title: T cells from paroxysmal nocturnal haemoglobinuria (PNH) patients show an altered CD40-dependent pathway.
abstract: Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoiesis disorder characterized by the expansion of a stem cell bearing a somatic mutation in the phosphatidylinositol glycan-A (PIG-A) gene, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. A number of data suggest the inability of the PIG-A mutation to account alone for the clonal dominance of the GPI-defective clone and for the development of PNH. In this context, additional immune-mediated mechanisms have been hypothesized. We focused on the analysis of T lymphocytes in three PNH patients bearing a mixed GPI(+) and GPI(-) T cell population and showing a marked cytopenia. To analyze the biological mechanisms underlying the control of T cell homeostasis in PNH, we addressed the study of CD40-dependent pathways, suggested to be of crucial relevance for the control of autoreactive T cell clones. Our data revealed significant, functional alterations in GPI(+) and GPI(-) T cell compartments. In the GPI(-) T cells, severe defects in T cell receptor-dependent proliferation, interferon-gamma production, CD25, CD54, and human leukocyte antigen-DR surface expression were observed. By contrast, GPI(+) T lymphocytes showed a significant increase of all these parameters, and the analysis of CD40-dependent pathways revealed a functional persistence of CD154 expression on the CD48(+)CD4(+) lymphocytes. The alterations of the GPI(+) T cell subset could be involved in the biological mechanisms underlying PNH pathogenesis.
authors.affiliation: Cattedra de Immunologia, Dipartimento de Biologia e Pathologia Cellulare e Molecolare, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Terrazzano
authors.forename: Michela
authors.initials: M
authors.lastname: Sica
authors.forename: Cristina
authors.initials: C
authors.lastname: Becchimanzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Costantini
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
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Ruggiero
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D000071178:CD48 Antigen; D049109:Cell Proliferation; D005260:Female; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D008565:Membrane Proteins; D015375:Receptors, Interleukin-2; C080086:phosphatidylinositol glycan-class A protein; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D007371:Interferon-gamma