Evaluation of murine experimental autoimmune thyroiditis as an appropriate model for autoimmune thyroid disease

Murine experimental autoimmune thyroiditis (EAT), is used as a model for human autoimmune thyroid disease. Both autoantibodies to thyroglobulin (TG) and lymphocytic infiltration of the thyroid gland are manifested in susceptible murine strains challenged with mouse thyroglobulin (MTG) and adjuvant (CFA or LPS), but little is known about the factors responsible for initiating the disease process. By studying the duration of EAT induced with either MTG/LPS or MTG/CFA I have demonstrated that the adjuvant can influence the course of the disease. Analysis of the binding specificities of the anti-TG autoantibodies established further differences. These findings indicate that the degree of qualitative differences between the two protocols is sufficient to rationalise the use of MTG/LPS induced EAT as a more appropriate model. The main conclusion to be drawn is that finer variations in antibody specificity may, either directly or indirectly, determine the disease process. In addition, it was established that the specificity of the autoantibody response is influenced by the prior history of the animal. For example, adult mice pretreated with aminotriazole (an anti-thyroid agent) had a reduced autoantibody response to MTG/LPS challenge. These autoantibodies also had lower binding activity to rat TG. The implications of this data are discussed in relation to the structure of the pre-immune repertoire and the elements of connectivity which continuously establish a state of tolerance to specific immunogenic epitopes. In vitro studies of the responsiveness of mouse thyroid follicular cells to the cytokine interferon-γ (IFN-γ), which is known to induce the expression of class II MHC antigens on human thyrocytes, further established the suitability of this animal model for investigating the pathogenic mechanisms which may lead to thyroiditis. IFN-γ also modulated the expression of TG in thyrocytes. Mouse thyrocytes which were stimulated with IFN-γ could present endogenously synthesized TG to MHC class Il-antigen restricted TG specific T cell hybridomas.