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

Alexander V. Misharin, Yuji Nagayama, Holly A. Aliesky, Basil Rapoport, Sandra M. McLachlan

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2948-2956
Number of pages9
JournalEndocrinology
Volume150
Issue number6
DOIs
StatePublished - Jun 2009

ASJC Scopus subject areas

  • Endocrinology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this