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First published online on April 12, 2005
This version published online on August 26, 2005
Endocrine Reviews, doi:10.1210/er.2004-0023
A more recent version of this article appeared on October 1, 2005
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*Substance via MeSH

Insight into Graves' Hyperthyroidism from Animal Models

Sandra M. McLachlan, Yuji Nagayama, and Basil Rapoport*

Autoimmune Disease Unit (S.M.M., B.R.), Cedars-Sinai Research Institute and University of California Los Angeles School of Medicine, Los Angeles, California 90048; and Department of Medical Gene Technology (Y.N.), Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-85001, Japan

* To whom correspondence should be addressed. E-mail: mclachlans{at}cshs.org.

Graves' hyperthyroidism can be induced in mice or hamsters by novel approaches, namely injecting cells expressing the TSH receptor (TSHR) or vaccination with TSHR-DNA in plasmid or adenoviral vectors. These models provide unique insight into several aspects of Graves' disease: 1) manipulating immunity toward Th1 or Th2 cytokines enhances or suppresses hyperthyroidism in different models, perhaps reflecting human disease heterogeneity; 2) the role of TSHR cleavage and A subunit shedding in immunity leading to thyroid-stimulating antibodies (TSAbs); and 3) epitope spreading away from TSAbs and toward TSH-blocking antibodies in association with increased TSHR antibody titers (as in rare hypothyroid patients). Major developments from the models include the isolation of high-affinity monoclonal TSAbs and analysis of antigen presentation, T cells, and immune tolerance to the TSHR. Studies of inbred mouse strains emphasize the contribution of non-MHC vs. MHC genes, as in humans, supporting the relevance of the models to human disease. Moreover, other findings suggest that the development of Graves' disease is affected by environmental factors, including infectious pathogens, regardless of modifications in the Th1/Th2 balance. Finally, developing immunospecific forms of therapy for Graves' disease will require painstaking dissection of immune recognition and responses to the TSHR.




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