HLA-B*1502-bound peptides: Implications for the pathogenesis of carbamazepine-induced Stevens-Johnson syndrome

Background: 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. Objective: We sought to identify HLA-B*1502-bound peptides that might be involved in CBZ-induced SJS/TEN. Methods: 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. Results: 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. Conclusion: Noncovalent interaction between a drug and an HLA complex might contribute to cytotoxic T cell-mediated cell death in patients with SJS/TEN. Clinical implications: An understanding of pharmacologic interaction of drugs with an HLA complex might lead to safer drugs that avoid SJS/TEN.