| First Author | Li CW | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 8 | Pages | 4079-90 |
| PubMed ID | 26703475 | Mgi Jnum | J:242272 |
| Mgi Id | MGI:5904861 | Doi | 10.1074/jbc.M115.694687 |
| Citation | Li CW, et al. (2016) Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis. J Biol Chem 291(8):4079-90 |
| abstractText | We previously showed that an HLA-DR variant containing arginine at position 74 of the DRbeta1 chain (DRbeta1-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 DRbeta1-Arg74. We hypothesized that blocking the binding of these peptides to DRbeta1-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 DRbeta1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DRbeta1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DRbeta1-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. |
