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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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).Wealso 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.

Original languageEnglish (US)
Pages (from-to)4079-4090
Number of pages12
JournalJournal of Biological Chemistry
Volume291
Issue number8
DOIs
StatePublished - Feb 19 2016
Externally publishedYes

Fingerprint

Autoimmune Thyroiditis
Antigen Presentation
T-cells
Thyroglobulin
Antigens
Peptides
Molecules
T-Lymphocytes
Chemical activation
Thyroid Diseases
Autoimmune Diseases
Thyroiditis
Inbred NOD Mouse
HLA-DR Antigens
Autoimmunity
Arginine
Thyroid Gland

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis. / Li, Cheuk Wun; Menconi, Francesca; Osman, Roman; Mezei, Mihaly; Jacobson, Eric M.; Concepcion, Erlinda; David, Chella S.; Kastrinsky, David B.; Ohlmeyer, Michael; Tomer, Yaron.

In: Journal of Biological Chemistry, Vol. 291, No. 8, 19.02.2016, p. 4079-4090.

Research output: Contribution to journalArticle

Li, CW, Menconi, F, Osman, R, Mezei, M, Jacobson, EM, Concepcion, E, David, CS, Kastrinsky, DB, Ohlmeyer, M & Tomer, Y 2016, 'Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis', Journal of Biological Chemistry, vol. 291, no. 8, pp. 4079-4090. https://doi.org/10.1074/jbc.M115.694687
Li, Cheuk Wun ; Menconi, Francesca ; Osman, Roman ; Mezei, Mihaly ; Jacobson, Eric M. ; Concepcion, Erlinda ; David, Chella S. ; Kastrinsky, David B. ; Ohlmeyer, Michael ; Tomer, Yaron. / Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 8. pp. 4079-4090.
@article{4c483c5ca8fa4b20be54e91729cf66eb,
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).Wealso 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.",
author = "Li, {Cheuk Wun} and Francesca Menconi and Roman Osman and Mihaly Mezei and Jacobson, {Eric M.} and Erlinda Concepcion and David, {Chella S.} and Kastrinsky, {David B.} and Michael Ohlmeyer and Yaron Tomer",
year = "2016",
month = "2",
day = "19",
doi = "10.1074/jbc.M115.694687",
language = "English (US)",
volume = "291",
pages = "4079--4090",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "8",

}

TY - JOUR

T1 - Identifying a small molecule blocking antigen presentation in autoimmune thyroiditis

AU - Li, Cheuk Wun

AU - Menconi, Francesca

AU - Osman, Roman

AU - Mezei, Mihaly

AU - Jacobson, Eric M.

AU - Concepcion, Erlinda

AU - David, Chella S.

AU - Kastrinsky, David B.

AU - Ohlmeyer, Michael

AU - Tomer, Yaron

PY - 2016/2/19

Y1 - 2016/2/19

N2 - 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).Wealso 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.

AB - 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).Wealso 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.

UR - http://www.scopus.com/inward/record.url?scp=84964501799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964501799&partnerID=8YFLogxK

U2 - 10.1074/jbc.M115.694687

DO - 10.1074/jbc.M115.694687

M3 - Article

C2 - 26703475

AN - SCOPUS:84964501799

VL - 291

SP - 4079

EP - 4090

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 8

ER -