AIRE is a transcription factor essential for central immune tolerance, primarily expressed in medullary thymic epithelial cells (mTECs) 1. It regulates expression of tissue-restricted antigens (TRAs)—self-proteins normally confined to peripheral organs—enabling their presentation to developing thymocytes via MHC-I and MHC-II molecules 1. This ectopic expression promotes negative selection of self-reactive T cells and regulatory T cell (Treg) development, preventing autoimmunity 2. AIRE functions as a histone modification sensor, binding to A/T-rich DNA sequences and selectively interacting with unmodified histone H3 to regulate chr21 accessibility 1. Beyond thymic roles, AIRE controls medullary dendritic cell accumulation and lymphocyte migration through XCL1 and chemokine ligand regulation 1. Extrathymic AIRE-expressing cells also contribute to peripheral tolerance mechanisms 3. Disruption of AIRE causes autoimmune polyendocrine syndrome type-1 (APECED/APS-1), an autosomal recessive disorder characterized by impaired T cell negative selection, reduced Treg function, and pathogenic autoantibody production 4. Approximately 100 mutations have been identified, with certain mutations exhibiting dominant-negative effects in milder autoimmune diseases including vitiligo and thyroiditis 5. Evidence suggests excessive interferon-γ response may drive organ-specific damage in APECED, potentially amenable to JAK inhibitor therapy 4.