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TitleExperimental autoimmune thyroiditis induced in mice by thyroglobulin T-cell determinants
AuthorVarada, Panduranga Rao, 1962-
DescriptionThesis (Ph.D.)--Memorial University of Newfoundland, Faculty of Medicine, 1997. Medicine
Pagination180 leaves : graphs
SubjectAutoimmune thyroiditis; T cells;
Subject.MESHThyroiditis, Autoimmune;T-Lymphocytes; Thyroiditis, Autoimmune; T-Lymphocytes;
Degree GrantorMemorial University of Newfoundland. Faculty of Medicine
NotesBibliography: leaves 149-180.
AbstractExperimental autoimmune thyroiditis (EAT) induced in mice following challenge with thyroglobulin (Tg) in adjuvant, serves as a model for Hashimoto's thyroiditis (HT). Earlier work in our laboratory established that EAT can be induced in mice following challenge with a 17mer MTg(2495-11) or an 18mer MTg(2695-13) peptide, in complete Freunds adjuvant: (2495-11) peptide induced thyroiditis in H-2 k, s haplotypes while (2695-13) peptide induced disease only in H-2s haplotype. In the present study, truncation analysis using a panel of peptide-specific TCR αβ+CD4 + CD8-T-cell hybridomas from EAT-susceptible C3H mice, identified two overlapping 9mer minimal determinants (2496-04) and (2499-07) within MTg(2495-11). The Ek -restricted (2496-04) determinant was immunogenic and pathogenic not only in C3H but also in SJL mice. Further, the determinants within MTg(2495-11) recognized by A s -restricted SJL T cells were mapped identical to those restricted by the Ek and Ak molecules. MTg(2496-04)-primed lymph node cells (LNC) secreted IL-2, IFN-γ but not IL-4 upon specific activation in vitro , suggesting that induction of Th1 cells follows priming with the minimal Tg peptide in SJL mice. In addition, TCR-Vβ 2, 4 and 17 genes were utilized by a panel of ten MTg(2496-04)-specific IL-2-secreting hybrid T-cell clones generated from this Th1 subset, thus providing the first evidence of multiple TCR-Vβ gene usage in EAT induced with a minimal Tg epitope. In parallel, work involving the 18mer MTg(2695-13) peptide established a panel of TCR αβ +CD4+ CD8 -IL-2 secreting T-cell hybridomas from SJL mice. Using two As -restricted (2695-13)-specific T-cell hybrids and three overlapping 12mer peptides spanning the core, N- and C-terminal regions of MTg(2695-13), two distinct T-cell determinants were localized within the 18mer peptide. The N-terminal 12mer (2695-06) was highly immunogenic and induced severe EAT following adoptive transfer of peptide-specific Th1 cells. A human homologue of MTg(2695-06) carrying two Ser substitutions of GLn2703 and Thr2704, on the other hand, showed contrasting immunopathogenic properties: it failed to activate Th1 cells; it did not cross-react with MTg(2695-06)-specific T cells and induced only mild thyroiditis. These findings highlight caution against extrapolating the epitope mapping data across heterologous Tgs despite their high homology. Finally, a computer search of SWISS-PROT data bank to identify sequences highly homologous with pathogenic Tg determinants, has led to identification of a 14mer adenoviral E1B(368-81) peptide (AVP). The viral peptide cross-reacted significantly with MTg(2696-04) at B- and T-cell level. AVP, however, failed to induce specific B- or T-cell responses. Despite its poor immunogenicity, AVP, when used as an Ag in vitro , conferred the EAT-inducing ability on MTg(2696-04)-primed LNC in adoptive transfer experiments. These findings suggest that viral peptides, such as AVP, when generated during infection, can amplify autoreactive T cells (via molecular mimicry) present in the host and thus, precipitate autoimmune thyroid disease.
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SourcePaper copy kept in the Centre for Newfoundland Studies, Memorial University Libraries
Local Identifiera1260835
RightsThe author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
CollectionElectronic Theses and Dissertations
Scanning StatusCompleted
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CONTENTdm file name126737.cpd