Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

J Biol Chem. 2016 Feb 19;291(8):4079-90. doi: 10.1074/jbc.M115.694687. Epub 2015 Dec 24.

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.

Keywords: cell surface protein; endocrinology; major histocompatibility complex (MHC); peptides; small molecule; structural model; thyroglobulin; thyroid; thyroid hormone; thyroiditis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Alkaloids
  • HLA-DRB1 Chains
  • Peptides
  • Thyroglobulin