TY - JOUR
T1 - Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: A clue to the riddle of TSAbs generation?
AU - Giménez-Barcons, Mireia
AU - Colobran, Roger
AU - Gómez-Pau, Ana
AU - Marín-Sánchez, Ana
AU - Casteràs, Anna
AU - Obiols, Gabriel
AU - Abella, Raúl
AU - Fernández-Doblas, Joaquín
AU - Tonacchera, Massimo
AU - Lucas-Martín, Ana
AU - Pujol-Borrell, Ricardo
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
U2 - 10.4049/jimmunol.1500183
DO - 10.4049/jimmunol.1500183
M3 - Article
VL - 194
SP - 4199
EP - 4206
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -