Mark S. Anderson, MD, PhD
The main research interest of our laboratory is to examine the genetic control of autoimmune disease susceptibility to gain a better understanding of the mechanisms by which immune tolerance can be broken. A major focus of our research effort involves the defective gene in the clinical disorder Autoimmune Polyglandular Syndrome Type 1 (APS1). APS1 is classically manifested by an autoimmune attack directed against multiple endocrine organs and is inherited in a monogenic autosomal recessive fashion. The defective gene termed AIRE (for Autoimmune Regulator) is a transcription factor that is highly expressed in specialized cells of the thymus called medullary epithelial cells (mTEC’s). Through studies on Aire knockout mice, we have determined that Aire helps protect against autoimmunity by helping promote the “ectopic” transcription of multiple self-antigens in mTEC’s. Thus, in the absence of Aire expression, there is a failure to express a range of self-antigens in the thymus and a subsequent failure in negative selection of developing autoreactive T cells. We also have recently identified and proven a mechanism by which a single point mutation in Aire can predispose to autoimmunity in an autosomal dominant fashion. These studies have revealed important self-antigen dosing relationships in the thymus with autoimmune susceptibility. These studies also suggest that in isolated kindreds, rare point mutations like this may predispose to autoimmunity. Finally, we have also identified a cell population outside of the thymus that expresses Aire and induces immune tolerance through a deletional mechanism. Taken together, our laboratory efforts have revealed unique pathways by which immune tolerance is maintained to prevent autoimmune responses.