title: G-CSF treatment of severe congenital neutropenia reverses neutropenia but does not correct the underlying functional deficiency of the neutrophil in defending against microorganisms.
abstract: The treatment of children affected by severe congenital neutropenia (SCN) with G-CSF strongly reduces the risk of sepsis by reversing neutropenia. However, SCN patients who respond to the treatment with the growth factor still have an elevated risk of succumbing to sepsis. Because the disease is usually caused by heterozygous mutations of ELA2, a gene encoding for neutrophil elastase (NE), we have investigated in G-CSF-responder and nonresponder patients affected by SCN the expression of polypeptides that constitute the antimicrobial machinery of these cells. In peripheral blood-derived neutrophils of patients with heterozygous mutations of ELA2 who were treated with G-CSF, NE was nearly absent as detected by immunofluorescence and immunoblotting, suggesting that production of the mutant protein interferes with normal gene expression. This defect was associated with abnormal expression of other granule-associated proteins such as myeloperoxidase, lactoferrin, cathepsin G, and human-neutrophil-peptide. Moreover, in one patient with partial response to G-CSF, we observed an impairment of neutrophil antimicrobial activity against Candida albicans, and, to a lower extent against Escherichia coli. Thereby, we propose that the treatment with G-CSF is not sufficient to correct all of the functional deficiency of neutrophils, and this might account for the consistent risk of infections observed in SCN patients.
authors.affiliation: Department of Pathology, Section of General Pathology, University of Verona, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Donini
authors.forename: Stefania
authors.initials: S
authors.lastname: Fontana
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Savoldi
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Laura
authors.initials: L
authors.lastname: Tassone
authors.forename: Francesca
authors.initials: F
authors.lastname: Gentili
authors.forename: Elena
authors.initials: E
authors.lastname: Zenaro
authors.forename: Daniela
authors.initials: D
authors.lastname: Ferrari
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Fulvio
authors.initials: F
authors.lastname: Porta
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Stefano
authors.initials: S
authors.lastname: Dusi
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D002176:Candida albicans / Q000378:metabolism; D056649:Cathepsin G; D002403:Cathepsins / Q000096:biosynthesis; D004926:Escherichia coli / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007781:Lactoferrin / Q000096:biosynthesis; D019272:Leukocyte Elastase / Q000235:genetics*; D009154:Mutation; D009503:Neutropenia / Q000151:congenital* / Q000188:drug therapy*; D009504:Neutrophils / Q000378:metabolism* / Q000382:microbiology*; D010455:Peptides / Q000737:chemistry; D009195:Peroxidase / Q000096:biosynthesis; D018805:Sepsis / Q000517:prevention & control*; D012697:Serine Endopeptidases / Q000096:biosynthesis
chemical_list: D010455:Peptides; D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase; D002403:Cathepsins; D007781:Lactoferrin; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase