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Horm Metab Res 2018; 50(12): 863-870
DOI: 10.1055/a-0755-7927
Review
© Georg Thieme Verlag KG Stuttgart · New York

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

Ricardo Pujol-Borrell
1   Immunology Division, Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Catalonia, Spain
2   Diagnostic Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain
3   Department of Cell Biology, Physiology and Immunology, Universitat Autonòma de Barcelona, Bellaterra, Catalonia, Spain
,
Daniel Álvarez-Sierra
2   Diagnostic Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain
3   Department of Cell Biology, Physiology and Immunology, Universitat Autonòma de Barcelona, Bellaterra, Catalonia, Spain
,
Dolores Jaraquemada
3   Department of Cell Biology, Physiology and Immunology, Universitat Autonòma de Barcelona, Bellaterra, Catalonia, Spain
,
Ana Marín-Sánchez
3   Department of Cell Biology, Physiology and Immunology, Universitat Autonòma de Barcelona, Bellaterra, Catalonia, Spain
,
Roger Colobran
1   Immunology Division, Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Catalonia, Spain
2   Diagnostic Immunology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Catalonia, Spain
3   Department of Cell Biology, Physiology and Immunology, Universitat Autonòma de Barcelona, Bellaterra, Catalonia, Spain
› Author Affiliations
Further Information

Publication History

received 31 July 2018

accepted 02 October 2018

Publication Date:
05 November 2018 (online)

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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.

Key words

TSHR - Graves’ disease - central tolerance - genetics of Graves’ disease - genetic association
 

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