Central control of autoimmunity

One of the mechanisms involved in controlling lymphocyte autoreactivity is the elimination, during T and B cell differentiation, of cells with the highest affinity for autoantigens. This is the process of "negative" selection. Tangible progress has been made in recent years in understanding the molecular mechanisms involved, particularly in the thymus. Analysis of another rare hereditary disease responsible for autoimmunity: the "Apeced" syndrome (Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy) has led to the identification of the AIRE(AutoImmune REgulator) protein as an essential mediator of the negative selection process. This molecule is expressed by thymic medullary epithelial cells. AIRE binds to inactive chromatin and helps recruit the factors that facilitate gene transcription to thousands of genes. As a result, these epithelial cells express small quantities of many of the body's proteins, such as insulin. Peptides derived from these proteins are delivered directly or indirectly by dendritic cells to T lymphocytes. Those with a high affinity for these self peptides receive cell death signals and are therefore eliminated. The intrathymic topology of presentation of these autoantigens is heterogeneous, increasing the probability of contact and hence elimination of autoreactive T clones. However, AIRE does not govern the expression of all self proteins at thymic level. Recently, the transcription factor Fezf2 was identified in mice as responsible for the expression of a fraction of them. The precise mechanism of action remains to be determined. An important unresolved question concerns the coordination of induction of thymic self protein expression by AIRE and Fezf2 to optimize negative selection of high-affinity autoreactive cells.