Fig. 1

Schematic examples for the (pro)hapten hypothesis, p-i concept and altered self-repertoire model (adopted from Ostrov et al. [16]). Upper part TCR monitor the antigens or ligands presented by the HLA molecules. These HLA ligands are typically peptides loaded onto the HLA molecule inside the antigen-presenting cells and subsequently exposed on the surface. Different allelic variants of HLA molecules result in different binding specificities and a specific profile of presented ligands. Here, peptide A, but not peptide B, can bind to the HLA molecule. Typically, T-cells do not react to presented self-peptides, as these auto-reactive T-cells are negatively selected during thymic development, but will react once they encounter an unknown ligand (e.g., a virus-derived peptide). In the lower part, three scenarios in which drugs can result in a HLA-dependent reaction: in (1) a HLA-specific drug haptenated peptide is presented, according to the (pro)hapten hypothesis; in (2) the HLA molecule itself is modified in a region exposed to the TCR, resulting in a reaction according to the p-i concept; and in (3) the binding specificity of the HLA molecule is altered by the presence of the drug, resulting in presentation of novel ligands such as peptide B, as in the altered self-repertoire hypothesis.