title: Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.
abstract: BACKGROUND
  Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), are life-threatening drug hypersensitivities with robust immune responses to drugs. Despite the strong HLA predisposition to drug hypersensitivities, such as HLA-B∗1502 to carbamazepine (CBZ)-induced SJS/TEN, it remains unknown whether particular T-cell receptors (TCRs) participate in recognition of small drug/peptide-HLA complexes.
  
  
  OBJECTIVE
  Using the strong HLA predisposition in patients with CBZ-induced SJS/TEN as a model, we aimed to study the use of TCR repertoire in patients with drug hypersensitivity.
  
  
  METHODS
  We enrolled patients with CBZ-SJS/TEN, tolerant control subjects, and healthy subjects who had no history of CBZ exposure. We isolated PBMCs from the subjects, cultured CBZ-specific T cells, and globally investigated the expression level and third complementarity-determining region length distribution of the TCR profile. We further assessed the pathogenic role of the disease-specific clonotype using real-time PCR-based tests and functional analysis.
  
  
  RESULTS
  On drug stimulation, CBZ-specific CD8(+) T cells were expanded in vitro and activated to release granulysin. Notably, VB-11-ISGSY was identified as the most predominant clonotype and shared among different subjects. This clonotype was present in 16 (84%) of 19 patients with SJS/TEN, absent in all 17 tolerant patients, and present at a low frequency in healthy subjects (4/29 [14%]). CBZ-specific cytotoxicity could be primed in vitro in the PBMCs of healthy subjects who are carriers of HLA-B∗1502 and VB-11-ISGSY; this cytotoxicity could be blocked by an anti-TCR-VB-11 antibody. Furthermore, a single T-cell clone expressing VA-22-FISGTY/VB-11-ISGSY showed significant cytotoxicity against HLA-B∗1502-positive antigen-presenting cells and CBZ.
  
  
  CONCLUSIONS
  This study establishes the key role of the TCR in the pathogenic mechanism of SJS/TEN, explains why some HLA-B∗1502 carriers are tolerant to CBZ, and provides a biomarker profile for drug hypersensitivity.
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Tai-Ming
authors.initials: TM
authors.lastname: Ko
authors.forename: Wen-Hung
authors.initials: WH
authors.lastname: Chung
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Wei
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Shih
authors.forename: Jung-Kuei
authors.initials: JK
authors.lastname: Chen
authors.forename: Chia-Hsien
authors.initials: CH
authors.lastname: Lin
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D002220:Carbamazepine / Q000009:adverse effects* / Q000276:immunology; D002469:Cell Separation; D002478:Cells, Cultured; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000927:Anticonvulsants; D015415:Biomarkers; D022801:Complementarity Determining Regions; D006680:HLA Antigens; D011948:Receptors, Antigen, T-Cell; D002220:Carbamazepine