For a long time it was thought that many self antigens were not expressed in the thymus or bone marrow, and that peripheral mechanisms must be the only way of generating tolerance to them. It is now clear that many (but not all) tissue-specific antigens, such as insulin, are expressed in the thymus by either thymic epithelial cells in the medulla or a CD8α+ subset of dendritic cells, and thus self-tolerance against these antigens can be generated centrally. How these ‘peripheral’ genes are turned on ectopically in the thymus is not yet completely worked out, but an important clue has been found. A single transcription factor, AIRE (for autoimmune regulator), is thought to be responsible for turning on many peripheral genes in the thymus (see Section 8-23). The AIRE gene is defective in patients with a rare inherited form of autoimmunity—APECED (autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy), also known as autoimmune polyglandular syndrome type 1 (APS-1)—that leads to destruction of multiple endocrine tissues, including insulin-producing pancreatic islets, and to fungal infections, particularly candidiasis. Mice engineered to lack the AIRE gene fail to express many peripheral genes in the thymus and develop a similar syndrome. This links AIRE to the expression of these genes, and the antigens they encode, indicating that an inability to express these antigens in the thymus leads to autoimmune disease (Fig. 15.4). The autoimmunity that accompanies AIRE deficiency takes time to develop and does not always affect all potential organ targets. So as well as emphasizing the importance of central tolerance, this disease shows that other layers of tolerance control have important roles.
In the absence of AIRE, T cells reactive to tissue-specifc antigens mature and leave the thymus In the thymus, T cells arise capable of recognizing tissue-speciÿc antigens Under control of the AIRE protein, thymic medullary cells express tissue-speciÿc proteins, leading to deletion of tissue-reactive T cells 15-4 Lymphocytes that bind self antigens with relatively low affinity activated.
Most circulating lymphocytes have a low affinity for self antigens but make no effector response to them, and may be considered ‘ignorant’ of self (see Section 8-6). Such ignorant but latently self-reactive cells can be recruited into autoimmune responses if their threshold for activation is exceeded by co-activating factors. One such stimulus is infection. Naive T cells with low affinity for a ubiquitous self-antigen can become activated if they encounter an activated dendritic cell presenting that antigen and expressing high levels of co-stimulatory signals or pro-inflammatory cytokines as a result of the presence of infection.