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Resistance to Apoptosis in Circulating a/ß and g/d
T Lymphocytes from Patients with Systemic Sclerosis
PAOLA CIPRIANI, ANTONIETTA FULMINIS, ELISA PINGIOTTI, ALESSANDRA MARRELLI, VASILIKI LIAKOULI, ROBERTO PERRICONE, ALBERTO PIGNONE, MARCO MATUCCI-CERINIC, and ROBERTO GIACOMELLI ABSTRACT. Objective. T cell activation plays a pivotal role in the immunopathogenesis of systemic sclerosis (SSc). Lymphocyte processes are tightly controlled by molecules activating either proliferation or programmed cell death (apoptosis). We investigated whether an imbalance in apoptotic function, increasing the survival rate of autoreactive cells, may lead to persistent autoreactive phenomena. Methods. We studied peripheral a/b and g/d T lymphocytes of 22 patients with SSc and 22 healthy controls for their spontaneous and stimulated (phytohemagglutinin, dexamethasone) apoptotic rate and surface phenotype including expression of Fas (CD95) and Bcl-2, determined by flow cytometry. sFas and sFas ligand in sera and supernatants were measured by ELISA. Caspase-3 activation in response to agonistic anti-Fas Mab treatment was assessed. Results. Lymphocytes of SSc patients showed a significant decrease in the percentage of apoptotic cells over time, in both unstimulated and stimulated cultures, compared to controls. We observed no difference between patients and controls, in stimulated or unstimulated cells, in the phenotypic expression of apoptotic cells, including surface Fas. SSc T cells were less susceptible to undergoing apoptosis after anti-Fas stimulation. We observed a significant decrease of apoptotic cells from stimulated culture of isolated SSc g/d T cells. Serum levels of sFas in SSc patients were significantly higher compared to controls. Similar data were obtained in the supernatants of stimulated and unstimulated cultures. By contrast, sFas ligand was always reduced. Bcl-2 expression in SSc was significantly elevated. A significant decrease in caspase-3 activity was detected in SSc patients after treatment by agonistic anti-Fas antibody. Conclusion. Resistance to apoptosis is present in a/b and g/d T cell lymphocyte subsets of patients with SSc, and several pathways seem to be connected in this setting. (J Rheumatol 2006;33:2003-14) Key Indexing Terms:
SYSTEMIC SCLEROSIS From the Department of Internal Medicine, University of L'Aquila, School of Medicine, Rheumatology Unit, University of Rome "Tor Vergata" School of Medicine, Rome; and Department of Rheumatology, University of Florence School of Medicine, Florence, Italy. Supported by PRIN 2004-06 from MIUR. P. Cipriani, MD, PhD; A. Fulminis, MD, PhD; E. Pingiotti, MD; A. Marrelli, MD; V. Liakouli, MD, Department of Internal Medicine, University of L'Aquila, School of Medicine; R. Perricone, MD, PhD, Associate Professor, Rheumatology Unit, University of Rome "Tor Vergata," School of Medicine; A. Pignone, MD, PhD, Associate Professor; M. Matucci Cerinic, MD, PhD, Full Professor of Rheumatology, University of Florence, School of Medicine; R. Giacomelli, MD, PhD, Full Professor of Internal Medicine, University of L'Aquila, School of Medicine. Address reprint requests to Prof. R. Giacomelli, Department of Internal Medicine and Public Health, University of L'Aquila – School of Medicine, via Vetoio 67100, L'Aquila, Italy. E-mail: roberto.giacomelli@cc.univaq.it Accepted for publication May 12, 2006.
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