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      Immunization with thyroglobulin induces Graves'-like disease in mice

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      The Journal of Endocrinology

      BioScientifica

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          Abstract

          We immunized AKR/N mice with bovine thyroglobulin (Tg) once every 2 weeks and monitored their time-dependent changes in 125I uptake activity in the thyroid glands. After 3 months, anti-Tg antibody was positive in all sera from the immunized mice. Serum free tri-iodothyronine (T 3) and free thyroxine (T 4) levels in the immunized mice ( n=6) were significantly higher than those in the saline injected (control) mice ( n=6). Neck counts as well as scintigraphy of the thyroid glands revealed that iodide uptake activity of the immunized mice was not suppressed, but was instead higher than that of the control mice. Two of the six immunized mice showed extremely high iodide uptake activity. The thyroid glands of these two mice were diffusely enlarged and the height of the epithelial cells was also increased. In addition, two mice with high iodide uptake activity produced a high titer of thyroid-stimulating antibody. Additional experiments showed that 4 out of 11 AKR/N mice and 3 out of 10 C57BL6 mice immunized with Tg had high serum free T 3/free T 4 levels, high 125I uptake activity of the thyroid, and positive thyroid-stimulating antibody activity. Diffuse goiter, thyrotoxicosis, high iodide uptake activity, and positive thyroid-stimulating antibody are the characteristics of Graves' disease. Thus, these mice exhibit the symptoms of Graves' disease. These results suggest that immunization with Tg induces Graves'-like disease in mice and that our methods will provide a new animal model of Graves' disease.

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          Most cited references 17

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          Chronic autoimmune thyroiditis.

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            Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity.

            Immune responses are initiated by HLA-DR+ cells, which present antigen to T cells. Observations that HLA-DR may be experimentally induced on thyroid epithelium and that HLA-DR occurs on thyrocytes in autoimmune thyroid diseases suggest a mechanism of autoimmunity with special relevance to organ-specific diseases. This involves the local aberrant expression of HLA-DR antigens by epithelial cells and their subsequent capacity to present autoantigens occurring on their surfaces to T lymphocytes. For autoantigens which T cells recognise infrequently because of their restricted tissue location and low concentration in the circulation, T-cell tolerance is unlikely, and so induction of autoreactive T cells would occur. Because interferon is the best known inducer of DR antigen expression and viral infections may predate endocrine autoimmunity, the following sequence seems likely: local viral infection which causes interferon production, or other local environmental factors which would induce DR expression, presentation of autoantigens, and subsequent autoimmune T-cell induction. These T cells would activate effector B and T cells. Whether the initial induction of autoimmune T cells leads to autoimmune disease would depend on factors such as abnormalities of the suppressor T-cell pathway, reported to coexist with autoimmunity and necessary to induce autoimmune disease in mice. This mechanism of autoimmune disease induction explains vague associations with viral infections and long latency periods before disease becomes manifest and gives a simple explanation for the well-documented association between HLA-DR and autoimmune diseases in man.
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              Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule.

              Graves disease is an autoimmune thyroid disease characterized by the presence of antibodies against the thyrotropin receptor (TSHR), which stimulate the thyroid to cause hyperthyroidism and/or goiter. By immunizing mice with fibroblasts transfected with both the human TSHR and a major histocompatibility complex class II molecule, but not by either alone, we have induced immune hyperthyroidism that has the major humoral and histological features of Graves disease: stimulating TSHR antibodies, thyrotropin binding inhibiting immunoglobulins, which are different from the stimulating TSHR antibodies, increased thyroid hormone levels, thyroid enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. The results suggest that the aberrant expression of major histocompatibility complex class II molecules on cells that express a native form of the TSHR can result in the induction of functional anti-TSHR antibodies that stimulate the thyroid. They additionally suggest that the acquisition of antigen-presenting ability on a target cell containing the TSHR can activate T and B cells normally present in an animal and induce a disease with the major features of autoimmune Graves.
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                Author and article information

                Journal
                J Endocrinol
                JOE
                The Journal of Endocrinology
                BioScientifica (Bristol )
                0022-0795
                1479-6805
                August 2009
                2 June 2009
                : 202
                : 2
                : 217-222
                JOE090089
                10.1677/JOE-09-0089
                2710975
                19491147
                © 2009 Society for Endocrinology

                This is an Open Access article distributed under the terms of the Society for Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funding
                Funded by: Ministry of Education, culture, sports, Japan
                Award ID: 21591127
                Categories
                Regular papers

                Endocrinology & Diabetes

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