ACTIVATION OF T-LYMPHOCYTE SUBSETS BY SYNTHETIC TSH RECEPTOR PEPTIDESAND RECOMBINANT GLUTAMATE-DECARBOXYLASE IN AUTOIMMUNE THYROID-DISEASEAND INSULIN-DEPENDENT DIABETES

We have postulated that a defect in specific antigenic induction of su ppressor T lymphocytes may account for the immunoregulatory disorder i n autoimmune thyroid disease. In this context, we have measured the pr oliferative responses of peripheral blood mononuclear cells (PBMC) to the synthetic peptides corresponding to the extracellular domain of th e TSH receptor (TSHR) and recombinant glutamate decarboxylase (GAD65) by means of H-3 thymidine incorporation. We have also studied the anti genic activation of CD4(+) and CD8(+) T lymphocytes by measuring human leukocyte antigen-DR (HLA-DR) expression on the cell surface by flow cytometric analysis. PBMC obtained from 47 patients with Graves' disea se (GD) [including 19 hyperthyroid GD (hyper GD)], 18 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), 18 with insuli n-dependent diabetes (IDDM), and 20 normal controls (N), were cultured for 7 days in the presence or absence of the pool peptides representi ng 3 different segments of TSHR or GAD65 at final concentration of 30 mu g/mL or 10 mu g/mL. The proportion of subjects whose PBMC gave a po sitive proliferative response with a stimulation index (SI) of over 2. 3 (i.e. above the mean +2 SD for N) to TSHR peptides was significantly higher in the hyper GD group than among euthyroid GD (eu GD), HT, IDD M, and N group. The corresponding differences in mean SI provided anal ogous results, showing significant responses above normal in only hype r GD. The CD4(+) T lymphocytes from hyper GD group were significantly more activated by TSHR peptides compared to eu GD, HT, IDDM, and N, an d this induction correlated to their thyroid hormone levels. quite dif ferently, the activation of CD8(+) T lymphocytes from both hyper GD an d eu GD group in response to TSHR peptides was impaired compared to HT , IDDM, and the N group; in contrast to the findings with CD4(+) T lym phocytes, this was independent of thyroid hormone levels. On the other hand, while the CD8(+) T lymphocytes from GD and N groups were activa ted equally by GAD65, the activation of CD8(+) T lymphocytes from the IDDM group by GAD65 was impaired compared to the GD and N groups. In c onclusion, the activation of CD8(+) T lymphocytes from GD and IDDM by relevant antigens (i.e. TSHR peptides for GD and GAD65 for IDDM) was i mpaired, but not by irrelevant antigens (i.e. GAD65 for GD and TSHR pe ptides for IDDM). There was also a modest stimulation of CD8(+) T cell s from all groups by tetanus toroid and cardiac myosin light chain pep tide, both irrelevant antigens. There thus appears to be a disease-spe cific defect in specific antigen induction of suppressor T lymphocytes which might be important in the pathogenesis of organ-specific autoim mune disease.