AIRE and immunological tolerance: insights from the study of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy Luigi D. Notarangelo, Cinzia Mazza, Concetta Forino, Evelina Mazzolari and Fabio Buzi Purpose of review To review the clinical and molecular features of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy and discuss recent advances in the function of the AIRE protein. We will summarize how AIRE contributes to immunological tolerance, and thus to the prevention of autoimmunity. Recent findings The organization of a well-structured thymic microenvironment and the interaction between nascent thymocytes and thymic epithelial cells have been shown to be essential for AIRE expression. AIRE is involved in the expression of ectopic proteins by medullary thymic epithelial cells. This allows the establishment of central tolerance and contributes to the prevention of organ-specific autoimmunity, as shown by findings in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (a disease caused by AIRE gene mutations) and in aire 7/7 mice. Summary Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy represents a unique model to investigate the cellular and molecular mechanisms that govern central tolerance and help prevent autoimmunity. Recent findings indicate that the compartmentalization of AIRE and interaction with other proteins are involved in this mechanism. The disturbance of AIRE expression may also be responsible for autoimmune manifestations in disorders with disrupted thymic structure other than autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy alone. Keywords AIRE, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, autoimmunity, immunological tolerance Curr Opin Allergy Clin Immunol 4:491–496. # 2004 Lippincott Williams & Wilkins. Department of Pediatrics and ‘Angelo Nocivelli’ Institute of Molecular Medicine, Children’s Hospital, University of Brescia, Brescia, Italy Correspondence to Luigi D. Notarangelo, MD, Department of Pediatrics, Children’s Hospital, University of Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy Tel: +39 030 3995715; fax: +39 030 3388099; e-mail: notarang@med.unibs.it Current Opinion in Allergy and Clinical Immunology 2004, 4:491–496 Abbreviations APECED autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy GAD glutamic acid decarboxylase HLA human leukocyte antigen HSR homogeneously staining region IFDM insulin-dependent diabetes mellitus LTbR lymphotoxin b receptor PHD plant homeodomain TEC thymic epithelial cell TSP tissue-specific protein # 2004 Lippincott Williams & Wilkins 1528-4050 Introduction Self-non-selfdiscrimination is the basis that allows the immune system to recognize and respond specifically to invading exogenous pathogens or autologous modified (tumour) cells without attacking endogenous cells and molecules. Consequently, the disruption of self-non- selfdiscrimination may lead to autoimmunity. Toleriza- tion to self involves various distinct mechanisms, which may occur both in the thymus (central tolerance) and in the periphery (peripheral tolerance). Central tolerance is mainly generated through clonal deletion of newly generated T cells that recognize self antigens with high avidity [1 . ]. However, not all autoreactive T cells are eliminated in the thymus. Some may in fact be exported. Immunological tolerance in the periphery is achieved by a variety of mechanisms, including the deletion of autoreactive clones through Fas-mediated apoptosis, immunological ignorance (in which self antigens and autoreactive T cells are sequestered in distinct compartments) and the interven- tion of regulatory T cells [2]. Whereas most autoimmune diseases are of multifactorial origin, some rare monogenic disorders have been described, which illustrate the importance of immuno- logical tolerance in preventing autoimmunity. In parti- cular, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (APECED), also known as auto- immune polyglandular syndrome 1, and immune dys- regulation, polyendocrinopathy, enteropathy, X-linked syndrome represent diseases caused by defects in central and peripheral tolerance, respectively [3 .. ]. Character- ization of the clinical, immunological, and molecular 491