Antiporters / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics; D009503:Neutropenia / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate
chemical_list: D017920:Antiporters; D016207:Cytokines; D009004:Monosaccharide Transport Proteins; C111261:glucose 6-phosphate(transporter); D005947:Glucose