| Experimental autoimmune thyroiditis (EAT), a murine model of Hashimoto's thyroiditis in humans, is a T cell-mediated autoimmune disease, characterized by destruction of thyroid follicles by infiltrating inflammatory cells. Immunization with thyroglobulin (Tg) - one of the major thyroid autoantigens - or Tg peptides in complete Freund's adjuvant is the classical way to elicit EAT in susceptible mouse strains.;In the second part of the thesis, I examined whether release of tissue antigens from necrotic thyroid epithelial cells can trigger dendritic cell (DC) maturation and initiation of a primary anti-self response. We found that exposure to necrotic - but not viable - thyrocytes ex vivo triggered phenotypic and functional maturation of bone marrow-derived DC. This enabled the immunogenic presentation of thyroid antigens, such as Tg, on the DC surface, leading to the development of EAT. These results support the view that thyroid epithelial cell necrosis may cause autoimmune thyroiditis via maturation of intrathyroidal DC.;Finally, I have examined the intrathymic presence of mRNA transcripts of mouse Tg which encode thirteen pathogenic peptides, scattered over a large (8.5 kb) sequence. We found that Tg mRNA transcripts in thymus, liver and kidney lack the 1-915 bp (including peptide 1-12) and 961-5013 bp (including peptide 1579-91) segments, spanning exons 1-7 and 9-22, respectively. These data demonstrate that certain known and perhaps other as yet unmapped pathogenic T-cell epitopes of Tg cannot be encoded by the truncated isoform(s) of intrathymic Tg mRNA. These findings also imply that central tolerance to endogenous Tg produced by thymic epithelial cells may be incomplete. It is not known, however, to what extent blood-borne Tg molecules that leak from the thyroid in small amounts contribute to the process of tolerance induction.;The first part of the thesis investigates the critical role of iodine in the immunopathogenicity of Tg. I have delineated three iodotyrosyl-containing peptides (aa. 117-132, 304-318, and 1931-1945) which are not immunogenic in their native form but become immunopathogenic in their iodinated form. Iodination of tyrosyls facilitates either peptide binding to MHC or T-cell recognition of the peptide. In addition, iodotyrosyl formation has increasing, neutral or decreasing effects on the immunogenic profiles of other three Tg peptides (a.a. 179-194, 2529-2545, and 2540-2554) which are immunogenic in their non-iodinated forms. In a parallel study, I attempt to generate highly iodinated Tg in vivo via NaI administration in the drinking water of mice. We found that this regimen did not facilitate the generation of highly iodinated Tg in vivo, but elicited goitrous hypothyrodism in SJL but not CBA/J mice. The mechanisms behind this phenomenon remain poorly understood, but it does not seem to have an autoimmune basis. |
