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HLA class I-drug-T-cell receptor interactions in SJS/TEN


Carbamazepine (CBZ) is associated with the severe cutaneous drug reaction Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN). CBZ-SJS/TEN has been associated with HLA-B*15:02 carriage and specific T-cell clonotypes. We aimed to characterize the interactions between specific T-cell receptor (TCR) clonotypes, HLA-B*15:02 and CBZ.


Peripheral blood mononuclear cells (PBMCs) were isolated from patients with CBZ-SJS/TEN and healthy controls, stimulated with 10ug/mL CBZ (Sigma, cat. no. C4024-5G) and cultured over a 9-14 day period. RNA was isolated at various time points and TCR V subtypes were assessed using digital droplet PCR (Bio-Rad QX100 droplet digital PCR system). Drug specific T-cell INF and granulysin responses were assessed by ELISpot and ICS. In silico modelling was used to examine the interaction between the known specific TCR V and V chains, CBZ and HLA-B*15:02.


CBZ specific T-cell INF and granulysin responses were detected many years following the original SJS/TEN reaction. Expansion of specific TCR CDR3 sequences was confirmed in CBZ SJS/TEN patient cultures. In silico modelling of the CBZ-HLA-B*15:02-TCR interaction suggests that CBZ binds non-covalently in the P4 binding pocket of the HLA-B*15:02 antigen binding cleft in a site that is typically occupied with bound peptide.


These findings raise two non-mutually exclusive possibilities: 1) CBZ may block peptide binding and be presented by HLA-B*15:02 in a solvent exposed manner available for direct recognition by the TCR, 2) CBZ binding the central portion of the HLA-B*15:02 antigen binding cleft may permit long peptides to bind conventionally at the peptide termini (in the A and F pockets) and bulge over the drug in the central residues to permit indirect recognition of CBZ (peptide mediated TCR contact).

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Rive, C., Pavlos, R., Ostrov, D. et al. HLA class I-drug-T-cell receptor interactions in SJS/TEN. Clin Transl Allergy 4 (Suppl 3), P2 (2014).

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