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Thyrotropin Receptor Epitopes and Their Relation to Histocompatibility Leukocyte Antigen-DR Molecules in Graves’ Disease

Endocrinology Division (H.I., S.Q., L.J.D.G.), Department of Medicine, and TB/HIV Research Lab (A.S.D.G.), Brown University, Providence, Rhode Island 02903; and EpiVax, Inc. (W.M., A.S.D.G.), Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Leslie J. De Groot, M.D., Brown University/Medicine/Endocrinology, Box G, Room E-308, 70 Ship Street, Providence, Rhode Island 02903. E-mail: leslie_degroot{at}brown.edu.

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 IC₅₀ 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.

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