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Blood, 1 June 2007, Vol. 109, No. 11, pp. 5036-5042.
Prepublished online as a Blood First Edition Paper on February 6, 2007; DOI 10.1182/blood-2006-10-052381.
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Submitted October 18, 2006
Accepted January 31, 2007
Highly homologous T-cell receptor beta sequences
support a common target for auto-reactive T cells in
most patients with paroxysmal nocturnal hemoglobinuria
Lucia Gargiulo, Sonia Lastraioli, Giannamaria Cerruti, Martina Serra, Fabrizio Loiacono, Simona Zupo, Lucio Luzzatto, and Rosario Notaro*
Laboratory of Human Genetics, Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy
Laboratory of Diagnostics of Lymphoproliferative Disorders, Istituto Nazionale per la Ricerca sul Cancro (IST), Genoa, Italy
Istituto Toscano Tumori (ITT), and Dept of Hematology, University of Florence, Florence, Italy
* Corresponding author; email: rosario.notaro{at}istge.it.
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 clone(s) expand by escaping negative selection exerted by auto-reactive T cells against normal (GPI+) hematopoiesis. By a systematic analysis of 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 one 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 non-peptide 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 non-peptide antigen(s) that could be the GPI anchor itself.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 non-peptide 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 non-peptide antigen(s) that could be the GPI anchor itself.
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