Research ArticleAUTOIMMUNITY

AIRE expression controls the peripheral selection of autoreactive B cells

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Science Immunology  12 Apr 2019:
Vol. 4, Issue 34, eaav6778
DOI: 10.1126/sciimmunol.aav6778

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AIRE and autoreactivity

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a condition caused by mutations in the autoimmune regulator (AIRE) gene and is associated with central T cell tolerance defects and circulating autoantibodies. Sng et al. now observe that T cell development altered by AIRE deficiency is associated with a greater frequency of autoreactive mature naïve B cells in the periphery. This defect in peripheral B cell tolerance is linked to fewer regulatory T cells that did not include common TCRβ clones found instead in the conventional T cell compartment. This T cell defect may not prevent the selection and expansion of autoreactive B cells to peripheral self-antigens, thus leading to autoantibody production.


Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue-specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in the peripheral accumulation of autoreactive mature naïve B cells. Proteomic arrays and Biacore affinity measurements revealed that unmutated antibodies expressed by these autoreactive naïve B cells recognized soluble molecules and cytokines including insulin, IL-17A, and IL-17F, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. AIRE-deficient patients also displayed decreased frequencies of regulatory T cells (Tregs) that lacked common TCRβ clones found instead in their conventional T cell compartment, thereby suggesting holes in the Treg TCR repertoire of these patients. Hence, AIRE-mediated T cell/Treg selection normally prevents the expansion of autoreactive naïve B cells recognizing peripheral self-antigens.

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