Horm Metab Res 2018; 50(12): 837-839
DOI: 10.1055/a-0799-5068
Editorial
© Georg Thieme Verlag KG Stuttgart · New York

Autoimmune Thyroid Diseases

J. Paul Banga
1   Emeritus Professor, Faculty of Life Sciences & Medicine, King’s College London, London, UK
2   Molecular Ophthalmology, Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany
,
Matthias Schott
3   Division for Specific Endocrinology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

received 14 November 2018

accepted 20 November 2018

Publication Date:
05 December 2018 (online)

Autoimmune thyroid diseases (ATD) are the most common autoimmune diseases in humans. ATD can be divided in Graves’ disease, a condition with predominantly stimulating TSH receptor antibodies leading to hyperthyroidism, and Hashimoto’s thyroiditis (HT), also named autoimmune thyroiditis, leading to hypothyroidism, depending on the grade of lymphocytic infiltration. This second Special Issue of ATD follows the highly successful first Special Issue on ATD of 2015 in Hormone and Metabolic Research to provide a collection of timely reviews by world-renowned experts in the field.

Rapoport and McLachlan [1] have made important contributions to our understanding of ATD for the past 40 years. For this special issue of Hormone and Metabolic Research, the Editors of the Special issue are fortunate for a timely review from the authors, where they provide a personal overview on the understanding of ATD with a special focus on Graves’ disease. As shown from their earlier studies, thyroid autoantigens such as the TSH receptor (TSHR) are the drivers of the autoimmune response. They have shown in their classical studies that the TSHR is the culprit as well as the victim in Graves’ disease because of its unique structure among the closely related gonadotropin receptors, by being uniquely prone to cleave into subunits. Importantly, there is convincing evidence that its shed extracellular A-subunit, not the holoreceptor, is the major antigen driving pathogenic thyroid stimulating autoantibody (TSAb) development. This has also been learned from animal models which are discussed within the review article. The authors finish by reporting on the latest studies on antigen specific therapy for Graves’ disease and the future of research in ATD.

The review article by Diana and colleagues [2] is focused on TSH receptor blocking antibodies in ATD. Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be performed either via competitive binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity (TBAb). Diana and colleagues give an overview on the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with ATD. The authors summarize the different methods used to measure TBAb and discuss their prevalence and clinical relevance.

Pujol-Borrell et al. [3] discusses recent advances in our understanding of TSHR polymorphism for genetic susceptibility of Graves’ disease. Within the review article, 2 hypotheses, both postulating TSHR gene regulatory mechanisms, are discussed. One postulates differential level of expression in the thymus, involving central tolerance. The other postulates a shift in TSHR differential splicing leading to the production of soluble proteins that will have easy access to antigen presenting cells, so it is focused to peripheral tolerance. A combination of the 2 hypotheses is feasible, especially in the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.

Kotwal and Stan [4] focus on current and future treatments for Graves’ disease and Graves’ opthalmopathy. Graves’ disease is classically managed with one of 3 treatment options – antithyroid drugs, radioactive iodine, and thyroidectomy. In recent years, there has been a shift towards antithyroid drugs, including long term therapy with these agents, given the advantage of avoiding hypothyroidism and the apparent safety of this approach. In addition, new therapies are (slowly) emerging, focusing on immunomodulation. Technological advances are opening doors to non-pharmaceutical interventions that aim to deal with both structural thyroid abnormalities as well as biochemical abnormalities of hyperthyroidism. Graves’ ophthalmopathy management is guided by its activity and severity status, with treatment options including smoking cessation, control of hyperthyroidism, local eye measures and glucocorticoid. In addition to these established treatment choices, new immunotherapy-based approaches are being tested. Some of them (tocilizumab and teprotumumab) are promising, but further evaluation is needed before we can establish their role in clinical care.

Marinò et al. [5] also deal with another therapeutic approach for Graves’ disease and Graves’ orbitopathy, focusing on selenium. Based on the role of oxidative stress in the pathogenesis of both Graves’ disease and Graves’ orbitopathy, the use of the antioxidant agent selenium has been proposed and several studies on the subject have been conducted, both in vitro and in vivo. Whereas a true benefit related to the use of selenium in patients with Graves’ hyperthyroidism has been questioned, its use in patients with mild Graves’ orbitopathy is generally believed to be beneficial because of which selenium has entered in the clinical practice for this eye condition.

The review article by Krause and colleagues [6] provides us with a timely review on pharmacological intervention strategies for the glycoprotein hormone receptor (GPHR) family, with emphasis on the TSHR. The molecular mechanisms for the activation of GPHRs that are closely associated with their unique structure are discussed, together with intervention strategies for this family of receptors. This takes us to pharmacological approaches of intervention for the TSHR to tackle Graves’ disease and Graves’ orbitopathy. A succinct review on all the small molecule antagonists reported to date for TSHR including the authors own TSHR antagonist S37a, are provided together a description of their structures, which will determine their future therapeutic applications.

We then move to pathogenesis of Hashimoto’s thyroiditis with special emphasis on thyroid peroxidase (TPO) by Williams and colleagues from a European/Australian collaboration [7]. TPO is an important enzyme responsible for the biosynthesis of thyroid hormones and is a major autoantigen in ATD such as the destructive Hashimoto’s thyroiditis. Although the structure of TPO has yet to be determined, its extracellular domain consists of 3 regions that exhibit a high degree of sequence similarity to domains of known 3-dimensional structure: the myeloperoxidase-like domain, complement control protein-like domain, and epidermal growth factor-like domain. Homology models of TPO can therefore be constructed, providing some structural context to its known function, as well as facilitating the mapping of regions that are responsible for its autoantigenicity. In the review, the authors highlight recent progress in this area, in particular how a molecular modeling approach has advanced the visualization and interpretation of epitope mapping studies for TPO, facilitating the dissection of the interplay between TPO protein structure, function, and autoantigenicity.

The association between thyroid cancer and thyroid autoimmunity has long been suggested, but remains to be elucidated for several decades. The article by Nagayama [8] provides an update on recent data. Although numerous papers demonstrated the significant increase in the prevalence of thyroid autoimmunity in patients with thyroid cancers as compared to those with benign nodules, and also the significant increase in the prevalence of papillary thyroid cancer (PTC) in patients with thyroid autoimmunity as compared to those without, there are some crucial biases that should be taken into account for their interpretation. However, a difference in the incidence of thyroid autoimmunity in patients with PTCs and those with other types of thyroid cancers appears to support the significant association of 2 conditions. Thyroid autoimmunity is, at least partly, likely to be elicited against antigens shared by normal and cancerous thyroid tissues, thereby inducing autoimmunity. At the same time, elevated TSH levels, which often accompany Hashimoto’s patients are a risk factor for thyroid cancer. However, it is still unclear whether or not the co-existence of thyroid autoimmunity impacts on cancer characteristics and prognosis.

Finally, Moshkelgosha and colleagues focus on the role of gut microbiome on experimental Graves’ disease [9]. Gut microbiome have been shown to be essential triggers in autoimmune disorders such as multiple sclerosis. In Graves’ disease, a link between Yersinia enterocolitica and germline counterparts of the thyroid stimulating antibodies has recently been shown, adding new knowledge on the role of bacteria in the pathogenesis of this thyroid condition [10]. Using mouse model of Graves’ disease and Graves’ orbitopathy, the authors show that different strains of inbred mice show differences in their gut microbiota which correlate with induction of thyroid stimulating autoantibodies and disease susceptibility. An understanding of correlation between gut microbial components and disease susceptibility will advance our knowledge on Graves’ disease and Graves’ orbitopathy.

In summary, this Special Issue in Hormone and Metabolic Research presents an overview on recent advances in our understanding of etiology, pathogenesis, and clinical aspects in autoimmune thyroid diseases. We hope the readers will enjoy reading these articles.

 
  • References

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