Genetic basis of altered central tolerance and autoimmune diseases: a lesson from AIRE mutations

The thymus is a specialized organ that provides an inductive environment for the development of T cells from multi-potent hematopoietic progenitors. Self non-self discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Tolerance represents a state of immunologic non-responsiveness in the presence of a particular antigen. Immune system becomes tolerant to self-antigens through the two main processes, central and peripheral tolerance. The central tolerance takes place within the thymus and represents the mechanism by which T cells binding with high avidity self-antigens, that are potentially autoreactive, are eliminated through the so called negative selection. This process is mostly mediated by medullary thymic epithelia cells (mTECs) and medullary dendritic cells (DCs). A remarkable event in the process is the expression of tissue specific antigens (TSA) by mTECs driven by the transcription factor autoimmune regulator (AIRE). Mutations in this gene result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a rare autosomal recessive disease (OMIM 240300). Thus far, this syndrome is the paradigm of a genetically determined failure of central tolerance and autoimmunty. Patients with APECED have a variable pattern of autoimmune reactions, involving different endocrine and nonendocrine organs. However, although APECED is a monogenic disorder, it is characterized by a wide variability of the clinical expression, thus implying a further role for disease-modifying genes and environmental factors in the pathogenesis. Studies on this polyreactive autoimmune syndrome gave an enormous contribution to unraveling several issues of the molecular basis of autoimmunity. This review will focus on the developmental, functional and molecular events governing central tolerance and on the clinical implication of its failure.