ROLE OF MHC CLASS I IN THE GENERATION OF AUTOIMMUNE DISEASES

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MHC class I genes, which provide immune surveillance against intracellular pathogens, are dynamically regulated by hormonal control. In the thyroid, thyroid stimulating hormone (TSH) represses class I transcription while triggering the production of thyroglobulin and secretion of thyroid hormone which, in turn, stimulates class I gene transcription. Together, these two hormones generate a dynamic cycle of class I regulation. These findings led us to suggest that this dynamic regulation maintains a constant level of cell surface presentation of self antigens; failure to appropriately regulate MHC class I genes would lead to excessive presentation of self antigens, and contribute to the generation of autoimmune disease. Consistent with this hypothesis, we have shown that in experimental models of autoimmune systemic lupus erythematosus and blepharitis, animals that fail to express class I are resistant to disease. This resistance is not due to the failure to generate CD8+ T cells in the absence of class I, since CD8-/- animals are highly susceptible to disease. Rather, the resistance appears to be due the failure to express class I in the periphery. Thus, in adoptive transfer experiments, susceptibility to the SLE-like disease is determined by the class I status of the recipient, not the class I status of the donor spleen cells. Studies are in progress to further define the role of peripheral class I expression in the induction and propagation of autoimmune disease. We also have studied the effect on induction of disease of a pharmacological agent, MMI, that we have shown reduces class I expression both in vitro and in vivo. MMI-treatment of mice with experimental SLE or blepharitis reduces the incidence and severity of disease. We have also found that in NZBxNZW mice, that develop a spontaneous systemic autoimmune disease, levels of class I expression increase significantly with age. MMI-treatment also reduces the severity and incidence of this spontaneous autoimmune disease.