title: Resistance to apoptosis in circulating alpha/beta and gamma/delta T lymphocytes from patients with systemic sclerosis.
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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, University of L'Aquila, School of Medicine, Rheumatology Unit, University of Rome Tor Vergata School of Medicine, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cipriani
authors.forename: Antonietta
authors.initials: A
authors.lastname: Fulminis
authors.forename: Elisa
authors.initials: E
authors.lastname: Pingiotti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marrelli
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Liakouli
authors.forename: Roberto
authors.initials: R
authors.lastname: Perricone
authors.forename: Alberto
authors.initials: A
authors.lastname: Pignone
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.forename: Roberto
authors.initials: R
authors.lastname: Giacomelli
mesh_terms: 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
chemical_list: 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