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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, CD1 / immunology
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Antigens, CD1 / metabolism
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B7-2 Antigen
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CD40 Antigens / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Division / immunology
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Female
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Glycosylphosphatidylinositols / deficiency*
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Glycosylphosphatidylinositols / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hemoglobinuria, Paroxysmal / blood*
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Hemoglobinuria, Paroxysmal / genetics
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Hemoglobinuria, Paroxysmal / immunology*
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Humans
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Interleukin-4 / pharmacology
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Lectins, C-Type / immunology
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Lectins, C-Type / metabolism
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Lipopolysaccharides / immunology
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Male
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Mannose Receptor
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Mannose-Binding Lectins / immunology
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Mannose-Binding Lectins / metabolism
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Monocytes / cytology
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Monocytes / immunology*
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Mutation / genetics
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Receptors, Cell Surface / immunology
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Receptors, Cell Surface / metabolism
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T-Lymphocytes / immunology
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
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Up-Regulation / immunology
Substances
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Antigens, CD
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Antigens, CD1
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B7-2 Antigen
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CD1a antigen
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CD40 Antigens
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CD86 protein, human
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Glycosylphosphatidylinositols
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Lectins, C-Type
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Lipopolysaccharides
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Mannose Receptor
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Mannose-Binding Lectins
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Membrane Glycoproteins
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Receptors, Cell Surface
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Interleukin-4
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Granulocyte-Macrophage Colony-Stimulating Factor