Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: A clue to the riddle of TSAbs generation?

Mireia Giménez-Barcons, Roger Colobran, Ana Gómez-Pau, Ana Marín-Sánchez, Anna Casteràs, Gabriel Obiols, Raúl Abella, Joaquín Fernández-Doblas, Massimo Tonacchera, Ana Lucas-Martín, Ricardo Pujol-Borrell

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Copyright © 2015 by The American Association of Immunologists, Inc. Graves' disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low-affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs.
Original languageEnglish
Pages (from-to)4199-4206
JournalJournal of Immunology
Volume194
Issue number9
DOIs
Publication statusPublished - 1 Jan 2015

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