The pathogenesis of autoimmune disease involves a complex interaction of environmental and genetic factors. Because of this complexity, the elucidation of the causative factors has proven to be difficult. My research program and the proposed studies involve a recently identified pathway that leads to autoimmunity due to a defect in the thymus. This recently discovered pathway involves a gene called Aire (for Autoimmune Regulator), that has been determined to be the culprit gene in a human autoimmune disease called APECED (Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy). The Aire gene appears to regulate the ectopic expression of self-antigens in specialized cells in the thymus, and in its absence, both humans and mice develop autoimmunity targeted to multiple organs. The studies here plan to expand on the initial findings of this thymic defect by looking at the control of immune tolerance in the Aire-deficient background. The proposed studies include identifying interacting genetic loci, detailing the molecular targeting of autoreactive cells in the autoimmune attack, and a more detailed molecular analysis of the self-antigen expression in the thymus using a unique transgenic approach. Because this autoimmunity model originated in human patients, its relevance to human disease is clear. It is my intention that the studies detailed here will also result in findings that can be brought back to patients and directly impact their clinical care.