The lack of thymic IRBP creates autoantibodies (green) against retinal IRBP.

The lack of just one self-antigen in the thymus can launch a tissue-specific autoimmune attack, report DeVoss et al. (page 2727).

T cells are taught which antigens to ignore as they develop in the thymus. Those whose antigen receptors recognize self-proteins are normally eliminated, preventing them from escaping into the circulation and later attacking self-tissues. The transcription factor Aire (autoimmune regulator) drives the expression of many tissue-specific antigens in the thymus; without Aire, mice develop a panoply of autoimmune diseases. But so far no studies have proven the link between defects in Aire-induced expression of tissue antigens in the thymus and the development of autoimmunity against those tissues.

The team showed that one of the problems that crops up in aire−/− mice—a spontaneous autoimmunity of the eye—is due to a T cell attack on an eye-specific interphotoreceptor retinoid binding protein (IRBP). IRBP, the authors found, was expressed at a low level in the wild-type thymus, but was missing in the aire−/− thymus. Wild-type mice transplanted with thymi lacking IRBP developed the same eye disease, proving that the lack of thymic IRBP was solely responsible for the disorder.

Humans lacking Aire also develop retinopathy, although they more commonly develop other organ-specific autoimmune diseases. Given that aire−/− mice develop a range of tissue-specific autoimmune disorders, the authors plan to test whether those that are common to humans can also be pinned on the loss of a single antigen.