title: Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients.
abstract: In paroxysmal nocturnal hemoglobinuria (PNH), clonal expansion of glycosylphosphatidylinositol-anchored proteins (GPI-AP)-deficient cells leads to a syndrome characterized by hemolytic anemia, marrow failure, and venous thrombosis. PNH is closely related to aplastic anemia and may share its immune pathophysiology. In vivo expansion of dominant T-cell clones can reflect an antigen-driven immune response but may also represent autonomous proliferation, such as in large granular lymphocytic (LGL)-leukemia. T-cell clonality can be assessed by a combination of T-cell receptor (TCR) flow cytometry and complementarity-determining-region-3 (CDR3) molecular analysis. We studied 24 PNH patients for evidence of in vivo dominant T-cell responses by flow cytometry; TCR-Vbeta-specific expansions were identified in all patients. In four cases, extreme expansions of one Vbeta-subset of CD8+/CD28-/CD56+ (effector) phenotype mimicked subclinical LGL-disease. The monoclonality of these expansions was inferred from unique CDR3-size peak distributions and sequencing of dominant clonotypes. We conclude that the molecular analysis of TCR-beta chain may demonstrate clonal LGL-like expansions at unexpected frequency in PNH patients. Our observations blur the classical boundaries between different bone marrow failure syndromes such as AA, PNH, and LGL, and support the hypothesis that in PNH, the mutant clone may expand as a result of an immune-escape from antigen-driven lymphocyte attack on hematopoietic progenitors.
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. amrisita@unina.it
authors.forename: A M
authors.initials: AM
authors.lastname: Risitano
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: P
authors.initials: P
authors.lastname: Muranski
authors.forename: M
authors.initials: M
authors.lastname: Wlodarski
authors.forename: C
authors.initials: C
authors.lastname: O'Keefe
authors.forename: E M
authors.initials: EM
authors.lastname: Sloand
authors.forename: N S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000595:Amino Acid Sequence; D001853:Bone Marrow / Q000473:pathology; D022801:Complementarity Determining Regions / Q000235:genetics; D017261:Glycosylphosphatidylinositols / Q000172:deficiency; D006801:Humans; D007945:Leukemia, Lymphoid / Q000209:etiology*; D008565:Membrane Proteins / Q000097:blood*; D010446:Peptide Fragments / Q000737:chemistry; D016133:Polymerase Chain Reaction / Q000379:methods; D013577:Syndrome; D013927:Thrombosis / Q000150:complications
chemical_list: D022801:Complementarity Determining Regions; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; D010446:Peptide Fragments; C080086:phosphatidylinositol glycan-class A protein