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

• DOI: 10.1189/jlb.0105026
• Publication Date: 2005-04-08T00:33:52Z
• Authors: Giuseppe Terrazzano; Michela Sica; Cristina Becchimanzi; Silvia Costantini; Bruno Rotoli; Serafino Zappacosta; Fiorella Alfinito; Giuseppina Ruggiero
• Keywords: Adult; CD4-Positive T-Lymphocytes; Male; T-Lymphocytes; CD40 Ligand; Hemoglobinuria, Paroxysmal; Membrane Proteins; Receptors, Interleukin-2; CD48 Antigen; Intercellular Adhesion Molecule-1; Interferon-gamma; 03 medical and health sciences; 0302 clinical medicine; Antigens, CD; Lymphopenia; Mutation; Humans; Female; CD40 Antigens; Cell Proliferation; Signal Transduction

AbstractParoxysmal 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-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.