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

Publication ,  Journal Article
Wei, C-Y; Chung, W-H; Huang, H-W; Chen, Y-T; Hung, S-I
Published in: J Allergy Clin Immunol
June 2012

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∗1502 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 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∗1502 molecule presented CBZ to CTLs without the involvement of intracellular drug metabolism or antigen processing. The HLA-B∗1502/peptide/β(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∗1502 binding and CTL response. In addition to HLA-B∗1502, 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∗1502 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∗1502. 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.

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Published In

J Allergy Clin Immunol

DOI

EISSN

1097-6825

Publication Date

June 2012

Volume

129

Issue

6

Start / End Page

1562 / 9.e5

Location

United States

Related Subject Headings

  • Young Adult
  • T-Lymphocytes, Cytotoxic
  • T-Lymphocytes
  • Stevens-Johnson Syndrome
  • Protein Binding
  • Peptides
  • Models, Molecular
  • Middle Aged
  • Male
  • Lymphocyte Activation
 

Citation

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Wei, C.-Y., Chung, W.-H., Huang, H.-W., Chen, Y.-T., & Hung, S.-I. (2012). Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol, 129(6), 1562-9.e5. https://doi.org/10.1016/j.jaci.2011.12.990
Wei, Chun-Yu, Wen-Hung Chung, Hsiao-Wen Huang, Yuan-Tsong Chen, and Shuen-Iu Hung. “Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.J Allergy Clin Immunol 129, no. 6 (June 2012): 1562-9.e5. https://doi.org/10.1016/j.jaci.2011.12.990.
Wei C-Y, Chung W-H, Huang H-W, Chen Y-T, Hung S-I. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2012 Jun;129(6):1562-9.e5.
Wei, Chun-Yu, et al. “Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome.J Allergy Clin Immunol, vol. 129, no. 6, June 2012, pp. 1562-9.e5. Pubmed, doi:10.1016/j.jaci.2011.12.990.
Wei C-Y, Chung W-H, Huang H-W, Chen Y-T, Hung S-I. Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2012 Jun;129(6):1562–9.e5.
Journal cover image

Published In

J Allergy Clin Immunol

DOI

EISSN

1097-6825

Publication Date

June 2012

Volume

129

Issue

6

Start / End Page

1562 / 9.e5

Location

United States

Related Subject Headings

  • Young Adult
  • T-Lymphocytes, Cytotoxic
  • T-Lymphocytes
  • Stevens-Johnson Syndrome
  • Protein Binding
  • Peptides
  • Models, Molecular
  • Middle Aged
  • Male
  • Lymphocyte Activation