Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome Chun-Yu Wei, MS, Wen-Hung Chung, MD, PhD,

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Presentation transcript:

Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome Chun-Yu Wei, MS, Wen-Hung Chung, MD, PhD, Hsiao-Wen Huang, MS, Yuan-Tsong Chen, MD, PhD, Shuen-Iu Hung, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 6, Pages 1562-1569.e5 (June 2012) DOI: 10.1016/j.jaci.2011.12.990 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 HLA-B∗1502–dependent activation of CBZ-specific CTLs in patients with CBZ-induced SJS/TEN. A and B, In vitro–expanded CTL TCLs displayed specific lysis against autologous B-LCLs in a CBZ concentration– and effector cells/target cells ratio–dependent manner. C, CBZ-specific CTL TCLs induced B-LCL cell death, as measured by means of annexin-V labeling in flow cytometry. HLA-B genotypes of B-LCLs are shown on the horizontal axis. D and E, Cytotoxicity of CBZ-specific T-cell clones against different HLA-B transfectants in the absence (Fig 1, D) or presence (Fig 1, E) of antibodies. ∗P < .01. NS, Not significant. Data of Fig 1, A, B, D, and E, were obtained by using the 51Cr-releasing assay. Results are representative of 3 independent experiments (means ± SDs). Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 No involvement of intracellular metabolism or antigen processing in the CTL activation in patients with CBZ-induced SJS/TEN. A, CTL TCLs failed to kill CBZ- or ECBZ-pulsed autologous B-LCLs. Autologous B-LCLs pretreated with or without drugs at 37°C overnight and washed extensively are shown as Pulsed B-LCL (n = 5). B, CBZ-specific CTL TCL proliferation against prefixed or nonfixed APCs (n = 3). ∗P < .05; ∗∗P < .001. GBP, Gabapentin; SI, stimulation index. Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 The interaction between HLA-B∗1502 protein and CBZ derivatives. A, Binding responses among 5 soluble HLA-B molecules and CBZ/ECBZ (500 μmol/L). B, Cytotoxicity of CTL TCLs against HLA-B transfectants and CBZ structure-related chemicals. C, Binding responses of HLA-B∗1502 recombinant protein toward CBZ-related compounds. D and E, Cytotoxicity of CTL TCLs against HLA-B∗1502 transfectants and CBZ-related compounds in the absence (Fig 3, D) or presence (Fig 3, E) of antibodies. ∗P < .01. NS, Not significant (Student t test). Data of Fig 3, B, D, and E, were obtained by using the 51Cr-releasing assay. Results are representative of 3 (Fig 3, B, D, and E) or 6 (Fig 3, A and C) independent experiments (means ± SDs). Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Key residues of HLA-B75 family members are involved in CBZ presentation and CTL activation. A, Summary of different residues and the ability of CBZ recognition of 8 HLA-B∗15 family members. B and C, Cytotoxicity of CTL TCLs against CBZ and KERTr transfectants expressing different HLA-B alleles and HLA-B∗1502 mutants (n = 5). D, Binding responses of HLA-B∗1502 mutant proteins toward CBZ-related compounds (n = 10). ∗P < .01; ∗∗P < .05; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Peptides loaded on HLA-B∗1502 are required for CBZ presentation and CTL activation. The influence of peptide on the presentation of CBZ by HLA-B∗1502 was evaluated by using acid treatment, peptide loading, and cytotoxicity assay by 51Cr-release. A total of 16 peptides, including 12 HLA-B∗1502–binding peptides and 4 non–HLA-B∗1502–binding peptides (listed in Table E2) were examined, and symbols represent each peptide in 4 independent experiments. Small horizontal lines indicate means. Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Computer modeling of the molecular interaction between HLA-B∗1502 and CBZ and its derivatives. A, Simulation of the best conformation for drug/HLA-B∗1502/peptide complex in the B pocket using the DS::CDOCKER module. CBZ (left) and ECBZ (right) were identified near Arg62 in the binding groove of HLA-B∗1502. B, Prediction of the interaction between HLA-B∗1502 and chemicals (left, CBZ; right, LIC) by using the Flexible Docking program. The green dashed line represents the hydrogen bond between 5-carboxamide of CBZ and Arg62 of HLA-B∗1502. HLA-B∗1502, PP5 peptide, and chemicals are shown in blue, yellow, and green, respectively. C, The ionic interaction between Arg62 and Glu63 of HLA-B∗1501 (left) occupied the functional group for CBZ binding. In comparison, Asn63 of HLA-B∗1502 (right) could not form stable binding with Arg62. Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Chemical structures of AEDs used in this study. Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Predictive conformation of the interaction between CBZ and peptide/HLA-B∗1502 protein as modeled by using the multiple copy simultaneous search program (MCSS). CBZ within 5 Å of peptide was selected for analysis and colored by predicted binding magnitude (MCSS score), which represents the interaction energy between the compound and protein/peptide complex. The binding magnitude from strong to weak is colored from blue to red, and the hot zones of each simulation are circled in yellow. Journal of Allergy and Clinical Immunology 2012 129, 1562-1569.e5DOI: (10.1016/j.jaci.2011.12.990) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions