title: Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis.
abstract: BACKGROUND
  Exposure of patients with cystic fibrosis to sulfonamides is associated with a high incidence of hypersensitivity reactions.
  
  
  OBJECTIVE
  To compare mechanisms of antigen presentation and characterize the phenotype and function of T cells from sulfamethoxazole-hypersensitive patients with and without cystic fibrosis.
  
  
  METHODS
  T cells were cloned from 6 patients and characterized in terms of phenotype and function. Antigen specificity and mechanisms of antigen presentation to specific clones were then explored. Antigen-presenting cell metabolism of sulfamethoxazole was quantified by ELISA. The involvement of metabolism in antigen presentation was evaluated by using enzyme inhibitors.
  
  
  RESULTS
  Enzyme inhibitable sulfamethoxazole-derived protein adducts were detected in antigen-presenting cells from patients with and without cystic fibrosis. A significantly higher quantity of adducts were detected with cells from patients with cystic fibrosis. Over 500 CD4(+) or CD8(+) T-cell clones were generated and shown to proliferate and kill target cells. Three patterns of MHC-restricted reactivity (sulfamethoxazole-responsive, sulfamethoxazole metabolite-responsive, and cross-reactive) were observed with clones from patients without cystic fibrosis. From patients with cystic fibrosis, sulfamethoxazole metabolite-responsive and cross-reactive, but not sulfamethoxazole-responsive, clones were observed. The response of the cross-reactive clones to sulfamethoxazole was dependent on adduct formation and was blocked by glutathione and enzyme inhibitors. Antigen-stimulated clones from patients with cystic fibrosis secreted higher levels of IFN-γ, IL-6, and IL-10, but lower levels of IL-17.
  
  
  CONCLUSIONS
  Sulfamethoxazole metabolism and protein adduct formation is critical for the stimulation of T cells from patients with cystic fibrosis. T cells from patients with cystic fibrosis secrete high levels of IFN-γ, IL-6, and IL-10.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Ayman
authors.initials: A
authors.lastname: Elsheikh
authors.forename: Luis
authors.initials: L
authors.lastname: Castrejon
authors.forename: Sidonie N
authors.initials: SN
authors.lastname: Lavergne
authors.forename: Paul
authors.initials: P
authors.lastname: Whitaker
authors.forename: Manal
authors.initials: M
authors.lastname: Monshi
authors.forename: Hayley
authors.initials: H
authors.lastname: Callan
authors.forename: Sabah
authors.initials: S
authors.lastname: El-Ghaiesh
authors.forename: John
authors.initials: J
authors.lastname: Farrell
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.forename: Daniel
authors.initials: D
authors.lastname: Peckham
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Naisbitt
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000276:immunology* / Q000378:metabolism; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation; D002999:Clone Cells; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004342:Drug Hypersensitivity / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D013420:Sulfamethoxazole / Q000009:adverse effects* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D013420:Sulfamethoxazole