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Regulation of TSHR expression in the thyroid and thymus may contribute to TSHR tolerance failure in graves’ disease patients via two distinct mechanisms Marín Sánchez, Ana María Alvarez De la Sierra, Daniel González López, Oscar Lucas-Martin, Ana Sellés Sanchez, Alicia Rudilla Salvador, Francesc Enrich Rande, Emma Colobran Oriol, Roger Pujol-Borrell, Ricardo [Marín-Sánchez A, Colobran R, Pujol-Borrell R] Immunologia, FOCIS Center of Excellence (FCE), Hospital Universitari Vall d'Hebron, Barcelona, Spain. Recerca en Immunologia Diagnòstica, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Biologia Cel•lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Barcelona, Spain. [Álvarez-Sierra D] Recerca en Immunologia Diagnòstica, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Biologia Cel•lular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, Barcelona, Spain. [González O] Servei de Cirurgia, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Lucas-Martin A] Endocrinology Division, Hospital Universitari Germans Trias Pujol, Badalona, Spain. [Sellés-Sánchez A] Recerca en Immunologia Diagnòstica, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Rudilla F] Laboratori d’Immunogenètica I Histocompatibilitat, Banc de Sang i Teixits, Grup de recerca en Medicina Transfusional, Hematologia i Hematoteràpia, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Tirotropina Graves, Malaltia de Expressió gènica CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Peptide::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Peptide::Receptors, Pituitary Hormone::Receptors, Thyrotropin DISEASES::Endocrine System Diseases::Thyroid Diseases::Goiter::Endocrine System Diseases::Thyroid Diseases::Graves Disease PHENOMENA AND PROCESSES::Genetic Phenomena::Gene Expression COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::receptores de superficie celular::aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::receptores de superficie celular::receptores de péptidos::aminoácidos, péptidos y proteínas::proteínas::proteínas de membranas::receptores de superficie celular::receptores de péptidos::receptores de hormonas hipofisarias::receptores de tirotropina ENFERMEDADES::enfermedades del sistema endocrino::enfermedades tiroideas::bocio::enfermedades del sistema endocrino::enfermedades tiroideas::enfermedad de Graves FENÓMENOS Y PROCESOS::fenómenos genéticos::expresión génica Graves’ disease; TSHR; Tolerance Malaltia de Graves; TSHR; Tolerància Enfermedad de Graves; TSHR; Tolerancia Graves' disease (GD) involves the presence of agonistic auto-antibodies against the thyrotropin receptor (TSHR), which are responsible for the clinical symptoms. While failure of TSHR tolerance is central to GD pathogenesis, the process leading to this failure remains poorly understood. Two mechanisms intimately linked to tolerance have been proposed to explain the association of SNPs located in TSHR intron 1 to GD: (1) differential alternative splicing in the thyroid; and (2) modulation of expression in the thymus. To elucidate the relative contribution to these two mechanisms to GD pathogenesis, we analyzed the level of full-length and ST4 and ST5 isoform expression in the thyroid (n = 49) and thymus (n = 39) glands, and the influence of intron 1-associated SNPs on such expression. The results show that: (1) the level of flTSHR and ST4 expression in the thymus was unexpectedly high (20% that of the thyroid); (2) while flTSHR is the predominant isoform, the levels are similar to ST4 (ratio flTSHR/ST4 = 1.34 in the thyroid and ratio flTSHR/ST4 in the thymus = 1.93); (3) next-generation sequencing confirmed the effect of the TSHR intron 1 polymorphism on TSHR expression in the thymus with a bias of 1.5 ± 0.2 overexpression of the protective allele in the thymus compared to the thyroid; (4) GD-associated intron 1 SNPs did not influence TSHR alternative splicing of ST4 and ST5 in the thyroid and thymus; and (5) three-color confocal imaging showed that TSHR is associated with both thymocytes, macrophages, and dendritic cells in the thymus. Our findings confirm the effect of intron 1 polymorphisms on thymic TSHR expression and we present evidence against an effect on the relative expression of isoforms. The high level of ST4 expression in the thymus and its distribution within the tissue suggest that this would most likely be the isoform that induces central tolerance to TSHR thus omitting most of the hinge and transmembrane portion. The lack of central tolerance to a large portion of TSHR may explain the relatively high frequency of autoimmunity related to TSHR and its clinical consequence, GD. This study was funded by Instituto de Salud Carlos III, grants PI14/00848, and PI17/00324, co-financed by the European Regional Development Fund (ERDF). DÁ-S is in recipient of a predoctoral fellowship from the Vall d’Hebron Research Institute (VHIR). 2020-02-24T13:24:57Z 2020-02-24T13:24:57Z 2019-07-18 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Marín-Sánchez A, Álvarez-Sierra D, González O, Lucas-Martin A, Sellés-Sánchez A, Rudilla F, et al. Regulation of TSHR expression in the thyroid and thymus may contribute to TSHR tolerance failure in Graves’ disease patients via two distinct mechanisms. Front Immunol . 2019 Jul 18;10:1695. 1664-3224 https://hdl.handle.net/11351/4675 10.3389/fimmu.2019.01695 31379878 000475915400001 http://hdl.handle.net/11351/4675 eng Frontiers in Immunology;10 https://www.frontiersin.org/articles/10.3389/fimmu.2019.01695/full Attribution 4.0 International https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf Frontiers Media Scientia