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

Giuseppe Terrazzano, Michela Sica, Cristina Becchimanzi, Silvia Costantini, Bruno Rotoli, Serafino Zappacosta, Fiorella Alfinito, Giuseppina Ruggiero

Research output: Contribution to journalArticlepeer-review

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoiesis 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-γ 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-dependeiit 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.

Original languageEnglish
Pages (from-to)27-36
Number of pages10
JournalJournal of Leukocyte Biology
Volume78
Issue number1
DOIs
Publication statusPublished - Jul 2005

Keywords

  • Cytopenia
  • GPI-defective clones
  • Immune response

ASJC Scopus subject areas

  • Cell Biology

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