title: Modulation of lymphocyte proliferation by antioxidants in chronic beryllium disease.
abstract: BACKGROUND
  Occupational exposure to beryllium (Be) can result in chronic granulomatous inflammation characterized by the presence of Be-specific CD4+ T cells. Studies show that oxidative stress plays a role in the pathogenesis of chronic inflammatory disorders.
  
  
  OBJECTIVE
  We hypothesized that Be-induced oxidative stress modulates the proliferation of Be-specific CD4+ T cells.
  
  
  METHODS
  Thirty-three subjects with chronic beryllium disease (CBD), 15 subjects with beryllium sensitization, and 28 healthy normal control subjects were consecutively enrolled from the Occupational and Environmental Health Clinic of the National Jewish Medical and Research Center.
  
  
  RESULTS
  All studies were performed with Ficoll-Hypaque-isolated peripheral blood mononuclear cells from subsets of the study subjects. Decreased intracellular levels of the thiol antioxidants, glutathione and cysteine, were observed in peripheral blood mononuclear cells from subjects with beryllium sensitization and CBD, as compared with healthy control subjects. Beryllium stimulation decreased intracellular thiol antioxidants by more than 40%, accompanied by increased reactive oxygen species levels and the proliferation of Be-specific blood CD4+ T cells from subjects with CBD. Be-induced T-cell proliferation was inhibited by treatment with the thiol antioxidant N-acetylcysteine or the catalytic antioxidant manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP). MnTBAP treatment also inhibited T-cell proliferation in response to the unrelated, MHC class II-restricted antigen tetanus toxoid. Treatment of CBD blood lymphocytes, but not antigen-presenting cells, with MnTBAP decreased Be-induced T-cell proliferation by more than 40%.
  
  
  CONCLUSIONS
  Beryllium can mediate a thiol imbalance leading to oxidative stress that may modulate the proliferation and clonal expansion of Be-specific blood CD4+ T cells. These data suggest that Be-induced oxidative stress plays a role in the pathogenesis of granulomatous inflammation in CBD.
authors.affiliation: Department of Medicine, Robert H. Hollis Laboratory of Environmental and Occupational Health Sciences, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
authors.forename: Dave R
authors.initials: DR
authors.lastname: Dobis
authors.forename: Richard T
authors.initials: RT
authors.lastname: Sawyer
authors.forename: May M
authors.initials: MM
authors.lastname: Gillespie
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Lee S
authors.initials: LS
authors.lastname: Newman
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001607:Berylliosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002908:Chronic Disease; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species