Thyrotropin receptor epitopes and their relation to histocompatibility leukocyte antigen-DR molecules in Graves' disease

J Clin Endocrinol Metab. 2006 Jun;91(6):2286-94. doi: 10.1210/jc.2005-2537. Epub 2006 Apr 4.


Context: Graves' disease (GD) is characterized by autoimmunity to the TSH receptor (TSHR).

Objective: We sought to identify T cell epitopes in TSHR that initiate this immune response and their interaction with human histocompatibility leukocyte antigen (HLA) molecules predisposing to GD.

Design: We examined the affinity of 31 overlapping peptides spanning the TSHR extracellular domain for binding in vitro to five purified HLA-DR molecules; DRB1*0101 (DR1), DRB1*1501 (DR2), DRB1*0301 (DR3), DRB1*1101 (DR5), and DRB1*0701 (DR7). We scanned the TSHR extracellular domain using a T cell epitope-mapping algorithm, EpiMatrix. We compared these results with clinical studies of GD patients measuring in vitro T cell responses to the peptides.

Setting: The study was conducted at a university laboratory.

Patients: Patients included 200 serial adult clinic patients with GD.

Intervention: There were no interventions.

Main outcome measurements: Binding affinity of epitopes, predicted affinity, and reported T cell stimulation data were measured.

Results: Most peptides bound with intermediate or high affinity to one or more HLA-DR molecule. Peptides binding to HLA-DR3 and HLA-DR5, which predispose to GD, exhibited moderate binding affinities overall, whereas most peptides binding to GD-protective HLA-DR7 bound with high affinity. These differences may relate to T cell selection in the thymus. Binding affinity of peptides correlated strongly with EpiMatrix-predicted affinity for HLA-DRB1*0101, DRB1*1501, DR3, and DRB1*0701 but not HLA-DR5. Average IC(50) values correlated significantly with clinical T cell stimulation data.

Conclusions: Three different methods for identifying immunogenic peptides did not provide a uniform picture of important TSHR epitopes. However, peptide 132-150 (GIFNTGLKMFPDLTKVYST) was identified by three methods as an important epitope in GD; the possible importance of peptides 145-163, 158-176, 207-222, 248-263, 272-291, and 343-362 was also identified.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • Epitopes, T-Lymphocyte*
  • Graves Disease / immunology*
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / metabolism*
  • Humans
  • Molecular Sequence Data
  • Peptide Fragments / metabolism
  • Receptors, Thyrotropin / immunology*
  • Receptors, Thyrotropin / metabolism


  • Epitopes, T-Lymphocyte
  • HLA-DR Antigens
  • Peptide Fragments
  • Receptors, Thyrotropin