title: Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation?
abstract: 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.
authors: Vall d'Hebron Institute de Recerca, 08035 Barcelona, Spain;
authors: Mireia
authors: M
authors: Giménez-Barcons
authors: Vall d'Hebron Institute de Recerca, 08035 Barcelona, Spain; Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain;
authors: Roger
authors: R
authors: Colobran
authors: Vall d'Hebron Institute de Recerca, 08035 Barcelona, Spain;
authors: Ana
authors: A
authors: Gómez-Pau
authors: Servei d'Immunologia, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain;
authors: Ana
authors: A
authors: Marín-Sánchez
authors: Servei de Endocrinologia, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain;
authors: Anna
authors: A
authors: Casteràs
authors: Servei de Endocrinologia, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain;
authors: Gabriel
authors: G
authors: Obiols
authors: Servei de Cirurgia, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain;
authors: Raúl
authors: R
authors: Abella
authors: Servei de Cirurgia, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain;
authors: Joaquín
authors: J
authors: Fernández-Doblas
authors: Department of Clinical and Experimental Medicine, Pisa University, 56126 Pisa, Italy; and.
authors: Massimo
authors: M
authors: Tonacchera
authors: Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Barcelona, Catalonia, Spain.
authors: Ana
authors: A
authors: Lucas-Martín
authors: Vall d'Hebron Institute de Recerca, 08035 Barcelona, Spain; Departament de Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Servei d'Immunologia, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain; rpujol@vhebron.net.
authors: Ricardo
authors: R
authors: Pujol-Borrell
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D007223:Infant; D008213:Lymphocyte Activation / Q000276:immunology*; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D011989:Receptors, Thyrotropin