Aire-mediated tolerance provided by this mechanism is pivotal: in humans, genomic mutations in Aire gene result in a devastating autosomal recessive monogenic disease called Autoimmune Polyglandular Syndrome type 1 (APS-1), with prototypical clinical manifestations that include hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (83, 84). This evidence concerns the gene AIRE and autoimmune polyendocrine syndrome type 1.