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. To study the role of class I in the etiology of spontaneous autoimmune disease, we have examined the NZBxNZW murine model of SLE. We have found that in NZBxNZW mice, levels of class I expression increase significantly with age. MMI-treatment, which prevents experimental SLE, also reduces the severity and incidence of this spontaneous autoimmune disease. To directly determine the role of class I in this spontaneous disease, the 2-microglobulin knock-out gene was introduced into each of the parental strains. Development of disease was monitored in the class I deficient F2 mice.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009400-09
Application #
6559073
Study Section
(EIB)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code