HLA-B1502-bound peptides : Implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome

• Published in: Journal of allergy and clinical immunology 2007-10, Vol.120 (4), p.870-877
• Main Authors: YANG, Chih-Wen Ou, HUNG, Shuen-Lu, JUO, Chiun-Gung, LIN, Ya-Ping, FANG, Wu-Hsiang, LU, I.-Hsuan, CHEN, Shui-Tein, CHEN, Yuan-Tsong
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Carbamazepine - adverse effects; Fundamental and applied biological sciences. Psychology; Fundamental immunology; HLA-B Antigens - metabolism; Humans; Immunopathology; Mass Spectrometry; Medical sciences; Peptides - analysis; Peptides - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Stevens-Johnson Syndrome - chemically induced
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2007.06.017

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can involve MHC-restricted presentation of a drug or its metabolites for T-cell activation. HLA-B(*)1502 tightly associated with carbamazepine (CBZ) induced these conditions in a Han Chinese population. We sought to identify HLA-B(*)1502-bound peptides that might be involved in CBZ-induced SJS/TEN. Soluble HLA-B(*)1502 was used to identify bound peptides in the presence and absence of CBZ by using liquid chromatography-tandem mass spectrometry. Peptide-binding assays were performed to detect the specific interaction between the HLA molecule and the identified peptides. Mass spectra were compared to detect CBZ-modified peptides. We identified more than 145 peptides bound to HLA-B(*)1502. In 13 of 15 peptides examined, we functionally confirmed their specificity with binding assays. Preferable uses of these peptides at the anchoring residues P2 and P9 were similar to those observed in other HLA-B alleles in the Han Chinese population. However, the preferable use of serine residues at the nonanchoring position (P) 5, P6, P7, and P8 appeared to be unique for the B(*)1502 peptides. No specific CBZ-modified peptides were detected when we compared the mass spectra of peptides detected in the presence or absence of the drug. Noncovalent interaction between a drug and an HLA complex might contribute to cytotoxic T cell-mediated cell death in patients with SJS/TEN. An understanding of pharmacologic interaction of drugs with an HLA complex might lead to safer drugs that avoid SJS/TEN.