Figure 1. Escape of autoreactive T and B cells from central tolerance and engagement in the periphery.

During differentiation, T and B cell precursors with self-reactivity are positively selected in the thymic cortex and bone marrow, respectively, and those with low avidity for self are exported to the periphery. In contrast, autoreactive T cells (aT) with high avidity for self-antigens expressed by medullary thymic epithelial cells (mTEC) under the control of AIRE or FEZF2 are deleted or differentiate to T_reg cells (T_R), while autoreactive B cells (aB) are deleted or receptor-edited. Central tolerance, however, is incomplete, and some autoreactive T and B cells are exported to the periphery. The exported cells are normally controlled by peripheral tolerance mechanisms, including inhibitory molecules, anergy, ignorance and suppression by Treg cells. However, in genetically-predisposed individuals, tissue damage, inflammation, and presentation of sequestered, cryptic, neo self-antigens or microbial mimics might provoke break of tolerance and autoimmunity.