Autoimmune polyendocrine syndrome type I (APS I), a rare genetic disorder of childhood, has proven an invaluable tool to understand autoimmune reactions and to develop new diagnostic tests. All the major scientific achievements in the area over the past twenty years have been accomplished by different European scientists, all participating in this proposal. APS I (OMIM 240300), also known as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy), is a severe autosomal recessive disorder caused by mutations in the AIRE gene on chromosome 21. The disorder begins in early childhood and the patients gradually develop autoimmune destruction of different endocrine and non-endocrine tissues and, in addition, mucocutaneous candidiasis. APS I is characterized by autoantibodies against several defined autoantigens often identical to those found in more common autoimmune disorders such as type 1 diabetes mellitus and Addison's diseae. The responsible gene, AIRE, has been identified and Aire-deficient mice, with the same genetic defect as the human disease, has been produced. Further studies establishing a pan-European patient data base and biobank, using MHC class I and class II tetramers to define the peptides from autoantigens of importance in patients and mice, on the function of the AIRE-gene, finding genes modulating the intensity and course of autoimmune reactions and on the cause for Candida albicans infection in APS I patients, will not only help patients with this rare disorder but will also increase our understanding in the pathogenesis of common autoimmune diseases that can lead to novel terapeutic strategies. The contributions of the Holländer lab to the EURAPS consortium is the analysis of the development and function of AIRE expressing thymic epithelial cells, the generation of mice conditionally deficient in AIRE expression, and the investigation of immunological effectors cells that have been selected in a thymic microenvironment deficient in AIRE.
