Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms
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 mec...
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| Format: | Article |
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Frontiers Media S.A.
2019-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.01695/full |
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| author | Ana Marín-Sánchez Ana Marín-Sánchez Ana Marín-Sánchez Daniel Álvarez-Sierra Daniel Álvarez-Sierra Oscar González Ana Lucas-Martin Alicia Sellés-Sánchez Francesc Rudilla Emma Enrich Roger Colobran Roger Colobran Roger Colobran Ricardo Pujol-Borrell Ricardo Pujol-Borrell Ricardo Pujol-Borrell |
| author_facet | Ana Marín-Sánchez Ana Marín-Sánchez Ana Marín-Sánchez Daniel Álvarez-Sierra Daniel Álvarez-Sierra Oscar González Ana Lucas-Martin Alicia Sellés-Sánchez Francesc Rudilla Emma Enrich Roger Colobran Roger Colobran Roger Colobran Ricardo Pujol-Borrell Ricardo Pujol-Borrell Ricardo Pujol-Borrell |
| author_sort | Ana Marín-Sánchez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T03:56:55Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T03:56:55Z |
| publishDate | 2019-07-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-12f757e9de684964b63eba553ec6460b2022-12-22T00:39:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-07-011010.3389/fimmu.2019.01695470458Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct MechanismsAna Marín-Sánchez0Ana Marín-Sánchez1Ana Marín-Sánchez2Daniel Álvarez-Sierra3Daniel Álvarez-Sierra4Oscar González5Ana Lucas-Martin6Alicia Sellés-Sánchez7Francesc Rudilla8Emma Enrich9Roger Colobran10Roger Colobran11Roger Colobran12Ricardo Pujol-Borrell13Ricardo Pujol-Borrell14Ricardo Pujol-Borrell15Immunology Division, FOCIS Center of Excellence, Hospital Universitari Vall d'Hebron, Barcelona, SpainDiagnostic Immunology Group, Vall d'Hebron Research Institute, Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, SpainDiagnostic Immunology Group, Vall d'Hebron Research Institute, Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, SpainSurgery Department, Hospital Universitari Vall d'Hebron, Barcelona, SpainEndocrinology Division, Hospital Universitari Germans Trias Pujol, Badalona, SpainDiagnostic Immunology Group, Vall d'Hebron Research Institute, Barcelona, SpainImmunogenetics and Histocompatibility Laboratory, Blood and Tissue Bank, Transfusional Medicine Group, Vall d'Hebron Research Institute, Barcelona, SpainImmunogenetics and Histocompatibility Laboratory, Blood and Tissue Bank, Transfusional Medicine Group, Vall d'Hebron Research Institute, Barcelona, SpainImmunology Division, FOCIS Center of Excellence, Hospital Universitari Vall d'Hebron, Barcelona, SpainDiagnostic Immunology Group, Vall d'Hebron Research Institute, Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, SpainImmunology Division, FOCIS Center of Excellence, Hospital Universitari Vall d'Hebron, Barcelona, SpainDiagnostic Immunology Group, Vall d'Hebron Research Institute, Barcelona, SpainDepartment of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, SpainGraves' 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.01695/fullGraves' diseaseTSHRtolerancesplicing isoformsthymusthyroid |
| spellingShingle | Ana Marín-Sánchez Ana Marín-Sánchez Ana Marín-Sánchez Daniel Álvarez-Sierra Daniel Álvarez-Sierra Oscar González Ana Lucas-Martin Alicia Sellés-Sánchez Francesc Rudilla Emma Enrich Roger Colobran Roger Colobran Roger Colobran Ricardo Pujol-Borrell Ricardo Pujol-Borrell Ricardo Pujol-Borrell Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms Frontiers in Immunology Graves' disease TSHR tolerance splicing isoforms thymus thyroid |
| title | Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms |
| title_full | Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms |
| title_fullStr | Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms |
| title_full_unstemmed | Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms |
| title_short | Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms |
| title_sort | regulation of tshr expression in the thyroid and thymus may contribute to tshr tolerance failure in graves disease patients via two distinct mechanisms |
| topic | Graves' disease TSHR tolerance splicing isoforms thymus thyroid |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.01695/full |
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