Activation of T lymphocyte subsets by synthetic TSH receptor peptides and recombinant glutamate decarboxylase in autoimmune thyroid disease and insulin-dependent diabetes.
We have postulated that a defect in specific antigenic induction of suppressor T lymphocytes may account for the immunoregulatory disorder in autoimmune thyroid disease. In this context, we have measured the proliferative responses of peripheral blood mononuclear cells (PBMC) to the synthetic peptides corresponding to the extracellular domain of the TSH receptor (TSHR) and recombinant glutamate decarboxylase (GAD65) by means of 3H thymidine incorporation. We have also studied the antigenic 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' disease (GD) [including 19 hyperthyroid GD (hyper GD)], 18 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), 18 with insulin-dependent diabetes (IDDM), and 20 normal controls (N), were cultured for 7 days in the presence or absence of the pool peptides representing 3 different segments of TSHR or GAD65 at final concentration of 30 micrograms/mL or 10 micrograms/mL. The proportion of subjects whose PBMC gave a positive 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, IDDM, and N group. The corresponding differences in mean SI provided analogous results, showing significant responses above normal in only hyper GD. The CD4+ T lymphocytes from hyper GD group were significantly more activated by TSHR peptides compared to eu GD, HT, IDDM, and N, and this induction correlated to their thyroid hormone levels. Quite differently, the activation of CD8+ T lymphocytes from both hyper GD and 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 lymphocytes, this was independent of thyroid hormone levels. On the other hand, while the CD8+ T lymphocytes from GD and N groups were activated 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 conclusion, the activation of CD8+ T lymphocytes from GD and IDDM by relevant antigens (i.e. TSHR peptides for GD and GAD65 for IDDM) was impaired, but not by irrelevant antigens (i.e. GAD65 for GD and TSHR peptides for IDDM). There was also a modest stimulation of CD8+ T cells from all groups by tetanus toxoid and cardiac myosin light chain peptide, both irrelevant antigens.(ABSTRACT TRUNCATED AT 400 WORDS)
Mukuta
T
T
Department of Medicine, Wellesley Hospital, University of Toronto, Ontario, Canada.
Yoshikawa
N
N
Arreaza
G
G
Resetkova
E
E
Leushner
J
J
Song
Y H
YH
Akasu
F
F
Onaya
T
T
Volpé
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D004700:Endocrine System Diseases / Q000503:physiopathology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000494:pharmacology*; D006111:Graves Disease / Q000503:physiopathology; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D011989:Receptors, Thyrotropin / Q000737:chemistry*; D011994:Recombinant Proteins; D016176:T-Lymphocyte Subsets / Q000187:drug effects*; D013967:Thyroiditis, Autoimmune / Q000503:physiopathology
D010446:Peptide Fragments; D011989:Receptors, Thyrotropin; D011994:Recombinant Proteins; D005968:Glutamate Decarboxylase