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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Yang, C-WO; Hung, S-I; Juo, C-G; Lin, Y-P; Fang, W-H; Lu, I-H; Chen, S-T; Chen, Y-T

Published Date

  • October 2007

Published In

Volume / Issue

  • 120 / 4

Start / End Page

  • 870 - 877

PubMed ID

  • 17697703

Pubmed Central ID

  • 17697703

International Standard Serial Number (ISSN)

  • 0091-6749

Digital Object Identifier (DOI)

  • 10.1016/j.jaci.2007.06.017

Language

  • eng

Conference Location

  • United States