Newer Insights into the Pathogenesis of Experimental Autoimmune Thyroiditis

Abstract

Experimental autoimmune thyroiditis (EAT), produced in the mouse by immunization with murine thyroglobulin plus complete Freund's adjuvant, represents a valuable model for studying the pathogenesis of human chronic (Hashimoto's) thyroiditis. A major issue requiring clarification is the difference between benign autoimmunity, characterized solely by production of autoantibodies to thyroglobulin, and pathogenic autoimmunity where injury occurs to the thyroid cells. In this article, we describe the role of two key cytokines, IL12 and IFNgamma, in modifying the pathogenic immune response. EAT, defined by cellular infiltration of the thyroid and the development of thyroglobulin-specific autoantibodies, is a dynamic process. Consequently, a cytokine may exert a different effect at different times during the disease process. For purposes of discussion, we propose that there are three stages in the development of EAT: priming; initiation; and progression. Administration of anti-IL12 during the priming stage and initiation dramatically decreases disease and lowers autoantibody levels. In contrast, injection of recombinant IL12 after disease was established significantly decreases the severity of disease and reduces autoantibody levels. Unlike IL-12, IFNgamma was not essential for the priming of EAT. However, the severity of disease in the anti-IFNgamma-treated initiation- and progression-treated animals was higher than in controls, implying a regulatory role for IFNgamma. These findings emphasize that EAT involves a complex array of pathogenic mechanisms. The balance of cytokines produced during the early phase of the autoimmune reaction probably determines the progression from a harmless autoimmune response to autoimmune disease.

Thyroid-Specific Expression of IFN-γ Limits Experimental Autoimmune Thyroiditis by Suppressing Lymphocyte Activation in Cervical Lymph Nodes

“…We showed that administration of a mAb that neutralizes IFN-␥ exacerbates disease. These results agree with our previous findings (29) and those by Stull et al (26), who showed that adoptive transfer of splenocytes cultured with thyroglobulin and a IFN-␥-neutralizing Ab causes a more severe granulomatous form of thyroiditis. The findings of these three studies contrast to those by Tang et al (25), who reported that blockade of IFN-␥ with a different neutralizing Ab abrogates EAT.…”

“…Previous studies have provided conflicting results on the role of IFN-␥ in murine EAT. IFN-␥ has been shown to promote (24,25), suppress (26), or have no influence on EAT induction (27)(28)(29). All these studies have relied on manipulations influencing systemic effects of IFN-␥, either by the injection of Abs that block IFN-␥ or by the use of knockout mice that lack IFN-␥ or its receptor.…”

Selective Induction of Dendritic Cells Using Granulocyte Macrophage-Colony Stimulating Factor, But Not fms-Like Tyrosine Kinase Receptor 3-Ligand, Activates Thyroglobulin-Specific CD4+/CD25+ T Cells and Suppresses Experimental Autoimmune Thyroiditis

“…The disease is characterized by lymphocytic infiltration of the thyroid and production of mouse thyroglobulin (mTg)-specific autoantibodies eventually leading to follicular destruction (22,23). Although the mechanism by which CD4 ϩ T cells cause destruction of the thyroid in EAT is not fully understood, the cytokines produced by Th1-type cells (e.g., IFN-␥) likely play an important role (24,25).…”

IL-10-Producing CD4+CD25+ Regulatory T Cells Play a Critical Role in Granulocyte-Macrophage Colony-Stimulating Factor-Induced Suppression of Experimental Autoimmune Thyroiditis

“…In HT, thyroglobulin (Tg)-specific T cells are generated, and they migrate to the thyroid. These cells produce IFN-␥, which induces the expression of MHC class II on thyrocytes and results in further expansion and accumulation of activated mouse Tg (mTg)-specific T cells (1)(2)(3)(4)(5). The mechanism(s) of thyroid destruction, although not completely understood, appears to involve cytokine production by thyroid-infiltrating T cells that can facilitate apoptosis of thyrocytes through caspase activation (6 -9).…”