DETECTION OF MAJOR T-CELL EPITOPES ON HUMAN THYROID-STIMULATING HORMONE-RECEPTOR BY OVERRIDING IMMUNE HETEROGENEITY IN PATIENTS WITH GRAVES-DISEASE

To examine the major immunogenic regions of the human TSH receptor (hT SHR), we examined 14 patients with Graves' disease and 14 healthy cont rol subjects for their peripheral blood T cell proliferative responses to 29 synthetic peptides representing the entire ectodomain of the hT SHR (TSHR-ecd). By combining an analytical approach encompassing the g rading of peptide-induced responses and nonparametric testing, we obta ined evidence for highly significant differences (P = <0.000001) in th e patient group compared with minor differences in the control group ( P = 0.045). To account for this difference, we identified four major T cell epitopes (amino acid 247-266, 202-221, 142-161, and 52-71), by m ultiple comparison analysis, in the patient group. Furthermore, we dem onstrated by radiolabeled PCR that the responding T cells were clonall y expanding. These findings demonstrate that despite likely difference s in human leukocyte antigen type among patients with Graves' disease, several distinct hTSHR epitopes elicited significant responses in the immune system of patients with Graves' disease, and that such patient s are most often poorly tolerant to particular epitopes of the TSH rec eptor ectodomain, The data support the notion of TSHR peptide antigens overriding human immune heterogeneity in patients with Graves' diseas e, and raise the possibility of applying analog peptide blockade to su ppress T cell responsivity.