title: GPI-defective monocytes from paroxysmal nocturnal hemoglobinuria patients show impaired in vitro dendritic cell differentiation.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, acquired hematopoietic disorder characterized by a phosphatidylinositol (PI) glycan-A gene mutation, which impairs the synthesis of the glycosyl-PI (GPI) anchor, thus causing the absence of all GPI-linked proteins on the membrane of the clonal-defective cells. The presence of a consistent GPI-defective monocyte compartment is a common feature in PNH patients. To investigate the functional behavior of this population, we analyzed its in vitro differentiation ability toward functional dendritic cells (DCs). Our data indicate that GPI-defective monocytes from PNH patients are unable to undergo full DC differentiation in vitro after granulocyte macrophage-colony stimulating factor and recombinant interleukin (IL)-4 treatment. In this context, the GPI-defective DC population shows mannose receptor expression, high levels of the CD86 molecule, and impaired CD1a up-regulation. The analysis of lipopolysaccharide and CD40-dependent, functional pathways in these DCs revealed a strong decrease in tumor necrosis factor alpha and IL-12 production. Finally, GPI-defective DCs showed a severe impairment in delivering accessory signals for T cell receptor-dependent T cell proliferation.
authors.affiliation: Cattera di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universitá Frederico II, Naples, Italy. giruggie@unina.it
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Ruggiero
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terrazzano
authors.forename: Cristina
authors.initials: C
authors.lastname: Becchimanzi
authors.forename: Michela
authors.initials: M
authors.lastname: Sica
authors.forename: Claudia
authors.initials: C
authors.lastname: Andretta
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Masci
authors.forename: Luigi
authors.initials: L
authors.lastname: Racioppi
authors.forename: Bruno
authors.initials: B
authors.lastname: Rotoli
authors.forename: Serafino
authors.initials: S
authors.lastname: Zappacosta
authors.forename: Fiorella
authors.initials: F
authors.lastname: Alfinito
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018949:Antigens, CD1 / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000172:deficiency* / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009154:Mutation / Q000235:genetics; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018949:Antigens, CD1; D051940:B7-2 Antigen; C419393:CD1a antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D017261:Glycosylphosphatidylinositols; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor