Accuri C6 Flow Cytometer System
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0105026

Received for publication January 17, 2005.
Revised February 25, 2005.
Accepted for publication March 9, 2005.

Article

T cells from paroxysmal nocturnal haemoglobinuria (PNH) patients show an altered CD40-dependent pathway

Giuseppe Terrazzano *, Michela Sica *, Cristina Becchimanzi {dagger}, Silvia Costantini {dagger}, Bruno Rotoli {dagger}, Serafino Zappacosta *, Fiorella Alfinito {dagger}, and Giuseppina Ruggiero *@

*Cattedra di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare, and {dagger}Cattedra di Ematologia, Dipartimento di Medicina Clinica e Sperimentale, Università di Napoli "Federico II," Naples, Italy

@ To whom correspondence should be addressed. E-mail: giruggie{at}unina.it.


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Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoieis disorder characterized by the expansion of a stem cell bearing a somatic mutation in the phosphatidylinositol glycan-A (PIG-A) gene, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. A number of data suggest the inability of the PIG-A mutation to account alone for the clonal dominance of the GPI-defective clone and for the development of PNH. In this context, additional immune-mediated mechanisms have been hypothesized. We focused on the analysis of T lymphocytes in three PNH patients bearing a mixed GPI+ and GPI- T cell population and showing a marked cytopenia. To analyze the biological mechanisms underlying the control of T cell homeostasis in PNH, we addressed the study of CD40-dependent pathways, suggested to be of crucial relevance for the control of autoreactive T cell clones. Our data revealed significant, functional alterations in GPI+ and GPI- T cell compartments. In the GPI- T cells, severe defects in T cell receptor-dependent proliferation, interferon-{gamma} production, CD25, CD54, and human leukocyte antigen-DR surface expression were observed. By contrast, GPI+ T lymphocytes showed a significant increase of all these parameters, and the analysis of CD40-dependent pathways revealed a functional persistence of CD154 expression on the CD48+CD4+ lymphocytes. The alterations of the GPI+ T cell subset could be involved in the biological mechanisms underlying PNH pathogenesis.

Key Words: GPI-defective clones • cytopenia • immune response