Autoimmune disease affects more than 8 million Americans, including 1 in 100 children. Despite its prevalence, the complex, polygenic inheritance of most autoimmune disorders has been an obstacle in understanding the pathogenesis of these diseases. Autoimmune Polyendocrinopathy Syndrome (APS) Type I is unusual among autoimmune diseases in that it is due to a defect in a single gene, Autoimmune Regulator (Aire). Aire plays an important role in preventing autoimmunity by upregulating the transcription of a variety of peripheral self-antigens in medullary thymic epithelial cells (mTECs) of the thymus, and the expression of these peripheral self-antigens drives the deletion of self-reactive T cells in the thymus (see Figure).
We have utilized mice with defects in the Aire gene to understand how Aire is important in preventing autoimmunity. We are currently focused on studying a mouse model with a dominant point mutation (G228W) in Aire which results in spontaneous autoimmunity in a number of organs, including the thyroid gland, peripheral nerves, and pancreatic islets. The G228W mouse model provides a unique opportunity to study the role of central tolerance in preventing autoimmunity toward these organs. We are also utilizing the G228W mouse model to inform us on how Aire functions. The ultimate goal is to translate our findings to human autoimmunity both in terms of understanding the mechanisms underlying human disease as well as in developing therapeutics for treating autoimmunity.