| Summary: | Thesis (Ph.D.)--Memorial University of Newfoundland, 1995. Medicine Bibliography: leaves 207-249 Experimental autoimmune thyroiditis (EAT) in mice induced by thyroglobulin (Tg) and adjuvant has been studied as a model for Hashimoto's thyroiditis. The disease is MHC-controlled and T-cell mediated but little is known about the nature and the number of immunopathogenic Tg T-cell epitopes. In this study, we attempted to define such epitopes by testing Tg sequences, previously identified as potential T-cell epitopes through the AMPHI and "tetramer motif algorithms, in various strains of mice for both immunogenicity and pathogenicity. From the three synthetic Tg peptides tested two sequences, TgPl and TgP2, were found to be pathogenic in classical high responder (H- 2k and/or H-2S) mice. The third sequence, TgP3, was not pathogenic in mice of k,b,d,s haplotypes. All three sequences were immunogenic in mice because they induced peptide-specific antibodies and/or T cells which were strain dependent. TgPl and TgP2 were shown to encompass non-dominant determinant(s) at both B- and T-cell levels. Similarly, TgP3 was found to involve non-dominant B-cell epitope(s) although its ability to be recognized by T cells was never tested. EAT induction with defined Tg T-cell epitopes constitutes a system where the fine mechanisms leading to thyroid autoimmunity can be extensively studied at both cellular and molecular levels. In an approach to study these mechanisms using defined Tg peptides, we attempted to map the H-2 region(s) responsible for EAT induction by TgPl. As in Tg-induced EAT, TgPl- induced EAT was shown to be under the direct control of MHC-region products and to follow a pattern similar to Tg disease susceptibility. However, within the k haplotype, expression of H-2E but not H-2A molecules was necessary for EAT induction, Moreover, TgPl was shown to elicit IgG specific antibodies which were reactive to purified Tg in vitro and Tg stored in the lumen of normal mouse thyroids. This finding may imply involvement of TgPl-specific IgG in EAT pathogenicity although such involvement has not been further investigated in this study. In summary, the application of algorithms for prediction of Tg T cell-reactive sites was proved to be successful and reliable. Defined tmmunopathogenic Tg T-cell epitopes can be used as tools to study immunoregulation in autoimmunity and to design specific immunotherapeutic strategies.
|
|---|