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Context: Hashimoto's thyroiditis (HT) is a common autoimmune disease leading to thyroid destruction due to lymphocytic infiltration. Only rare data are available regarding the recognition of specific cellular antigens, e.g. of thyroperoxidase (TPO) and thyroglobulin (Tg)., Objective: The aim of this study was to quantify and characterize TPO- and Tg-epitope-specific CD8-positive T cells of HT patients., Design: Six different human leukocyte antigen (HLA)-A2 restricted, TPO- or Tg-specific tetramers were synthesized and used for measuring CD8-positive T cells in HT patients and controls., Results: The frequency of peripheral TPO- and Tg-specific CD8-positive T cells was significantly higher in HLA-A2-positive HT patients (2.8 ± 9.5%) compared with HLA-A2-negative HT patients (0.5 ± 0.7%), HLA-A2-positive nonautoimmune goiter patients (0.2 ± 0.4%), and HLA-A2-positive healthy controls (0.1 ± 0.2%). The frequency of Tg-specific T cells (3.0%) was very similar to those of TPO-specific CD8-positive T cells (2.9%). Subgroup analyses revealed a steady increase of the number of epitope-specific CD8-positive T cells from 0.6 ± 1.0% at initial diagnosis up to 9.4 ± 18.3% in patients with long-lasting disease. Analyses of the number of thyroid-infiltrating cells as well as the cytotoxic capacity revealed a similar picture for TPO- and Tg-specific T cells., Conclusion: We here report for the first time that both antigens, TPO and Tg, are recognized by CD8-positive T cells and are involved in the thyroid destruction process leading to clinical disease manifestation.

Graves' disease is an organ-specific autoimmune disease, and intrathyroidal lymphocytes seem to be the major source of thyroid autoantibodies. Consequently, the intensity of the intrathyroidal lymphocytic infiltration is generally believed to reflect the activity of the autoimmune process. We, therefore, investigated the correlation of microsomal (enzyme immunoassay), thyroglobulin (RIA), and TSH receptor antibodies (RRA) with the degree of intrathyroidal infiltration by immunoglobulin G-producing plasma cells, activated T-cells, antigen-presenting cells, and the total number of lymphocytes. The immunocompetent cells were identified immunohistologically with monoclonal antibodies for immunoglobulins kappa and lambda, UCHL1, and the S100 antibody, respectively, in 26 thyroid glands of patients suffering from Graves' disease. The intensity of lymphocytic infiltration was determined by the point-counting method and by counting all lymphocytes and the labeled lymphocytes in 3 x 51 visual fields or 3 slides/thyroid gland. Microsomal antibodies correlated significantly (P = 0.001) with the total number of lymphocytes (r = 0.86), kappa (r = 0.71), lambda (r = 0.71), UCHL1 (r = 0.9), and S100 (r = 0.9) positive cells. These correlations were also significant for thyroglobulin antibodies. However, TSH receptor antibodies showed no significant correlations with any of the populations of immunocompetent cells. Patients with preoperatively undetectable TSH receptor or microsomal antibodies showed a broad variation of intrathyroidal infiltration by the immunocompetent cells investigated. Microsomal antibody titers, therefore, seem to reflect the intensity of the intrathyroidal autoimmune process in Graves' disease better than TSH receptor antibodies. However, the broad baseline variation in intrathyroidal infiltration observed with nondetectable thyroid antibodies will not always allow determination of the intensity of the intrathyroidal autoimmune process from microsomal or thyroglobulin antibody titers.

Specific receptors for endothelin-1 (ET), a newly described vasoconstrictor peptide isolated from endothelium, have been identified in endocrine tissues such as hypothalamus, adrenal and pituitary. ET binding or action, not previously described in thyroid, were explored in this study. ET binding in cultured human thyrocytes was assayed at 4 C, 25 C, and 37 C, for 0.5-6 h with [125I]ET (0.1 nmol/L), and nonspecific binding estimated by coincubation with unlabeled ET (100 nmol/L). At 4 C, maximum specific binding was reached after 4 h; at 25 C and 37 C, specific binding increased in a time-dependent manner over 6 h with increased binding obtained at higher temperature. At 37 C after 2 h, 11% specific bound ET localized to surface membranes with 89% internalized. Scatchard analysis of surface membrane binding at 4 C for 4 h showed high affinity single class ET receptor (Kd = 0.20 nmol/L) and binding capacity of 4045 sites per cell. ET binding to thyroid cells had no effect on production of cAMP or cGMP. ET (0.1 nmol/L) significantly (P less than 0.001) inhibited thyroglobulin release from thyroid cells after 6 days with no effect on thymidine incorporation. Thus, we have identified specific receptors for endothelin in human thyrocytes, and an inhibitory action of the peptide on thyroglobulin release which is mediated by a noncyclic nucleotide mechanism.

The effects of betamethasone on thyroid autoantibody responses and outcome of radioiodine therapy were determined over a period of 1 yr in a prospective randomized study of 40 patients with Graves' disease. Twenty patients were given placebo tablets, and 20 patients were treated with beta-methasone from 3 weeks before until 4 weeks after 131I therapy. At the time of inclusion in the study, the mean serum concentrations of TSH receptor antibodies, thyroid peroxidase antibodies, and thyroglobulin antibodies (TgAb) were increased in both groups. Three weeks of treatment with betamethasone reduced the thyroid peroxidase antibody and TgAb titers as well as the serum concentrations of thyroid hormones. A decrease in the TSH receptor antibody level was not statistically significant. After radioiodine therapy, transient increases in thyroid autoantibody levels were observed. The titers of the different antibodies generally changed in parallel. In some patients a detectable level of a given antibody was found only after the radioiodine treatment, and in two cases, TgAb did not appear at all, although the two other antibodies increased temporarily. Betamethasone delayed, but did not abolish, the 131I-induced antibody peaks. Betamethasone also caused a reduction in the total serum immunoglobulin G, a reduction which persisted throughout the study period. When the study ended, 17 patients given placebo and 9 patients given betamethasone (P less than 0.001) were receiving replacement therapy due to the development of hypothyroidism. These patients at this point in time had lower antibody levels than those not requiring T4. The results of this study demonstrate that betamethasone reduces and modifies the thyroid autoantibody responses as well as the outcome of radioiodine therapy in patients with Graves' disease. From a clinical point of view, these effects may be in opposite directions.