title: PNH cells are as sensitive to T-cell-mediated lysis as their normal counterparts: implications for the pathogenesis of paroxysmal nocturnal haemoglobinuria.
abstract: The mechanism responsible for the bone marrow failure that is almost invariable in paroxysmal nocturnal haemoglobinuria (PNH) is unknown. Based on the close association between PNH and idiopathic aplastic anaemia, a plausible pathogenetic model predicts that, in PNH, autoreactive T cells specific for haemopoietic stem cells (HSCs) cause depletion of normal HSCs, whereas PNH HSCs escape this T-cell-mediated attack. In this study, we addressed the hypothesis that PNH HSCs are resistant to the cytotoxic effect of T cells because they lack surface expression of one or more glycosylphosphatidylinositol (GPI)-linked molecules. We tested the sensitivity of normal and PNH Epstein-Barr virus (EBV)-transformed B-cell lymphoblastoid cell lines (BLCLs) to the cytotoxic effect of autologous EBV-specific T-cell lines and clones from a patient with PNH in an in vitro experimental system. We found that the PNH BLCLs were no less sensitive to T-cell-mediated cytotoxicity than non-PNH isogenic BLCLs, indicating that GPI-linked molecules on the surface of target cells are not required for killing by T cells. This suggests that the mechanism whereby PNH HSCs survive T-cell attack is not because of the lack of surface expression of one or more GPI-linked molecules. By implication, other mechanisms become more probable.
authors.affiliation: Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: A
authors.initials: A
authors.lastname: Karadimitris
authors.forename: R
authors.initials: R
authors.lastname: Notaro
authors.forename: G
authors.initials: G
authors.lastname: Koehne
authors.forename: I A
authors.initials: IA
authors.lastname: Roberts
authors.forename: L
authors.initials: L
authors.lastname: Luzzatto
mesh_terms: D018957:CD59 Antigens / Q000378:metabolism; D016923:Cell Death; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006457:Hemoglobinuria, Paroxysmal / Q000276:immunology*; D004854:Herpesvirus 4, Human; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018957:CD59 Antigens