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Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis.

Cheuk Wun Li1, Francesca Menconi1, Roman Osman2

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The Journal of Biological Chemistry
|December 26, 2015
PubMed
Summary
This summary is machine-generated.

Researchers identified cepharanthine, a small molecule that blocks the binding of thyroglobulin peptides to a specific HLA variant linked to autoimmune thyroid diseases (AITD). This discovery offers a potential new therapeutic strategy for AITD.

Keywords:
cell surface proteinendocrinologymajor histocompatibility complex (MHC)peptidessmall moleculestructural modelthyroglobulinthyroidthyroid hormonethyroiditis

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Area of Science:

  • Immunology
  • Genetics
  • Pharmacology

Background:

  • Autoimmune thyroid diseases (AITD) are linked to a specific HLA class II variant, DRβ1-Arg74.
  • Five thyroglobulin (Tg) peptides have been identified that bind to DRβ1-Arg74, potentially driving T-cell activation in thyroiditis.

Purpose of the Study:

  • To identify small molecules capable of blocking the binding of Tg peptides to DRβ1-Arg74.
  • To investigate the potential of blocking this interaction to inhibit T-cell activation in autoimmune thyroiditis.

Main Methods:

  • Screening of a diverse compound library to identify inhibitors of peptide binding to DRβ1-Arg74.
  • Induction of experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DRβ1-Arg74.
  • Assessment of cepharanthine's ability to block T-cell activation by Tg peptides, specifically Tg.2098, in EAT models.

Main Results:

  • Cepharanthine was identified as a compound that effectively blocks peptide binding to DRβ1-Arg74.
  • Tg.2098 was confirmed as the dominant peptide in inducing EAT in the mouse model.
  • Cepharanthine demonstrated the ability to block T-cell activation by Tg peptides, including Tg.2098, in mice with EAT.

Conclusions:

  • Cepharanthine is the first small molecule identified that can inhibit the binding and presentation of Tg peptides to T-cells in the context of autoimmune thyroiditis.
  • Cepharanthine shows promise as a potential therapeutic agent for human AITD.