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.


CONCLUSIONS
Noncovalent interaction between a drug and an HLA complex might contribute to cytotoxic T cell-mediated cell death in patients with SJS/TEN.


CONCLUSIONS
An understanding of pharmacologic interaction of drugs with an HLA complex might lead to safer drugs that avoid SJS/TEN.
Yang
Chih-Wen Ou
CW
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Hung
Shuen-Iu
SI
Juo
Chiun-Gung
CG
Lin
Ya-Ping
YP
Fang
Wu-Hsiang
WH
Lu
I-Hsuan
IH
Chen
Shui-Tein
ST
Chen
Yuan-Tsong
YT
D002220:Carbamazepine / Q000009:adverse effects*; D015235:HLA-B Antigens / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D010455:Peptides / Q000032:analysis / Q000378:metabolism*; D013262:Stevens-Johnson Syndrome / Q000139:chemically induced*
D015235:HLA-B Antigens; D010455:Peptides; D002220:Carbamazepine