THYROTROPIN RECEPTOR T-CELL EPITOPES IN AUTOIMMUNE THYROID-DISEASE

The human TSH receptor represents the primary target of thyroid-stimul ating immunoglobulins responsible for the hyperthyroidism of Graves' d isease. In the present series of investigations, the distribution of T cell epitopes has been mapped using synthetic peptides spanning the e ntire extracellular region of the human TSH receptor, in vitro prolife rative responses of the mononuclear cells were measured using flow cyt ometric analysis of bromodeoxyuridine incorporation into nuclei, In 8 of 11 samples from patients with Graves' disease, at least one (and up to 9) regions of the human TSH receptor induced proliferation, with t he mean stimulation index being 39.8 +/- 47.3. No single universal sti mulatory peptide was identified, In contrast, stimulation was not obse rved in three control subjects, while one control subject showed minim al stimulation (index of 5.7) to peptides encompassing a limited area (amino acids 31-65). The immunodominant epitope of patients with recen t-onset Graves' disease was localized between amino acids 271 and 365, whereas the immunodominant epitope of patients with disease duration greater than I year localized between amino acids 91 and 215. We concl ude that the bromodeoxyuridine incorporation method is a useful and im portant tool for detecting antigen-induced iymphocyte proliferation. T he TSH receptor-specific T cells from different Graves' disease patien ts recognize variable distinct sites within the extracellular region o f the TSH receptor, and the immunodominant epitope apparently shifts t oward the N-terminus of the receptor protein during the course of trea ted Graves' disease. (C) 1995 Academic Press, Inc.