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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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Submitted November 12, 2004
Accepted May 30, 2005
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 R Zocchi, Anna-Maria Massaro, Lucia Garbarino, Sonia Lastraioli, Lucia Gargiulo, Lucio Luzzatto, and Rosario Notaro
Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy
Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy; Laboratory of Clinical Immunology, Department of Internal Medicine, University of Genoa, Genoa, Italy
Laboratory of Tumor Immunology, San Raffaele Scientific Institute, Milan, Italy
Laboratory of Immunology, National Institute for Cancer Research, Genoa, Italy; Laboratory of Tumor Immunology, San Raffaele Scientific Institute, Milan, Italy
Laboratory of Hystocompatibility /IBMDR, Galliera Hospital, Genoa, Italy
Laboratory of Human Genetics, National Institute for Cancer Research, Genoa, Italy
University of Genoa, Genoa, Italy
* Corresponding author; email: alessandro.poggi{at}istge.it.
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a large clonal population of blood cells deriving from hematopoietic stem cells (HSC) 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 PNH patients. 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 PNH patients elicited a powerful cytolytic activity in a re-directed killing assay, indicating that these IRS belong to the activating type. This was confirmed by clonal analysis: activating IRS+ T cell clones are >50% in PNH patients but < 5% in healthy donors. Moreover, the ligation of IRS induces (a) production of TNF and IFN and (b) brisk cytolytic activity against cells bearing appropriate IRS counter-ligands. In addition, these IRS+ T cells show 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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