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

Abstract

An HLA-DR variant containing Arginine at position 74 of the DRbeta1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases (AITD), Graves' disease (GD) and Hashimoto's thyroiditis (HT), while Glutamine at position DRbeta1-74 is protective. We hypothesized that the DRbeta1-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 DRbeta1-Arg74 with much weaker binding to the protective variant DRbeta1-Gln74. The aim of our study was to examine in vivo whether an hTg peptide that binds strongly and specifically to DRbeta1-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 DRbeta1-Arg74 variant, thus making them an ideal in vivo model to test the presentation of hTg peptides by DRbeta1-Arg74 HLA-DR. Induction of EAT in the DR3 mice lead to T-cell stimulation and proliferation to Tg.2098, a strong and specific DRbeta1-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 DRbeta-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 DRbeta-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-DRbeta-Arg74, is a major human T-cell epitope and participant in the pathoetiology of AITD.

• Authors: Francesca Menconi, Amanda Huber, Roman Osman, Erlinda Concepcion, Eric M Jacobson, Mihaela Stefan, Chela S David, Yaron Tomer
• Journal: Journal of autoimmunity (J Autoimmun) Vol. 35 Issue 1 Pg. 45-51 (Aug 2010) ISSN: 1095-9157 [Electronic] England
• PMID: 20303712 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes, T-Lymphocyte
• HLA-DR3 Antigen
• Histocompatibility Antigens Class II
• Interleukin-2
• Peptide Fragments
• Thyroglobulin

Topics

• Animals
• Antigen Presentation (genetics)
• Cell Proliferation
• Epitope Mapping
• Epitopes, T-Lymphocyte (immunology)
• Genetic Predisposition to Disease
• HLA-DR3 Antigen (genetics)
• Histocompatibility Antigens Class II (genetics)
• Interleukin-2 (metabolism)
• Lymphocyte Activation (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Peptide Fragments (immunology)
• Polymorphism, Genetic
• Protein Binding (genetics, immunology)
• T-Lymphocytes (immunology, metabolism, pathology)
• Thyroglobulin (immunology)
• Thyroiditis, Autoimmune (genetics, immunology)