Editors' ChoiceHuman Genetics

Fresh AIRE for autoimmune disease genetics

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Science Translational Medicine  22 Jul 2015:
Vol. 7, Issue 297, pp. 297ec124
DOI: 10.1126/scitranslmed.aac8567

Autoimmune polyendocrine syndrome type 1 (APS1)—a syndrome characterized by multiorgan autoimmunity and autoantibody production—is caused by mutations in AIRE (autoimmune regulator). AIRE is now understood to be a key transcriptional regulator in the thymus, where it induces the expression of diverse self-peptides so that developing autoreactive T cells can be recognized and eliminated. Patients with autosomal recessive APS1 carry homozygous AIRE mutations. Oftedal and colleagues now report a previously underappreciated class of dominant AIRE mutations that also cause autoimmunity.

The authors initially identified a patient with clinical features of APS1 but a usually late disease onset. Genomic sequencing revealed a monoallelic mutation in AIRE that was shared with other family members with autoimmunity. No mutation on the second allele was found, suggesting that this variant could dominantly impair AIRE function, and cellular studies validated that this was the case. When the authors expressed the newly identified mutant AIRE in a thymic cell line, it colocalized with coexpressed wild-type AIRE and prevented target gene induction. Following this lead, the authors discovered that other autoimmunity-associated AIRE mutations also exhibited similar dominant negative effects. In fact, AIRE mutations could be classified as recessive or dominant-negative on the basis of their transcriptional effects. The dominant mutations clustered in the protein’s first PHD1 domain, which interacts with chromatin in a specific epigenetic state and is essential for AIRE-induced transactivation. Consistent with these in vitro findings, the authors identified additional patients who carried monoallelic mutations affecting the AIRE PHD1 domain. They exhibited a spectrum of autoimmune disease features—generally milder, less penetrant, later onset, and more organ-specific than is typical for APS1.

AIRE mutations therefore explain a broader range of disease than previously appreciated, highlighting the diverse phenotypes that can arise from mutations in one gene. In addition to “classical” APS1 characterized by early-onset multiorgan autoimmune disease, the authors describe a new “nonclassical” form of disease caused by dominant-negative AIRE mutations associated with later onset, milder phenotypes, and incomplete penetrance. Just how many people are affected by some form this nonclassical syndrome remains to be determined.

B. E. Oftedal et al., Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity 42, 1185–1196 (2015). [Abstract]

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