Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome

• Published in: Journal of allergy and clinical immunology Vol. 128; no. 6; pp. 1266 - 1276.e11
• Main Authors: Ko, Tai-Ming, Chung, Wen-Hung, Wei, Chun-Yu, Shih, Han-Yu, Chen, Jung-Kuei, Lin, Chia-Hsien, Chen, Yuan-Tsong, Hung, Shuen-Iu
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.12.2011; Elsevier; Elsevier Limited
• Subjects: Adult; Allergy and Immunology; antibodies; Anticonvulsants - adverse effects; antigen-presenting cells; Biological and medical sciences; biomarkers; Biomarkers - analysis; Bullous diseases of the skin; Carbamazepine - adverse effects; Carbamazepine - immunology; CD8-positive T-lymphocytes; Cell Separation; Cells, Cultured; Cloning; Complementarity Determining Regions - genetics; Complementarity Determining Regions - immunology; Cytotoxicity; Dermatology; Drug hypersensitivity; Drug Hypersensitivity - genetics; Drug Hypersensitivity - immunology; drugs; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Predisposition to Disease - genetics; HLA; HLA Antigens - genetics; HLA Antigens - immunology; Humans; immune response; Immune system; Immunopathology; Lymphocytes; Male; Medical sciences; Patients; polymerase chain reaction; Real-Time Polymerase Chain Reaction; receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Stevens-Johnson syndrome; Stevens-Johnson Syndrome - chemically induced; Stevens-Johnson Syndrome - genetics; Stevens-Johnson Syndrome - immunology; T cell receptors; T-cell receptor; T-Lymphocytes - drug effects; third complementarity-determining region; toxic epidermal necrolysis; Stevens-Johnson syndrome; TCR; HSS; VA; VB; toxic epidermal necrolysis; T-cell receptor; third complementarity-determining region; 51Cr; GBP; CBZ; CTL; OXC; Drug hypersensitivity; HLA; TEN; B-LCL; CDR3; SJS; CA; CB; Gabapentin; α-Chain constant region; Hypersensitivity syndrome; B-lymphoblastoid cell lines; Oxcarbazepine; β-Chain constant region; α-Chain variable region; Cytotoxic T lymphocyte; Chromium 51; β-Chain variable region; Carbamazepine; Bullous dermatosis; HLA-System; Skin disease; Erythroderma; Major histocompatibility system; Immunology; T-Lymphocyte; Class I histocompatibility antigen; Drug; Immunopathology; T cell receptor; Stomatology; Hypersensitivity; Use; Tricyclic compound; Eye disease; Carboxamide; Dibenzazepine derivatives; Lyell syndrome
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2011.08.013

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. 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. 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. 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. 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.