Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy  Lisa M. Wheatley, MD, MPH, Marshall Plaut, MD, Julie M. Schwaninger, MS, Aleena Banerji, MD, Mariana Castells, MD, PhD, Fred D. Finkelman, MD, Gerald J. Gleich, MD, Emma Guttman-Yassky, MD, PhD, Simon A.K. Mallal, MB BS, FRACP, FRCPA, Dean J. Naisbitt, PhD, David A. Ostrov, PhD, Elizabeth J. Phillips, MD, FRCPC, FRACP, Werner J. Pichler, MD, Thomas A.E. Platts-Mills, MD, PhD, FRS, Jean-Claude Roujeau, MD, Lawrence B. Schwartz, MD, PhD, Lauren A. Trepanier, DVM, PhD  Journal of Allergy and Clinical Immunology  Volume 136, Issue 2, Pages 262-271.e2 (August 2015) DOI: 10.1016/j.jaci.2015.05.027 Copyright © 2015 Terms and Conditions

Fig 1 Mechanisms that mediate HLA- or TCR-associated drug hypersensitivity. A, Under normal circumstances, HLA-bound self-peptides that bind with high affinity to a TCR result in the deletion of T cells bearing the autoreactive receptor. B, In the prohapten/hapten hypothesis, a reactive drug metabolite (a hapten) is generated and binds covalently to a self-peptide, generating a new composite antigen that can bind to HLA and be presented to the TCR and activate T cells. This presentation is processing dependent and requires activation of the innate immune system. C, The pharmacologic interaction hypothesis posits that a drug (shown in red) binds noncovalently either to (1) HLA; (2) TCR; or, rarely, (3) both simultaneously, facilitating interaction and resulting in T-cell activation. This interaction with the HLA or TCR is rapid and independent of metabolism or processing. Binding of the drug results in a change in the HLA-peptide-TCR complex and does not require any change in the peptide that is bound, differentiating this from both the hapten (Fig 1, B) and the altered repertoire (Fig 1, D) models. D, In the altered peptide repertoire hypothesis a drug binds noncovalently to the peptide-binding groove of the HLA molecule, altering the repertoire of self-peptides that bind in the groove. Because the combination of HLA and self-peptide is new, the circulating T cells are not tolerant to the neoantigen, thus stimulating T-cell activation. This pathway is processing dependent. Note: In the figure only HLA class I (brown) with β2-microglobulin (green) is depicted, but HLA class II molecules are involved in some cases. Journal of Allergy and Clinical Immunology 2015 136, 262-271.e2DOI: (10.1016/j.jaci.2015.05.027) Copyright © 2015 Terms and Conditions