Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.
The overexpression of major histocompatibility complex (MHC) class I molecules in endocrine epithelial cells is an early feature of autoimmune thyroid disease and insulin-dependent diabetes mellitus, which may reflect a cellular response, e.g., to viruses or toxins. Evidence from a transgenic model in pancreatic beta cells suggests that MHC class I overexpression could play an independent role in endocrine cell destruction. We demonstrate in this study that the transgenic overexpression of an allogeneic MHC class I protein (H-2Kb) linked to the rat thyroglobulin promoter, in H-2Kk mice homozygous for the transgene, leads to thyrocyte atrophy, hypothyroidism, growth retardation, and death. Thyrocyte atrophy occurred in the absence of lymphocytic infiltration. Tolerance to allogeneic class I was revealed by the reduced ability of primed lymphocytes from transgenic mice to lyse H-2Kb target cells in vitro. This nonimmune form of thyrocyte destruction and hypothyroidism recapitulates the beta-cell destruction and diabetes that results from transgenic overexpression of MHC class I molecules in pancreatic beta cells. Thus, we conclude that overexpression of MHC class I molecules may be a general mechanism that directly impairs endocrine epithelial cell viability.
Frauman
A G
AG
Burnet Clinical Research Unit, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Chu
P
P
Harrison
L C
LC
D000818:Animals; D001284:Atrophy; D001327:Autoimmune Diseases / Q000209:etiology; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D004274:DNA, Recombinant / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005805:Genes, MHC Class I / Q000235:genetics*; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification; D006579:Heterozygote; D006720:Homozygote; D007519:Isoantigens / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis; D013602:T-Lymphocytes, Cytotoxic; D013954:Thyroglobulin / Q000235:genetics; D013961:Thyroid Gland / Q000473:pathology* / Q000648:ultrastructure
D004274:DNA, Recombinant; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007519:Isoantigens; D011994:Recombinant Proteins; D013954:Thyroglobulin