PMID- 32726429
OWN - NLM
STAT- MEDLINE
DCOM- 20210720
LR  - 20210720
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 177
IP  - 2
DP  - 2020 Oct 1
TI  - Identification of Flucloxacillin-Haptenated HLA-B*57:01 Ligands: Evidence of 
      Antigen Processing and Presentation.
PG  - 454-465
LID - 10.1093/toxsci/kfaa124 [doi]
AB  - Flucloxacillin is a beta-lactam antibiotic associated with a high incidence of 
      drug-induced liver reactions. Although expression of human leukocyte antigen 
      (HLA)-B*57:01 increases susceptibility, little is known of the pathological 
      mechanisms involved in the induction of the clinical phenotype. Irreversible 
      protein modification is suspected to drive the reaction through the modification 
      of peptides that are presented by the risk allele. In this study, the binding of 
      flucloxacillin to immune cells was characterized and the nature of the peptides 
      presented by HLA-B*57:01 was analyzed using mass spectrometric-based 
      immunopeptidomics methods. Flucloxacillin modification of multiple proteins was 
      observed, providing a potential source of neoantigens for HLA presentation. Of 
      the peptides eluted from flucloxacillin-treated C1R-B*57:01 cells, 6 putative 
      peptides were annotated as flucloxacillin-modified HLA-B*57:01 peptide ligands 
      (data are available via ProteomeXchange with identifier PXD020137). To conclude, 
      we have characterized naturally processed drug-haptenated HLA ligands presented 
      on the surface of antigen presenting cells that may drive drug-specific CD8+ 
      T-cell responses.
CI  - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the 
      Society of Toxicology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Waddington, James C
AU  - Waddington JC
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Meng, Xiaoli
AU  - Meng X
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Illing, Patricia T
AU  - Illing PT
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 
      3800, Australia.
FAU - Tailor, Arun
AU  - Tailor A
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Adair, Kareena
AU  - Adair K
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Whitaker, Paul
AU  - Whitaker P
AD  - Regional Adult Cystic Fibrosis Unit, St James's Hospital, Leeds LS9 7TF, United 
      Kingdom.
FAU - Hamlett, Jane
AU  - Hamlett J
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Jenkins, Rosalind E
AU  - Jenkins RE
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Farrell, John
AU  - Farrell J
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Berry, Neil
AU  - Berry N
AD  - Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United 
      Kingdom.
FAU - Purcell, Anthony W
AU  - Purcell AW
AD  - Infection and Immunity Program and Department of Biochemistry and Molecular 
      Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 
      3800, Australia.
FAU - Naisbitt, Dean J
AU  - Naisbitt DJ
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
FAU - Park, Brian Kevin
AU  - Park BK
AD  - MRC Centre for Drug Safety Science, Department of Molecular & Clinical 
      Pharmacology, University of Liverpool, Liverpool L69 3GE, United Kingdom.
LA  - eng
GR  - MR/R009635/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B57 antigen)
RN  - 0 (Ligands)
RN  - 43B2M34G2V (Floxacillin)
SB  - IM
MH  - *Antigen Presentation
MH  - *Floxacillin/toxicity
MH  - HLA-B Antigens
MH  - Humans
MH  - Ligands
OTO - NOTNLM
OT  - haptenated HLA ligands
OT  - immune-mediated liver injury
OT  - intracellular covalent binding
EDAT- 2020/07/30 06:00
MHDA- 2021/07/21 06:00
CRDT- 2020/07/30 06:00
PHST- 2020/07/30 06:00 [pubmed]
PHST- 2021/07/21 06:00 [medline]
PHST- 2020/07/30 06:00 [entrez]
AID - 5877955 [pii]
AID - 10.1093/toxsci/kfaa124 [doi]
PST - ppublish
SO  - Toxicol Sci. 2020 Oct 1;177(2):454-465. doi: 10.1093/toxsci/kfaa124.