Resistance to apoptosis in circulating alpha/beta and gamma/delta T lymphocytes from patients with systemic sclerosis.
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.


CONCLUSIONS
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.
Cipriani
Paola
P
Department of Internal Medicine, University of L'Aquila, School of Medicine, Rheumatology Unit, University of Rome Tor Vergata School of Medicine, Rome, Italy.
Fulminis
Antonietta
A
Pingiotti
Elisa
E
Marrelli
Alessandra
A
Liakouli
Vasiliki
V
Perricone
Roberto
R
Pignone
Alberto
A
Matucci-Cerinic
Marco
M
Giacomelli
Roberto
R
D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism* / Q000473:pathology*; D019014:fas Receptor / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D053222:Fas Ligand Protein; D008934:Mitogens; D010835:Phytohemagglutinins; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D019014:fas Receptor; D003907:Dexamethasone; D053148:Caspase 3