Abstract

Transgenic mice with the human thyrotropin-receptor (TSHR) A-subunit targeted to the thyroid are tolerant of the transgene. In transgenics that express low A-subunit levels (Lo-expressors), regulatory T cell (Treg) depletion using anti-CD25 before immunization with adenovirus encoding the A-subunit (A-sub-Ad) breaks tolerance, inducing extensive thyroid lymphocytic infiltration, thyroid damage and antibody spreading to other thyroid proteins. In contrast, no thyroiditis develops in Hi-expressor transgenics or wild-type mice. Our present goal was to determine if thyroiditis could be induced in Hi-expressor transgenics using a more potent immunization protocol: Treg depletion, priming with Complete Freund's Adjuvant (CFA) + A-subunit protein and further Treg depletions before two boosts with A-sub-Ad. As controls, anti-CD25 treated Hi- and Lo-expressors and wild-type mice were primed with CFA+ mouse thyroglobulin (Tg) or CFA alone before A-sub-Ad boosting. Thyroiditis developed after CFA+A-subunit protein or Tg and A-sub-Ad boosting in Lo-expressor transgenics but Hi- expressors (and wild-type mice) were resistant to thyroiditis induction. Importantly, in Lo-expressors, thyroiditis was associated with the development of antibodies to the mouse TSHR downstream of the A-subunit. Unexpectedly, we observed that the effect of bacterial products on the immune system is a “double-edged sword”. On the one hand, priming with CFA (mycobacteria emulsified in oil) plus A-subunit protein broke tolerance to the A-subunit in Hi-expressor transgenics leading to high TSHR antibody levels. On the other hand, prior treatment with CFA in the absence of A-subunit protein inhibited responses to subsequent immunization with A-sub-Ad. Consequently, adjuvant activity arising in vivo after bacterial infections combined with a protein autoantigen can break self-tolerance but in the absence of the autoantigen, adjuvant activity can inhibit the induction of immunity to autoantigens (like the TSHR) displaying strong self-tolerance.

Highlights

  • Transgenic mice with the A-subunit of the human thyrotropin receptor (TSHR) targeted to the thyroid gland exhibit tolerance to the transgene

  • We found that massive thyroiditis, associated with thyroid damage and thyroid antibody spreading to Tg and thyroid peroxidase (TPO), was induced by Treg depletion using anti-CD25 before immunization with TSHR adenovirus in transgenic mice expressing low, but not high, levels of the human TSHR A-subunit in the thymus and thyroid [2,4]

  • The goal of the present study was to determine if a potent immunization protocol, namely complete Freund’s Adjuvant (CFA)+A-subunit protein, followed by boosting with Asub-adenovirus in Treg depleted animals could break tolerance and induce thyroiditis in Hi-expressor transgenics

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Summary

Introduction

Transgenic mice with the A-subunit of the human thyrotropin receptor (TSHR) targeted to the thyroid gland exhibit tolerance to the transgene. Unlike wild type littermates, the transgenics do not respond to immunization with a low dose of adenovirus encoding the autoantigen, the human TSHR A-subunit [1]. Two transgenic lines express different amounts of TSHR A-subunit in the thyroid gland and the thymus [2,3]. Because of different expression levels in the thymus, these mouse lines have different levels of self-tolerance to the human A-subunit. Transgenic mice that express high levels of the transgene (Hi-expressors) generate little or no TSHR antibody in response to high dose A-subunit adenovirus immunization, even if pre-treated with anti-CD25 to deplete regulatory T cells (Treg)[2,3]. TSHR antibodies induced using adjuvant are non-stimulatory and do not induce hyperthyroidism

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