Tg.2098 is a major human thyroglobulin T-cell epitope

Francesca Menconi, Amanda Huber, Roman Osman, Erlinda Concepcion, Eric M. Jacobson, Mihaela Stefan, Chela S. David, Yaron Tomer

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

An HLA-DR variant containing Arginine at position 74 of the DRβ1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases (AITD), Graves' disease (GD) and Hashimoto's thyroiditis (HT), while Glutamine at position DRβ1-74 is protective. We hypothesized that the DRβ1-Arg74 variant is able to present pathogenic thyroglobulin (Tg) peptides to T-cells more efficiently, thereby triggering thyroid autoimmunity. Indeed, we have previously identified 4 human Tg (hTg) peptides that bind specifically to DRβ1-Arg74 with much weaker binding to the protective variant DRβ1-Gln74. The aim of our study was to examine in vivo whether an hTg peptide that binds strongly and specifically to DRβ1-Arg74 is capable of stimulating T-cells during the induction of thyroiditis in a " humanized" mouse expressing human DR3, and in patients positive for Tg antibodies. Sequencing of exon 2 of the DR transgene in the DR3 mice, null for endogenous MHC II molecules, confirmed that they expressed the disease-associated DRβ1-Arg74 variant, thus making them an ideal in vivo model to test the presentation of hTg peptides by DRβ1-Arg74 HLA-DR. Induction of EAT in the DR3 mice lead to T-cell stimulation and proliferation to Tg.2098, a strong and specific DRβ1-Arg74 binder, while a non-binding control peptide, Tg.2766 did not induce this response. Moreover, Tg.2098 stimulated T-cells from 4 individuals who were positive for thyroglobulin antibodies, demonstrating that Tg.2098 is an immunogenic peptide capable of being presented in vivo and activating T-cells in EAT and AITD. Energetic analysis of the complex formed by Tg.2098 and DRβ-Arg74 has shown that the origin of the affinity was determined by residues 1, 7 and 9 in the peptide, while the selectivity of the peptide for the MHC was determined by the Asp in position 4. The disease-protective substitution R74Q, leads to reduction in affinity due to changes in local interaction with D4 as well as non-local interaction with other residues. The electrostatic potential on the surface of the DRβ-Arg74-Tg.2098 complex has a unique signature which may be recognized by T-cell receptors leading to autoimmune thyroiditis. Taken together these findings suggest that Tg.2098, a strong and specific binder to the disease-associated HLA-DRβ-Arg74, is a major human T-cell epitope and participant in the pathoetiology of AITD.

Original languageEnglish (US)
Pages (from-to)45-51
Number of pages7
JournalJournal of Autoimmunity
Volume35
Issue number1
DOIs
StatePublished - 2010

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T-Lymphocyte Epitopes
Thyroglobulin
Peptides
Thyroid Diseases
T-Lymphocytes
HLA-DR Antigens
Autoimmune Diseases
Peptide T
Autoimmune Thyroiditis
Thyroiditis
Hashimoto Disease
Antibodies
Graves Disease
Genetic Predisposition to Disease
T-Cell Antigen Receptor
Glutamine
Static Electricity
Autoimmunity
Transgenes
Arginine

Keywords

  • Gene
  • HLA
  • Thyroglobulin
  • Thyroiditis

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Menconi, F., Huber, A., Osman, R., Concepcion, E., Jacobson, E. M., Stefan, M., ... Tomer, Y. (2010). Tg.2098 is a major human thyroglobulin T-cell epitope. Journal of Autoimmunity, 35(1), 45-51. https://doi.org/10.1016/j.jaut.2010.01.004

Tg.2098 is a major human thyroglobulin T-cell epitope. / Menconi, Francesca; Huber, Amanda; Osman, Roman; Concepcion, Erlinda; Jacobson, Eric M.; Stefan, Mihaela; David, Chela S.; Tomer, Yaron.

In: Journal of Autoimmunity, Vol. 35, No. 1, 2010, p. 45-51.

Research output: Contribution to journalArticle

Menconi, F, Huber, A, Osman, R, Concepcion, E, Jacobson, EM, Stefan, M, David, CS & Tomer, Y 2010, 'Tg.2098 is a major human thyroglobulin T-cell epitope', Journal of Autoimmunity, vol. 35, no. 1, pp. 45-51. https://doi.org/10.1016/j.jaut.2010.01.004
Menconi F, Huber A, Osman R, Concepcion E, Jacobson EM, Stefan M et al. Tg.2098 is a major human thyroglobulin T-cell epitope. Journal of Autoimmunity. 2010;35(1):45-51. https://doi.org/10.1016/j.jaut.2010.01.004
Menconi, Francesca ; Huber, Amanda ; Osman, Roman ; Concepcion, Erlinda ; Jacobson, Eric M. ; Stefan, Mihaela ; David, Chela S. ; Tomer, Yaron. / Tg.2098 is a major human thyroglobulin T-cell epitope. In: Journal of Autoimmunity. 2010 ; Vol. 35, No. 1. pp. 45-51.
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