title: 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.affiliation: From the Division of Endocrinology.
authors.forename: Cheuk Wun
authors.initials: CW
authors.lastname: Li
authors.affiliation: From the Division of Endocrinology.
authors.forename: Francesca
authors.initials: F
authors.lastname: Menconi
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Roman
authors.initials: R
authors.lastname: Osman
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Mihaly
authors.initials: M
authors.lastname: Mezei
authors.affiliation: From the Division of Endocrinology.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Jacobson
authors.affiliation: From the Division of Endocrinology.
authors.forename: Erlinda
authors.initials: E
authors.lastname: Concepcion
authors.affiliation: the Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and.
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: David B
authors.initials: DB
authors.lastname: Kastrinsky
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Michael
authors.initials: M
authors.lastname: Ohlmeyer
authors.affiliation: From the Division of Endocrinology, the Bronx Veterans Affairs Medical Center, Bronx, New York 10468 Yaron.Tomer@mssm.edu.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013954:Thyroglobulin / Q000235:genetics / Q000276:immunology; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D000470:Alkaloids; D059811:HLA-DRB1 Chains; D010455:Peptides; D013954:Thyroglobulin
keywords: cell surface protein; endocrinology; major histocompatibility complex (MHC); peptides; small molecule; structural model; thyroglobulin; thyroid; thyroid hormone; thyroiditis