Central Tolerance Mechanisms to TSHR in Graves’ Disease: Contributions to Understand the Genetic Association

Abstract

In the last 3 years, the association of thyrotropin receptor gene (TSHR) variations to Graves’ disease (GD) has been confirmed. It is now well established that a 30 Kb region of intron 1 of the TSHR gene is linked to GD predisposition. Elucidating the mechanism(s) by which these polymorphisms confer susceptibility is difficult but would constitute an important advance in endocrine autoimmunity in general. Two 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 in peripheral tolerance. A combination of the 2 hypothesis is feasible, especially under the light of recent evidence that have identified epigenetic factors acting on TSHR intron 1.

Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms

“…This is relevant if we consider the peculiar distribution of TSHR expression within the thymus. Different from most other restricted tissue antigens (RTAs), while the TSHR receptor is only minimally expressed by medullary thymic epithelial cells (mTECs), it is expressed at relatively high levels by double positive thymocytes themselves, for which it appears to play a role in maturation and differentiation (9, 36, 38, 41). Therefore, it should be assumed that there are two sources of TSHR protein in the thymus: (1) the TSHR anchored in the thymocyte membrane and the soluble ST4 and ST5 isoforms generated by alternative splicing.…”

“…The products of these genes participate in the regulation of the immune response and have been implicated in other autoimmune diseases but do not explain why the autoimmune response focuses on the thyroid gland. Common polymorphisms have also been found in the genes specifically expressed in the thyroid [e.g., the thyrotropin receptor [ TSHR ] or thyroglobulin [ TG ] (7, 8)]; however, only the association with TSHR has been repeatedly confirmed [reviewed in (4, 5, 9, 10)]. Since the loss of tolerance to TSHR is the central mechanism for GD pathogenesis, there is a great interest in understanding how these TSHR polymorphisms contribute to the failure of tolerance.…”

“…The TSH holoreceptor (TSHR) and the two short isoforms (ST4 and ST5) are depicted, showing that the short isoforms contained less than half of the potential immunogenic regions of the receptor, including a large proportion of the extracellular domain, specially the hinge. C, C peptide; SP, signal peptide; LRR, Leucine Reach Repeats; TMD, transmembrane domain; CM, Cytoplasmic Motifs [This figure is based on Figure 1 and Figure 2 of manuscript (9). Reproduced with permission of Thieme editorial].…”

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].…”

Autoimmune Thyroid Diseases

“…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.…”