AIRE – The Autoimmune Regulator

Abstract Autoimmune diseases, caused by continuous immune responses against self‐antigens, have an uncertain aetiology. Although breakdown of self‐tolerance is considered to be the key event in the disease process, the underlying mechanisms are still enigmatic. So far, only a small number of genes that seem to be relevant to the pathogenesis of autoimmune diseases have been found. One of these genes is the autoimmune regulator ( AIRE ), mutation in which is responsible for the development of autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED) showing autosomal recessive inheritance. AIRE is a transcriptional regulator expressed predominantly by medullary thymic epithelial cells. Elucidation of how defective function of AIRE results in the development of organ‐specific autoimmunity is expected to shed light on not only the pathogenesis of autoimmune disease but also the fundamental question of how the immune system is educated to discriminate between self and nonself in the thymus. Key Concepts Autoimmune regulator (AIRE) is responsible for the development of organ‐specific autoimmune disease in a monogenic fashion. AIRE is expressed predominantly by thymic stromal cells (medullary thymic epithelial cells: mTECs) and controls the negative selection and production of regulatory T cells in the thymus. Production of a wide variety of autoantibodies (e.g. anti‐IFNs and anti‐Th17 cytokines) associated with autoimmune pathology and/or candidiasis infection is a prominent feature of AIRE deficiency. AIRE deficiency results in reduced transcription of a wide variety of tissue‐restricted antigen genes by mTECs. AIRE regulates the differentiation program of mTECs. Elucidation of AIRE function is expected to clarify the fundamental issue of how the immune system discriminates self from nonself. Identification of the target genes controlled by AIRE is essential for clarifying the exact function of AIRE in self‐tolerance.