Overexpression of transgenic class I MHC alloantigen (H-2Kb) in the thyroid: acquired tolerance and nonimmune thyroid atrophy

Abstract

We previously demonstrated that overexpression of transgenic class I MHC proteins in the beta cells of mice leads to non-immune beta cell destruction and insulin-dependent diabetes. Overexpression of MHC, an early feature of autoimmune diabetes, may therefore directly impair endocrine cell function. To test whether this is a general phenomenon we expressed class I MHC transgenically in the thyroid. The rat thyroglobulin promoter was subcloned into a vector containing the mouse class I MHC (H-2K b ) genomic clone. This fusion construct was injected into the pronuclei of (CBA x BIO.BR) F 2 mice (H-2K k haplotype) and transferred to oviducts of (CBA x C57) pseudo-pregnant mice. Transgenic offspring were identified by probing mouse tail DNA with the 32 P-labelled thyroglobulin promoter. Despite expression of the alloantigen in the thyroid cells there was no inflammatory infiltration of the thyroid. Heterozygous mice had no histologic changes in the thyroid but developed modest hypothyroxinaemia. Homozygous mice developed neonatal growth retardation (~ 50% of littermates’ weight), biochemical hypothyroidism and death by 18-21 days of age. Histology revealed reduction in follicular size and in thyrocyte height, but again no cellular infiltrate. To further study the mechanisms of tolerance in these animals we examined the ability of spleen cells from transgenic mice and their non-transgenic littermates to destroy target cells syngeneic and allogeneic to the transgene. H-2K b spleen cells (from BIOA (5R) mice) were irradiated and transgenic and non-transgenic spleen cells were primed against them for 5 days. Transgenic spleen cells were tolerant to H-2K b bearing target cells (EL4), but not to H-2 d (P815) cells, as determined by release of 51 Cr from labelled targets. We conclude that these transgenic mice have developed tolerance to the peripheral expression of an alloantigen, whose overexpression leads to non-immune mediated thyroid destruction and hypothyroidism. MHC class I overexpression, an early feature of autoimmune thyroid disease, may thus play a direct role in thyrocyte destruction.