Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

Abstract

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.

Conditional up-regulation of MHC class I in skeletal muscle leads to self-sustaining autoimmune myositis and myositis-specific autoantibodies

“…For example, it is known that muscle, besides expressing little or no MHC class I, constitutively expresses TGF-␤, and that myocytes are very resistant to apoptosis (27)(28)(29)(30)(31), apparently through the up-regulation of antiapoptotic molecules when under an apoptotic threat (32). Although it is possible that the initiation of muscle fiber damage seen in this model results from other deleterious effects of the aberrant expression of MHC class I, as was considered in the earlier observations on pancreatic ␤ cells, oligodendrocytes, and thyrocytes (8)(9)(10), the events that follow clearly reflect an immunological process.…”

“…The overexpression can occur in the absence of an inflammatory infiltrate, suggesting that it may be independent of and precede the effects of cytokines released from infiltrating mononuclear cells. Transgenic overexpression of MHC class I in several tissues has resulted in the destruction of the target tissue leading to insulin-dependent diabetes, a shivering phenotype with severe demyelination of the central nervous system, and Graves' disease in the absence of lymphocyte infiltration (8)(9)(10). In these mice, the transgenic MHC class I expression was driven by the respective tissue-specific promoters during the development of immune system in utero, with uncertain effects on tolerance.…”

Transcriptional regulation of HLA-A and -B: differential binding of members of the Rel and IRF families of transcription factors.

“…However, quantitative differences in expression which lead to a higher probability of CTL recognition may also be an important factor. Increased expression can have deleterious consequences, as shown by the onset of diabetes (56) and thyroiditis (57) in transgenic mice overexpressing H-2 class I genes in pancreatic f8 cells and thyrocytes, respectively, and spondyloarthropathies in transgenic rats expressing high levels of HLA-B27 (58). Therefore, the differential regulation of HLA-A and -B expression by cell type-specific and cytokine-induced transcription factors is likely to have important consequences for immune function and pathology.…”

Transforming growth factor beta 1 (TGF-beta 1) controls expression of major histocompatibility genes in the postnatal mouse: aberrant histocompatibility antigen expression in the pathogenesis of the TGF-beta 1 null mouse phenotype.

“…5) (14,16,31,32). However, increased MHC expression does not necessarily lead to tissue damage (33), and in some cases, high MHC expression causes tissue damage through nonimmune mechanisms (34,35). Other processes, such as the establishment of tolerance to organ-localized self-antigen, are potentially under the influence of TGF-p.…”