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

doi:10.1074/jbc.m115.694687

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.

Highlights

We previously showed that an HLA-DR variant containing arginine at position 74 of the DR␤1 chain (DR␤1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD)
AITD are the commonest autoimmune diseases in the United States [1, 31], but their treatment is still largely based on symptom relief and not on reversing the autoimmune response to the thyroid
In particular treatment of Graves disease (GD) is not satisfactory, anti-thyroid medications such as Methimazole are associated with serious side effects including liver dysfunction and agranulocytosis [32, 33]; thyroidectomy is associated with potential surgical risks; and radioactive iodine was shown to worsen or trigger de novo Graves ophthalmopathy [34]

Summary

Introduction

We previously showed that an HLA-DR variant containing arginine at position 74 of the DR␤1 chain (DR␤1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DR␤1-Arg pockets. In view of the important interaction between these Tg peptides and the HLA-DR␤1-Arg peptide binding pocket, we hypothesized that blocking the presentation of these peptides to autoreactive T-cells that escaped tolerance could be used to treat AITD. Such a targeted therapy could prevent the continuous activation of T-cells against thyroid antigens that is necessary to maintain the autoimmune response in AITD and FEBRUARY 19, 2016 VOLUME 291 NUMBER 8. The aim of this study was to identify small molecule inhibitors that can block Tg peptide presentation by HLA-DR␤1-Arg as a potential new treatment modality for AITD

Objectives

Results

Conclusion