Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome

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• 作者：Chun-Yu Wei ; MS^a ; ^b ; ^c ; Wen-Hung Chung ; MD ; PhD^d ; Hsiao-Wen Huang ; MS^b ; Yuan-Tsong Chen ; MD ; PhD^b ; ^{chen0010@ibms.sinica.edu.tw} ; Shuen-Iu Hung ; PhD^b ; ^e ; ^{sihung@ym.edu.tw}
• 关键词：Carbamazepine ; drug hypersensitivity ; HLA ; Stevens-Johnson syndrome ; toxic epidermal necrolysis
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 期刊代码：158_00916749
• 类别：med
• 出版时间：June, 2012
• 卷：129
• 期：6
• 页码：1562-1569.e5
• 文件大小：1313 K

摘要

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Background

Increasing studies have revealed that HLA alleles are the major genetic determinants of drug hypersensitivity; however, the underlying molecular mechanism remains unclear.

Objective

We adopted the HLA-B鈭?502 genetic predisposition to carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) as a model to study the pathologic role of HLA in delayed-type drug hypersensitivity.

Methods

We in聽vitro expanded CBZ-specific cytotoxic T lymphocytes (CTLs) from patients with CBZ-induced SJS/TEN and analyzed the interaction between HLA-B and CBZ analogs based on CTL response, surface plasmon resonance, peptide-binding assay, site-directed mutagenesis, and computer modeling.

Results

The endogenous peptide-loaded HLA-B鈭?502 molecule presented CBZ to CTLs without the involvement of intracellular drug metabolism or antigen processing. The HLA-B鈭?502/peptide/尾₂-microglobulin protein complex showed binding affinity toward chemicals sharing 5-carboxamide on the tricyclic ring, as with CBZ. However, modifications of the ring structure of CBZ altered HLA-B鈭?502 binding and CTL response. In addition to HLA-B鈭?502, other HLA-B75 family members could also present CBZ to activate CTLs, whereas members of the HLA-B62 and HLA-B72 families could not. Three residues (Asn63, Ile95, and Leu156) in the peptide-binding groove of HLA-B鈭?502 were involved in CBZ presentation and CTL activation. In particular, Asn63 shared by members of the B75 family was the key residue. Computer simulations revealed a preferred molecular conformation of the 5-carboxamide group of CBZ and the side chain of Arg62 on the B pocket of HLA-B鈭?502.

Conclusions

This study demonstrates a direct interaction of HLA with drugs, provides a detailed molecular mechanism of HLA-associated drug hypersensitivity, and has clinical correlations for CBZ-related drug-induced SJS/TEN.