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Abacavir induces loading of novel self-peptides into HLA-B*57:01: an autoimmune model for HLA-associated drug hypersensitivity

Friday, November 08, 2013 — Poster Session IV

2:00 p.m. – 4:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • MA Norcross
  • S Luo
  • L Lu
  • MT Boyne
  • M Gomarteli
  • AD Rennels
  • J Woodcock
  • DH Margulies
  • C McMurtrey
  • S Vernon
  • WH Hildebrand
  • R Buchli


BACKGROUND: To understand the immunochemistry of abacavir drug reactions associated with HLA-B57:01, we investigated the effects of abacavir on HLA-B57:01 epitope-binding in vitro and the quality and quantity of self-peptides presented by HLA-B57:01 from abacavir-treated cells. METHODS: An HLA-B57:01-specific epitope-binding assay was developed to test for effects of abacavir on self-peptide binding. To examine whether abacavir alters the peptide repertoire in HLA-B57:01, a B-cell line secreting soluble HLA was cultured in the presence or absence of abacavir, peptides were eluted, and mapped by mass spectroscopy to identify drug-unique peptides. RESULTS: Abacavir enhanced binding of self-peptide LF9 to HLA-B57:01 in a dose-dependent manner. Peptides isolated from abacavir-treated HLA-B57:01 B cell showed amino acid sequence differences compared with peptides from untreated cells. Novel drug-induced peptides lacked typical HLA-B57:01 peptide motif and instead contained predominantly isoleucine or leucine residues at carboxyl-terminal, and bound to soluble HLA-B57:01 with high affinity that was not altered by abacavir addition. CONCLUSION: Our results support a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLA-B57:01. Drug-induced loading of novel self-peptides into HLA, generates an array of neo-antigen peptides that drive polyclonal T-cell autoimmune responses and multiorgan systemic toxicity.

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