title: Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells.
abstract: To probe the pathophysiologic mechanisms underlying neutropenia in patients with chronic idiopathic neutropenia (CIN) with hypoplastic and left-shifted granulocytic series in the bone marrow (BM), we have studied granulocytopoiesis in 32 adults with CIN by evaluating the number and survival characteristics of cells in several stages of granulocyte differentiation using flow cytometry and BM culture assays. We found that patients with CIN displayed a low percentage of CD34(+)/CD33(+) cells, defective granulocyte colony-forming unit (CFU-G) growth potential of BM mononuclear or purified CD34(+) cells, and low CFU-G recovery in long-term BM cultures (LTBMCs), compared with controls (n = 46). A low percentage of CD34(+)/CD33(+) cells in patients was associated with accelerated apoptosis and Fas overexpression within this cell compartment compared with controls. No significant difference was documented in the percentage of apoptotic cells or the Fas(+) cells within the fractionated CD34(+)/CD33(-), CD34(-)/CD33(+), and CD34(-)/CD33(-)/CD15(+) BM subpopulations or the peripheral blood neutrophils, suggesting that the underlying cellular defect in CIN probably concerns the committed granulocyte progenitors. LTBMC stromal layers from patients produced abnormally high amounts of tumor necrosis factor alpha and cytokine levels in culture supernatants inversely correlated with the number of myeloid progenitor cells and positively with the proportion of apoptotic CD34(+) cells. Patient LTBMC stromal layers displayed pathologic interferon gamma and Fas-ligand mRNA expression and failed to support normal myelopoiesis. These data suggest that impaired granulocytopoiesis in CIN is probably due to overproduction of inflammatory cytokines by immune cells within the BM microenvironment that may exert an inhibitory effect on myelopoiesis by inducing Fas-mediated apoptosis in the granulocyte progenitors.
authors.affiliation: Department of Hematology of the University of Crete School of Medicine and Institute of Molecular Biology and Biotechnology, Heraklion, Crete, Greece. epapadak@med.uoc.gr
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kosteas
authors.forename: Claudia
authors.initials: C
authors.lastname: Gemetzi
authors.forename: Athina
authors.initials: A
authors.lastname: Damianaki
authors.forename: Helen
authors.initials: H
authors.lastname: Koutala
authors.forename: Juergen
authors.initials: J
authors.lastname: Bux
authors.forename: George D
authors.initials: GD
authors.lastname: Eliopoulos
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000473:pathology; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D006098:Granulocytes / Q000473:pathology*; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D023461:Myeloid Progenitor Cells / Q000473:pathology*; D038042:Myelopoiesis; D009503:Neutropenia / Q000209:etiology / Q000473:pathology*; D017154:Stromal Cells / Q000166:cytology
chemical_list: D016207:Cytokines