Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

  title={Immune self-reactivity triggered by drug-modified HLA-peptide repertoire},
  author={Patricia T. Illing and Julian P. Vivian and Nadine L. Dudek and Lyudmila Kostenko and Zhenjun Chen and Mandvi Bharadwaj and John J Miles and Lars Kjer-Nielsen and Stephanie Gras and Nicholas A. Williamson and Scott R. Burrows and Anthony Wayne Purcell and Jamie Rossjohn and James McCluskey},
Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens–Johnson syndrome (SJS), are… 
Human leukocyte antigens (HLA) associated drug hypersensitivity: consequences of drug binding to HLA
Drug hypersensitivity is the end result of a drug interaction with certain HLA molecules and TCRs, the sum of which determines whether the ensuing immune response is going to be harmful or not.
Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles
The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets, and provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.
Human leukocyte antigen and idiosyncratic adverse drug reactions.
Cells + HLA-B*18:01Self-Peptide Naturally Presented by Immunogenic EBV Epitope and a T Cell Cross-Reactivity between a Highly
This is the first report of the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8 + T cells, and illustrates how aberrant immune responses and immunopathological diseases could be generated byEBV infection.
Immunopharmacogenomics: Mechanisms of HLA‐Associated Drug Reactions
New insights into immunological, pharmacological, and genetic mechanisms underpinning HLA associated drug reactions and the implications for future translation into clinical care are focused on.
Pharmacology: A false sense of non-self
A mechanism through which these small-molecule drugs affect antigen presentation and consequently the T-cell response is described, which leads to the systemic reaction manifesting as AHS.
Structural Elements Recognized by Abacavir-Induced T Cells
The data suggest the T cell polyclonal response to abacavir consists of multiple subsets, including T cells that recognize self peptide/HLA-B*57:01 complexes and crossreact with viral peptide/(HLA)-B*,57: 01 complexes due to similarity in TCR contact residues.
T Cell Cross-Reactivity between a Highly Immunogenic EBV Epitope and a Self-Peptide Naturally Presented by HLA-B*18:01+ Cells
This is the first report confirming the natural presentation of a self-peptide cross-recognized in the context of self-HLA by EBV-reactive CD8+ T cells, and the strong antiviral T cell response is primarily dependent on the alanine/arginine mismatch at position 7.
Abacavir inhibits but does not cause self-reactivity to HLA-B*57:01-restricted EBV specific T cell receptors
Abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule, and provides an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions.
The role of HLA genes in pharmacogenomics: unravelling HLA associated adverse drug reactions
The road to understanding the interaction between abacavir and the HLA-B*57:01 molecule is explored and the current state of understanding of interactions between other drugs and HLA molecules implicated in adverse drug reactions, which appear to involve multiple mechanisms are reviewed.


Drug hypersensitivity and human leukocyte antigens of the major histocompatibility complex.
Recent advances in the field of HLA-associated drug hypersensitivities are reviewed, with each drug exhibiting striking specificity for presentation by defined HLA allotypes.
HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.
The results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese, and in particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.
Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome.
  • T. Ko, W. Chung, S. Hung
  • Medicine, Biology
    The Journal of allergy and clinical immunology
  • 2011
Crystal structures of two peptide-HLA-B*1501 complexes; structural characterization of the HLA-B62 supertype.
Structures of two immunogenic peptide-HLA-B*1501 complexes are described and Mutual comparisons of these two structures with structures from other HLA supertypes define and explain the specificity of the P2 and P9 peptide anchor preferences in the B62 HLAsupertype.
Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant
The results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacvir hypersensitivity.