TY - JOUR
T1 - Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis
AU - Elsheikh, Ayman
AU - Castrejon, Luis
AU - Lavergne, Sidonie N.
AU - Whitaker, Paul
AU - Monshi, Manal
AU - Callan, Hayley
AU - El-Ghaiesh, Sabah
AU - Farrell, John
AU - Pichler, Werner J.
AU - Peckham, Daniel
AU - Park, B. Kevin
AU - Naisbitt, Dean J.
N1 - Funding Information:
A.E. and S.E.-G. are PhD students supported by the Egyptian government . L.C. is a PhD student supported by the Mexican National Council for Science and Technology . M.M. is a PhD student supported by the Saudi Arabian government . This work was supported by a grant from the Wellcome Trust ( 078598/Z/05/Z ) as part of the Centre for Drug Safety Science supported by the Medical Research Council ( G0700654 ).
Funding Information:
Disclosure of potential conflict of interest: S. N. Lavergne and D. J. Naisbitt have received research support from the Wellcome Trust . B. K. Park has received research support from the Medical Research Council . The rest of the authors have declared that they have no conflict of interest.
PY - 2011/6
Y1 - 2011/6
N2 - 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. Conclusion: 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.
AB - 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. Conclusion: 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.
KW - Human
KW - T cells
KW - cystic fibrosis
KW - drug hypersensitivity
KW - drug metabolism
UR - http://www.scopus.com/inward/record.url?scp=79957834898&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2010.12.1119
DO - 10.1016/j.jaci.2010.12.1119
M3 - Artículo
SN - 0091-6749
VL - 127
SP - 1543-1551.e3
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -