Aire deficiency, from preclinical models to human apeced disease

Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare life-threatening autoimmune disease that attacks multiple organs and has its onset in childhood. It is an inherited condition caused by a variety of mutations in the autoimmune regulator (AIRE) gene that encodes a protein whose function has been uncovered by the generation and study of Aire-KO mice. These provided invaluable insights into the link between AIRE expression in medullary thymic epithelial cells (mTECs), and the broad spectrum of self-antigens that these cells express and present to the developing thymocytes.However, these murine models poorly recapitulate all phenotypic aspects of human APECED. Unlike Aire-KO mice, the recently generated Aire-KO rat model presents visual features, organ lymphocytic infiltrations and production of autoantibodies that resemble those observed in APECED patients, making the rat model amain research asset. In addition, ex vivo models of AIRE-dependent self-antigen expression in primary mTECs have been successfully set up. Thymus organoids based on pluripotent stem cell-derived TECs from APECED patients are also emerging, and constitute a promising tool to engineer AIRE-corrected mTECs and restore the generation of regulatory T cells. Eventually, these new models will undoubtedly lead to main advances in the identification and assessment of specific and efficient newtherapeutic strategies aiming to restore immunological tolerance in APECED patients.