Studies in Mice Deficient for the Autoimmune Regulator (Aire) and Transgenic for the Thyrotropin Receptor Reveal a Role for Aire in Tolerance for Thyroid Autoantigens
Open Access
- 5 March 2009
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 150 (6), 2948-2956
- https://doi.org/10.1210/en.2008-1690
Abstract
The autoimmune regulator (Aire) mediates central tolerance for many autoantigens, and autoimmunity occurs spontaneously in Aire-deficient humans and mice. Using a mouse model of Graves’ disease, we investigated the role of Aire in tolerance to the TSH receptor (TSHR) in Aire-deficient and wild-type mice (hyperthyroid-susceptible BALB/c background). Mice were immunized three times with TSHR A-subunit expressing adenovirus. The lack of Aire did not influence T-cell responses to TSHR protein or TSHR peptides. However, antibody levels were higher in Aire-deficient than wild-type mice after the second (but not the third) immunization. After the third immunization, hyperthyroidism persisted in a higher proportion of Aire-deficient than wild-type mice. Aire-deficient mice were crossed with transgenic strains expressing high or low-intrathyroidal levels of human TSHR A subunits. In the low-expressor transgenics, Aire deficiency had the same effect on the pattern of the TSHR antibody response to immunization as in nontransgenics, although the amplitude of the response was lower in the transgenics. High-expressor A-subunit transgenics were unresponsive to immunization. We examined intrathymic expression of murine TSHR, thyroglobulin, and thyroid peroxidase (TPO), the latter two being the dominant autoantigens in Hashimoto’s thyroiditis (particularly TPO). Expression of the TSHR and thyroglobulin were reduced in the absence of Aire. Dramatically, thymic expression of TPO was nearly abolished. In contrast, the human A-subunit transgene, lacking a potential Aire-binding motif, was unaffected. Our findings provide insight into how varying intrathymic autoantigen expression may modulate thyroid autoimmunity and suggest that Aire deficiency may contribute more to developing Hashimoto’s thyroiditis than Graves’ disease.Keywords
This publication has 56 references indexed in Scilit:
- Vitamin D Deficiency Modulates Graves’ Hyperthyroidism Induced in BALB/c Mice by Thyrotropin Receptor ImmunizationEndocrinology, 2009
- High Prevalence of Thyroid Autoimmunity in Apulian Patients with Autoimmune Polyglandular Syndrome Type 1Thyroid®, 2008
- Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in AireJCI Insight, 2008
- Modulation of Aire regulates the expression of tissue-restricted antigensMolecular Immunology, 2008
- Shared and Unique Susceptibility Genes in a Mouse Model of Graves’ Disease Determined in BXH and CXB Recombinant Inbred MiceEndocrinology, 2007
- Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD miceJCI Insight, 2006
- Detection of thyroglobulin mRNA as truncated isoform(s) in mouse thymusImmunology, 2005
- Peptide Scanning for Thyrotropin Receptor T-Cell Epitopes in Mice Vaccinated with Naked DNAThyroid®, 2002
- A new mathematical model for relative quantification in real-time RT-PCRNucleic Acids Research, 2001
- Photo-affinity labelling of the thyrotropin receptorFEBS Letters, 1982