Somatic mutations can be potent drivers of cancer but their role in other diseases remains unresolved. Writing in Nature, a team led by Iñigo Martincorena now highlights that they may be just as important in autoimmune disease. The group used whole-exome, deep targeted NanoSeq and single-cell DNA sequencing to survey the mutational landscape of thyroid tissue from patients with Graves’ disease and Hashimoto thyroiditis. Their analysis identified pervasive expansions of clones with independent, likely loss-of-function mutations in genes encoding key immune checkpoints, such as TNFRSF14 (also known as HVEM) and CD274 (encoding PD-L1). Individual samples harbored hundreds of mutant clones, suggestive of powerful selection for immune escape. These findings are reminiscent of tumor formation wherein immune escape is a key requisite. Perhaps similar mechanisms are at play here; mutations that bestow cells with the ability to evade immune detection confer a crucial fitness boost. Here, the endpoint is autoimmunity rather than malignancy, but the implications are that the principles of Darwinian evolution — so often associated with cancer — might also be at the heart of autoimmune disorders.
