Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis.

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). We also 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.

• Authors: Cheuk Wun Li, Francesca Menconi, Roman Osman, Mihaly Mezei, Eric M Jacobson, Erlinda Concepcion, Chella S David, David B Kastrinsky, Michael Ohlmeyer, Yaron Tomer
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 8 Pg. 4079-90 (Feb 19 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 26703475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Alkaloids
• HLA-DRB1 Chains
• Peptides
• Thyroglobulin

Topics

• Alkaloids (chemistry, pharmacology)
• Animals
• Antigen Presentation (drug effects)
• HLA-DRB1 Chains (genetics, immunology)
• Humans
• Lymphocyte Activation (drug effects)
• Mice
• Mice, Transgenic
• Peptides (genetics, immunology)
• T-Lymphocytes (immunology, pathology)
• Thyroglobulin (genetics, immunology)
• Thyroiditis, Autoimmune (genetics, immunology, pathology)