AIRE-mutations and autoimmune disease

• Autoimmune regulator (AIRE) plays a key role in development of central immunological tolerance.
• Biallelic mutations cause organ-specific autoimmunity with chronic candidiasis called APS-1.
• Single mutations in the PHD1 and SAND domains can cause a milder clinical picture with vitiligo and pernicious anemia.
• The role of AIRE mutations and polymorphisms in common autoimmune diseases remains to be defined.

The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders.