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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2399-2408.
Prepublished online as a Blood First Edition Paper on June 14, 2005; DOI 10.1182/blood-2004-11-4315.
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IMMUNOBIOLOGY
Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors
Alessandro Poggi,
Simone Negrini,
Maria Raffaella Zocchi,
Anna-Maria Massaro,
Lucia Garbarino,
Sonia Lastraioli,
Lucia Gargiulo,
Lucio Luzzatto, and
Rosario Notaro
From the Laboratory of Experimental Oncology and the Laboratory of Human Genetics, National Institute for Cancer Research, the Laboratory of Clinical Immunology, Department of Internal Medicine, University of Genoa, and the Laboratory of Hystocompatibility/IBMDR, Galliera Hospital, Genoa, Italy; and the Laboratory of Tumor Immunology, San Raffaele Scientific Institute, Milan, Italy.
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a large clonal population of blood cells deriving from hematopoietic stem cells (HSCs) deficient in glycosylphosphatidylinositol (GPI)-anchored surface molecules. A current model postulates that PNH arises through negative selection against normal HSCs exerted by autoreactive T cells, whereas PNH HSCs escape damage. We have investigated the inhibitory receptor superfamily (IRS) system in 13 patients with PNH. We found a slight increase in the proportion of T cells expressing IRS. In contrast to what applies to healthy donors, the engagement of IRS molecules on T cells from patients with PNH elicited a powerful cytolytic activity in a redirected killing assay, indicating that these IRSs belong to the activating type. This was confirmed by clonal analysis: 50% of IRS+ T-cell clones in patients with PNH were of the activating type, while only 5% were of the activating type in healthy donors. Moreover, the ligation of IRS induces (1) production of tumor necrosis factor  (TNF-) and interferon  (IFN-) and (2) brisk cytolytic activity against cells bearing appropriate IRS counter-ligands. In addition, these IRS+ T cells show natural killer (NK)-like cytolytic activity to which GPI- cells were less sensitive than GPI+ cells. Thus, T cells with NK-like features, expressing the activating isoforms of IRS, may include effector cells involved in the pathogenesis of PNH.
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