title: Highly homologous T-cell receptor beta sequences support a common target for autoreactive T cells in most patients with paroxysmal nocturnal hemoglobinuria.
abstract: Deficiency of glycosylphosphatidylinositol (GPI)-anchored molecules on blood cells accounts for most features of paroxysmal nocturnal hemoglobinuria (PNH) but not for the expansion of PNH (GPI(-)) clone(s). A plausible model is that PNH clones expand by escaping negative selection exerted by autoreactive T cells against normal (GPI(+)) hematopoiesis. By a systematic analysis of T-cell receptor beta (TCR-beta) clonotypes of the CD8+ CD57+ T-cell population, frequently deranged in PNH, we show recurrent clonotypes in PNH patients but not in healthy controls: 11 of 16 patients shared at least 1 of 5 clonotypes, and a set of closely related clonotypes was present in 9 patients. The presence of T-cell clones bearing a set of highly homologous TCR-beta molecules in most patients with hemolytic PNH is consistent with an immune process driven by the same (or similar) antigen(s)-probably a nonpeptide antigen, because patients sharing clonotypes do not all share identical HLA alleles. These data confirm that CD8+ CD57+ T cells play a role in PNH pathogenesis and provide strong new support to the hypothesis that the expansion of the GPI(-) blood cell population in PNH is due to selective damage to normal hematopoiesis mediated by an autoimmune attack against a nonpeptide antigen(s) that could be the GPI anchor itself.
authors.affiliation: Laboratory of Human Genetics, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gargiulo
authors.forename: Sonia
authors.initials: S
authors.lastname: Lastraioli
authors.forename: Giannamaria
authors.initials: G
authors.lastname: Cerruti
authors.forename: Martina
authors.initials: M
authors.lastname: Serra
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loiacono
authors.forename: Simona
authors.initials: S
authors.lastname: Zupo
authors.forename: Lucio
authors.initials: L
authors.lastname: Luzzatto
authors.forename: Rosario
authors.initials: R
authors.lastname: Notaro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000276:immunology; D018959:CD57 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D005260:Female; D017261:Glycosylphosphatidylinositols / Q000737:chemistry; D006680:HLA Antigens / Q000737:chemistry; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D018959:CD57 Antigens; D017261:Glycosylphosphatidylinositols; D006680:HLA Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta