Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis

Cheuk Wun Li, Francesca Menconi, Roman Osman, Mihaly Mezei, Eric M. Jacobson, Erlinda Concepcion, Chella S. David, David B. Kastrinsky, Michael Ohlmeyer, Yaron Tomer

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

We previously showed that an HLA-DR variant containing arginine at position 74 of the DRβ1 chain (DRβ1 -Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD).Wealso identified 5 thyroglobulin (Tg) peptides that bound to DRβ1 -Arg74. We hypothesized that blocking the binding of these peptides to DRβ1 -Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DRβ1 -Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DRβ1 -Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DRβ1 -Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD.

Original languageEnglish (US)
Pages (from-to)4079-4090
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number8
DOIs
Publication statusPublished - Feb 19 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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