T-cells recognize multiple epitopes in the human thyrotropin receptor extracellular domain

Area of Science:

• Immunology
• Endocrinology
• Autoimmunity

Background:

• Graves' disease (GD) involves an autoimmune attack on the TSH receptor (TSHR).
• T-lymphocytes play a regulatory role in the immune system and are implicated in GD pathogenesis.
• Understanding T-cell interactions with TSHR is crucial for elucidating GD mechanisms.

Purpose of the Study:

• To investigate T-cell responses to the TSHR extracellular domain (rhTSHR-ECD) and its synthetic peptides in patients with GD.
• To identify specific TSHR epitopes that trigger T-cell responses in GD.
• To compare T-cell reactivity patterns in GD with those in Hashimoto's thyroiditis (HT), colloid nodular goiter (CNG), and normal controls.

Main Methods:

• Peripheral blood mononuclear cells (PBMCs) and T-cell lines from GD, HT, CNG patients, and normal controls were stimulated with rhTSHR-ECD and 31 synthetic peptides.
• T-cell responses were assessed using stimulation index (SI) values.
• Human leukocyte antigen (HLA) typing was performed, and antibody levels (microsomal antibody, TSHR antibody) were measured.

Main Results:

• All GD patients showed T-cell reactivity to at least one TSHR peptide, with heterogeneous responses spanning the entire ECD.
• Significant differences in T-cell reactivity compared to controls were observed for specific peptide regions (e.g., 44-88, 119-176, 227-263, 343-376).
• Peptides 158-176, 237-252, 248-263, and 343-362 were identified as potentially immunodominant epitopes in GD, particularly in HLA-DQA1 0501 allele-positive individuals.

Conclusions:

• The TSHR extracellular domain contains multiple T-cell epitopes that are targets in Graves' disease.
• Specific peptides, including 158-176 and 343-362, are critical for T-cell activation in GD.
• These findings advance our understanding of the cellular immune response in GD and may inform future therapeutic strategies.