The role of the spleen in experimental autoimmune thyroiditis.
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We have investigated the role of the spleen in the humoral and cellular immune response of rats with experimental autoimmune thyroiditis (EAT) induced by immunization with thyroglobulin and Freund's complete adjuvant. Animals subjected to splenectomy within 4 days of immunization developed lower thyroglobulin antibody levels and less severe thyroiditis compared to sham operated controls. There was no impairment in the ability of the animals to recover spontaneously from the disease after splenectomy. Together with the results obtained using splenocyte infusions, this suggests that suppressor cell production within the spleen plays only a small part in the normal immunological control which is presumably responsible for spontaneous regression of the disease.Keywords:
Splenocyte
Thyroglobulin
Autoimmune thyroiditis
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We have investigated the role of the spleen in the humoral and cellular immune response of rats with experimental autoimmune thyroiditis (EAT) induced by immunization with thyroglobulin and Freund's complete adjuvant. Animals subjected to splenectomy within 4 days of immunization developed lower thyroglobulin antibody levels and less severe thyroiditis compared to sham operated controls. There was no impairment in the ability of the animals to recover spontaneously from the disease after splenectomy. Together with the results obtained using splenocyte infusions, this suggests that suppressor cell production within the spleen plays only a small part in the normal immunological control which is presumably responsible for spontaneous regression of the disease.
Splenocyte
Thyroglobulin
Autoimmune thyroiditis
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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.
Thyroglobulin
Autoimmune thyroiditis
Anti-thyroid autoantibodies
Thyroid peroxidase
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Experimental autoimmune thyroiditis (EAT), which to some extent represents an experimental model of human chronic lymphocytic thyroiditis, is an organ-specific autoimmune disease characterized by autoantibody production to thyroid antigens (Ag) and mononuclear infiltration of the thyroid gland. EAT induced by immunization with human thyroglobulin (hTG) with Freund's adjuvant in CBA/J (H-2K) mice is associated with prominent B and T cell responses. We report that oral administration of hTG effectively reduces the immune responses in EAT in mice in an Ag-specific manner. Both cellular and humoral immune responses are reduced in a dose-dependent manner. Histological evidence of disease is dramatically reduced. Suppression of the immune responses is seen 2 weeks after Ag challenge, with partial inhibition of proliferative and antibody responses. Six weeks after immunization, further inhibition is observed of both T and B cell responses. Hyporesponsiveness of T and B cell reactivity is seen only to hTG; T and B cell responses to other immunogens are not affected, including purified protein derivative and the nonrelated Ag BSA. This model may provide the basis for immunotherapy of autoimmune thyroid diseases in man.
Thyroglobulin
Autoimmune thyroiditis
Mononuclear cell infiltration
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We have analysed the isoelectric focusing (IEF) spectra of antithyroglobulin autoantibodies in the sera of patients with autoimmune thyroiditis, and of anti-dsDNA autoantibodies in the sera of patients with systemic lupus erythematosus (SLE), NZB/NZW F1 hybrid, MRL-lpr/lpr and MRL/++ male and female mice. Ninety-two per cent of patients with anti-thyroglobulin autoantibodies had a polyclonal spectrotype compared with only 25% of SLE patients analysed for anti-dsDNA. Fifty-five per cent of the latter had monoclonal spectrotypes, the remainder being either biclonal or having a dominant clone on a polyclonal background. By contrast, only two out of 61 autoimmune thyroiditis patients expressed monoclonal anti-thyroglobulin autoantibodies. All of the lupus mice had highly restricted spectrotypes (monoclonal or biclonal) of anti-dsDNA autoantibodies. The implications of these results for the aetiology of autoimmunity are discussed.
Thyroglobulin
Autoimmune thyroiditis
clone (Java method)
Anti-thyroid autoantibodies
Polyclonal antibodies
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Thyroglobulin
Autoimmune thyroiditis
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Abstract The effects of anti‐receptor (anti‐idiotypic) immunity on autoimmune responses have been investigated in Buffalo (BUF) rats with autoimmune thyroiditis. As compared to other animal models of autoimmune desease, BUF rat thyroiditis has the following advantages: it occurs in an inbred strain, arises spontaneously ( i.e. without the experimental administration of autoantigens and adjuvants) and is characterized by the production of autoantibodies to only one autoantigen, thyroglobulin. Finally, its pathogenesis is mediated by autoantibodies to rat thyroglobulin, and therefore this model is particularly suitable to study the effects of anti‐idiotypic reactions on those autoimmune disorders whose damage is caused by humoral immunity. The experiments reported in the present study show that first, heterologous anti‐idiotypic antibodies to autoantibodies against rat thyroglobulin have been produced and characterized. It has then been demonstrated that such anti‐idiotypic antibodies are capable of inhibiting the in vitro binding between thyroglobulin and thyroglobulin autoantibodies obtained from BUF rats. It has also been shown that repeated injections of anti‐idiotypic antibodies into sublethally X‐irradiated BUF rats with autoimmune thyroiditis were followed by a significant change in the levels of circulating autoantibodies to rat thyroglobulin. These results provide evidence that in spite of the complexity of autoantigens and the heterogeneity of autoimmune responses, established autoimmune diseases may be controlled by sequential immunosuppression and anti‐idiotypic immunity.
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Autoimmune thyroiditis
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We have developed a thyroglobulin-specific haemolytic plaque assay and investigated potential sites of autoantibody synthesis in good and poor responder strains of rats immunized with thyroglobulin and in rats subjected to thymectomy and sub-lethal irradiation which subsequently develop thyroiditis spontaneously. The bone marrow appears to be the most important site of thyroglobulin antibody synthesis in all groups, but spleen and cervical lymph nodes are also involved. No thyroglobulin plaque-forming cells could be found in the thyroid. These results imply widespread involvement of the humoral immune system in organ-specific autoimmune processes.
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Thymectomy
Autoimmune thyroiditis
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Thyroglobulin
NOD mice
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Chickens of the Obese strain (OS) develop a spontaneous, hereditary autoimmune thyroiditis during the first weeks of life which parallels human Hashimoto's thyroiditis in all clinical, histopathological and serological aspects. This review summarizes the results from investigations on this strain with special emphasis on the pathogenic effector mechanisms leading to the autoimmune destruction of the thyroid gland. The fact that this model disease arises in an avian species is particularly advantageous because of the clear-cut anatomical and functional division of the immune system. Data are discussed which suggest the following pathogenesis of spontaneous autoimmune thyroiditis: B cells and their products, i.e. thyroglobulin autoantibodies, play a decisive role in the initial phases of the disease, such antibodies are first vertically transferred from the mother hen via the egg yolk into the embryo and newly hatched chick, the immune system of which then takes over their production. T-helper cells are required for the formation of the thyroglobulin autoantibodies. These antibodies can either be complement-fixing or mediate destruction of the target cells via antibody-dependent cellular cytotoxicity (ADCC). B cells themselves also destroy thyroid epithelial cells directly in ADCC-like fashion. Cytotoxic T cells seem to play a minor role in the beginning, but add to the destruction of the thyroid gland later. The underlying defect appears to be a deficient intrathymic maturation of suppressor cells leading to a lack of their emigration to the periphery. The development of the disease is under multigenic control, involving at least three loci. Genes associated with the B locus [the major histocompatibility complex (MHC) of the chicken] and a non-B locus seem to be responsible for the immunological hyperreactivity of the OS towards autologous (thyroid and non-thyroid) and exogenous antigens. The third locus is considered to determine a primary thyroid defect thus predisposing this organ as a prime target for the manifestation of autoimmune disease in the OS.
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Autoimmune thyroiditis
Pathogenesis
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