Reflections on Thyroid Autoimmunity: A Personal Overview from the Past into the Future

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.

Receptor autoimmunity: diagnostic and therapeutic implications

“…For two centuries GD has been known for its clinical characteristics and the evolution of its knowledge derived from seminal contributions of several authors (Flaiani, Parry, Graves and von Basedow) [11]. The clinical picture of GD is now summarized in the 'GD triad' , consisting of hyperthyroidism, orbitopathy (Graves' eye disease) and dermopathy (pre-tibial myxedema) [12]: the multiple clinical forms of GD (from highly localized thyroid disease to systemic extrathyroidal autoimmune disease, involving retro-orbit, skin and bone) [13] are now considered explicable by the variable forms of the TSHR interested by immune activation (monomeric or dimeric), the heterogeneous sites of TSHR expression (thyrocytes, fibroblasts, adipocytes, bone cells, and other cell types) and the multiplicity of biochemical signals and pathways employed by TSHR (G protein dependent or G-protein independent) [14]. TSHR is a member of class A family of G-protein coupled receptors (with the close relatives follitropin and lutropin/choriogonadotropin receptors) that is essential for the function and growth of the thyroid gland and activates different signaling pathways required for thyroid hormones synthesis and release.…”

“…Recently, starting from the knowledge of the molecular structure of TSHR, promising results have been highlighted by the use of an antigen-specific immunotherapy of Graves' disease and Graves' orbitopathy, using small amounts of synthetic peptides derived from the TSH receptor, that mimic naturally processed CD+T cell-epitopes [64,65]. This first demonstration of the effectiveness of a specific therapy, which induces immunotolerance for Graves' endocrinopathy [13], paves the way for new therapeutic approaches in many, if not all, autoimmune receptor diseases.…”

Hormone and Metabolic Research: 50 Years of Research

“…Most recently, we also focused on thyroid diseases, e. g. autoimmune thyroid disease; here another three special issues were published highlighting the genetic cause as well as the immunological background, diagnostic procedures and therapeutic options in Graves' disease and autoimmune thyroiditis, including a most recent special issue [16][17][18][19][20][21][22][23][24].…”

Association between Uranium Exposure and Thyroid Health: A National Health and Nutrition Examination Survey Analysis and Ecological Study

“…Thyroid health problems may be indicated by increased levels of thyroid-related antibodies, including thyroglobulin antibodies (TgAb) and anti-thyroid peroxidase (anti-TPO). The presence of these antibodies has been associated with a diagnosis of autoimmune disease of the thyroid [22,23], although anti-TPO is a more specific marker for autoimmune thyroiditis than TgAb [24]. Kim et al found that while anti-TPO was not associated with thyroid malignancy, positive TgAb could predict thyroid cancer in patients with thyroid nodules [24].…”