Figures & data
Table 1 A selection of HLA allele associations with drug-induced hypersensitivity reactions
Figure 1 Allele frequency distribution for HLA-A*31:01 and HLA-B*15:02.
Notes:
HLA-A*31:01 is widely distributed in comparison with HLA-B*15:02, which is predominantly concentrated in South East Asia. Adapted from Gonzalez-Galarza FF, Takeshita LY, Santos EJ, et al. New features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acid Research. 2015;28:D784–788.Citation64
Table 2 Studies investigating the association between HLA-A*31:01 and carbamazepine hypersensitivity
Figure 2 Proposed mechanisms of T-cell activation by drugs/drug metabolites.
Notes: (A) Hapten hypothesis: The hapten hypothesis postulates that a drug or its metabolite (yellow star) is able to bind covalently with self-proteins (blue square). The hapten–protein complex is recognized as foreign by APCs which take up and process the hapten–protein complex producing a pool of drug modified peptides (yellow triangle and blue triangle). The drug modified peptide is presented in association with MHC and is recognized by the TCR as a neoantigen and activates the immune response. (B) In the PI model the drug (yellow star) is able to bind noncovalently to either the TCR or MHC leading to activation of the immune system. (C) In the altered self-peptide repertoire model, the drug (yellow star) binds to the antigen binding cleft of the MHC. This results in presentation of novel peptides (green triangle) to the TCR and activation of the immune system.
Abbreviations: APC, antigen processing cell; MHC, major histocompatibility complex; PI, direct pharmacologic interaction of drugs with immune receptors; TCR, T-cell receptor.
Abbreviations: APC, antigen processing cell; MHC, major histocompatibility complex; PI, direct pharmacologic interaction of drugs with immune receptors; TCR, T-cell receptor.
Table 3 Characteristics for HLA-A*31:01 pharmacogenetic screening test in CBZ hypersensitivity
Figure 3 A comparison of the wording in the carbamazepine summary of product characteristics approved by the European Medicines Agency for testing for HLA alleles.
Notes: Adapted from Electronic Medicines Compendium website. Available from https://www.medicines.org.uk/emc/medicine/24201.Citation65
Abbreviations: AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; HLA, human leukocyte antigen; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.
Abbreviations: AGEP, acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; HLA, human leukocyte antigen; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.
