Sunday, August 31, 2008

Tolerating Aire - Out of the Thymus

The immune system protects us against infections but it must also tolerate the many different proteins that constitute our bodies. T lymphocytes of the immune system that react against the body’s own proteins could trigger autoimmunity, so they are usually deleted during their maturation in the thymus. A protein called Aire (Autoimmune regulator) turns on expression in the thymus of nearly 2,000 genes that are otherwise expressed in only a few organs and tissues, thereby exposing new T cells to these proteins and avoiding autoimmune disease. Indeed, mutations in Aire result in a broad autoimmunity against many organs and tissues. Previously, Aire was thought by many to be expressed only in the thymus.

Gardner and colleagues detected Aire in rare stromal (non-lymphoid) cells they called extrathymic Aire-expressing cells (eTACs) within the spleen, lymph nodes, and Peyer’s patches (nodes associated with the gut). These cells are located between the T and B cell areas of these organs but are highly mobile. Surprisingly, Aire turned on different genes in eTACs than were turned on in the thymus, suggesting that Aire expression in eTACs is not a ‘safety net’ for T cells that accidentally escaped the thymus but rather acts to delete additional autoreactive T cells. In eTACS, Aire turned on fewer than 200 genes, but several of these are suspected to be involved in autoimmunity, including desmoglein 1a (in pemphigous foliaceus) and the N-methyl-D-aspartate receptor 2C (in lupus). In an animal model of type 1 diabetes, eTACs expressing glucose-6-phosphate-related protein deleted T cells specific for this protein and prevented onset of this autoimmune disease (Fig. 2f shown, open squares represent mice expressing glucose-6-phosphatase-related Adig in eTACs).

These findings suggest that manipulating eTACs is a promising approach to therapy for autoimmune disease. Comparing eTACs in healthy people and autoimmune patients might also help identify deficiencies that can be corrected to prevent or ameliorate disease.

Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008 Aug 8;321(5890):843-7.

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