Graves' disease is an autoimmune disorder caused by pathogenic thyroid stimulating antibodies (TSAb) that mimic TSH in activating the TSH receptor (TSHR). The resulting hyperthyroidism can be treated but there is no cure. A critical barrier to studying its pathogenesis, as well as investigation of novel therapies, is that Graves' disease only occurs in humans. Therefore, the development of a mouse model that spontaneously develops pathogenic TSHR antibodies would represent a highly significant advance, providing insight into the pathogenesis of Graves' disease and facilitating investigation of potential approaches for specific immunotherapy for cure, rather than treatment of this common human disease. By crossing transgenic mice that express the human TSHR A-subunit in the thyroid to another mouse strain that spontaneously develops thyroiditis, we have developed the first animal model, hTSHR/NOD-H2h4 mice, that spontaneously develops pathogenic TSAb.
Our first aim will be to optimize and characterize the hTSHR/NOD-H2h4 mouse model. We will complete back-crossing to the parent strain for a total of 10 generations to ensure that hTSHR/NOD-H2h4 mice have 100% of NOD-H2h4 background genes. We will then determine the time course of pathogenic TSHR antibody generation, titer and maintenance of levels, as well as characterize the model for thyroid function, thyroid histology and the full compendium of thyroid autoantibodies.
Our second aim i s to investigate factors that may influence the spontaneous development of pathogenic TSAb in this model including the role of central tolerance by measuring intrathymic expression of the human TSHR A-subunit (and the other thyroid antigens). We will also assess the influence of regulatory T cells on TSHR Ab development, determine epitopes recognized by T-cells, as well as the influence of environmental factors (vitamin D3 and selenium) on TSAb levels.
Our third aim i s to suppress the development and, particularly on-going production, of TSAb. Approaches to be used will be injecting TSHR A-subunit protein, an approach that may cause deviation of TSAb to a benign, non-pathogenic form. We will also attempt to induce tolerance to the TSHR by a number of approaches, including injecting immature dendritic cells pulsed with purified TSHR A-subunit protein, as well as by blocking the second signal between T-cells and antigen presenting cells.

Public Health Relevance

Graves' hyperthyroidism is caused by thyroid stimulating antibodies (TSAb) to the thyrotropin receptor (TSHR) that arise spontaneously in humans but not in animals. We have developed the first animal model that spontaneously develops TSAb and can be used to investigate disease pathogenesis. Moreover, this spontaneous mouse model can be used to test novel interventions to decrease thyroid stimulating antibodies with the goal of pointing the way to curing, not simply treating, this common autoimmune disease in humans.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Spain, Lisa M
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Cedars-Sinai Medical Center
Los Angeles
United States
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McLachlan, Sandra M; Aliesky, Holly A; Rapoport, Basil (2018) Aberrant Iodine Autoregulation Induces Hypothyroidism in a Mouse Strain in the Absence of Thyroid Autoimmunity. J Endocr Soc 2:63-76
McLachlan, Sandra M; Lesage, Sylvie; Collin, Roxanne et al. (2017) Genes Outside the Major Histocompatibility Complex Locus Are Linked to the Development of Thyroid Autoantibodies and Thyroiditis in NOD.H2h4 Mice. Endocrinology 158:702-713
Ludwig, Ralf J; Vanhoorelbeke, Karen; Leypoldt, Frank et al. (2017) Mechanisms of Autoantibody-Induced Pathology. Front Immunol 8:603
McLachlan, Sandra M; Aliesky, Holly; Banuelos, Bianca et al. (2017) Variable Effects of Dietary Selenium in Mice That Spontaneously Develop a Spectrum of Thyroid Autoantibodies. Endocrinology 158:3754-3764
McLachlan, Sandra M; Rapoport, Basil (2017) Thyroid Autoantibodies Display both ""Original Antigenic Sin"" and Epitope Spreading. Front Immunol 8:1845
Rapoport, Basil; Banuelos, Bianca; Aliesky, Holly A et al. (2016) Critical Differences between Induced and Spontaneous Mouse Models of Graves' Disease with Implications for Antigen-Specific Immunotherapy in Humans. J Immunol 197:4560-4568
Rapoport, Basil; McLachlan, Sandra M (2016) TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev 37:114-34
Rapoport, Basil; McLachlan, Sandra M (2016) TSH Receptor Cleavage Into Subunits and Shedding of the A-Subunit; A Molecular and Clinical Perspective. Endocr Rev 2016:23-42
Rapoport, Basil; Aliesky, Holly A; Banuelos, Bianca et al. (2015) A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor. J Immunol 194:4154-61
Pelletier, A-N; Aliesky, H A; Banuelos, B et al. (2015) Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice. Genes Immun 16:268-74

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