Abstract
After investigating thyroid autoimmunity for more than 40 years, we present a personal
perspective on the field. Despite effective therapies for Graves’ hyperthyroidism
and Hashimoto’s thyroiditis, cures are elusive. Novel forms of therapy are being developed,
such as small molecule inhibitors of the TSH receptor (TSHR), but cure will require
immunotherapy. This goal requires advances in understanding the pathogenesis of thyroid
autoimmunity, the ‘keys’ for which are the thyroid antigens themselves. Presently,
however, greater investigative focus is on non-thyroid specific immune cell types
and molecules. Thyroid autoantigens are the drivers of the autoimmune response, a
prime example being the TSHR. In our view, the TSHR is the culprit as well as the
victim in Graves’ disease because of its unique structure. Unlike the closely related
gonadotropin receptors, the TSHR cleaves into subunits and there is strong evidence
that its shed extracellular A-subunit, not the holoreceptor, is the major antigen
driving pathogenic thyroid stimulating autoantibodies (TSAb) development. There is
no Graves’ disease of the gonads. Studies of potential antigen-specific immunotherapies
require an animal model. Such models have been developed in which TSAb can be induced
or, more importantly, arise spontaneously. Not appreciated until recently by thyroid
investigators is that B cell surface autoantibodies are highly efficient ‘antigen
receptors’ and the epitope to which an autoantibody binds influences antigen processing
and which peptide is presented to T cells. These animal models and recombinant human
autoantibodies cloned from Graves’ and Hashimoto’s B cells (plasma cells) are available
for study by future generations.
Key words
Graves’ disease - TSH receptor - autoantibodies - thyroid peroxidase - thyroglobulin
