Rare Hereditary Autoimmune Disease Found to Have More Common Form

Researchers have discovered that single-allele mutations in the gene that causes recessive autoimmune polyendocrine syndrome type-1 (APS-1) can cause a less severe but more common condition. Findings may help identify, diagnose, and treat a number of autoimmune diseases.

APS-1, caused by recessive (double-allele) mutation in the AIRE (AutoImmune REgulator) gene, is a constellation of medical problems ranging from attack on and destruction of multiple tissues and organs, to chronic infections. According to the new study, led by Dr. Jakub Abramson of the Weizmann Institute of Science (Rehovot, Israel) and Dr. Eystein S. Husebye of the University of Bergen (Bergen, Norway), APS-1 was thought to be exceedingly rare but now appears to have a less severe form that affects at least 1 in 1,000 people. Their results suggest that a number of autoimmune disorders may be linked to mutations in AIRE.


AIRE normally prevents such autoimmune attacks by overseeing the training of immune cells to ignore self-made antigens. AIRE is almost exclusively expressed in the thymus, where T-cells undergo a “basic training” before being released into the bloodstream for defense missions. In the thymus, AIRE operates in medullary thymic epithelial cells (mTECs), which act as “examiners,” checking that released T-cells will not react to self-antigens. mTECs create a comprehensive genomic expression library of self-antigens and test T-cells for their reactions—T-cells that attack a self-antigen are eliminated in the thymus. AIRE controls the expression of the thousands of self-antigen genes within the thymus. In another recent study (Nature Immunology), Dr. Abramson’s group discovered that AIRE is itself regulated by SIRT1, present at exceptionally high levels in mTECs and keeps AIRE activated.

Current medical wisdom assumes that clinical symptoms will arise only if both AIRE alleles are dysfunctional. Dr. Abramson and Dr. Husebye challenged this widely accepted notion and found that even a single-allele mutation may disrupt function and cause devastating autoimmunity. AIRE proteins bind one another, forming an active complex. A specific mutation in one copy is enough to disrupt function of the entire complex in a dominant-like manner.

The study arose from an unusual clinical observation in Dr. Husebye’s lab where a patient had an autoimmune syndrome suggesting recessive AIRE mutations, but was revealed to be mutated in only one allele. Among the patient’s children: those carrying the single-allele mutation had also developed an autoimmune disorder, but it was milder and did not match the symptoms of the recessive syndrome. Drs. Abramson and Husebye hypothesized that such dominant AIRE mutations may be a common cause of autoimmune disorders. The two research groups performed lab experiments and examined medical data from families in Norway, Finland, and Russia who suffered from various forms of autoimmunity. They found that many of those with single-allele AIRE mutations had been diagnosed with various autoimmune disorders.

“A dominant AIRE malfunction could explain the mechanism of a number of autoimmune diseases,” said Dr. Abramson. Further research revealed that only mutations at certain sites of the AIRE gene confer dominance over the healthy gene. Interestingly, however, the healthy gene is not completely negated: The dominant version of the disease is less severe, appears later in life, and may affect fewer organs than in APS-1.

The study, by Oftedal BE et al., was published June 16, 2015, in the journal Immunity.

Related Links:
Weizmann Institute of Science
University of Bergen