Programming of neuroendocrine self-tolerance in the thymus and its defect in the development of neuroendocrine autoimmunity

The thymus may be compared to a computer highly specialized in the programming of central immunological self-tolerance. A unique thymus first appeared some 500 million years ago in cartilaginous fishes, at the same time or shortly after the emergence of the adaptive immune system. A new paradigm of neuroendocrine self-peptides has been proposed, together with the definition of neuroendocrine self. Neuroendocrine self-peptides are secreted by thymic epithelial cells (TECs) not according to the classic model of neurosecretion, but are processed for presentation by the thymic major histocompatibility complex (MHC) machinery. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. Presentation of neuroendocrine self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells directed toward neuroendocrine antigens, which emerge during the random recombination of gene segments encoding variable parts of the T cell receptor for the antigen (TCR). Quite paradoxically, neuroendocrine self-peptide presentation in the thymus also generates regulatory T (tTreg) cells that inhibit, in the periphery, those self-reactive T cells having escaped thymic negative selection. Several arguments indicate that the origin of autoimmunity directed against neuroendocrine glands results from a primary defect in the intrathymic programming of self-tolerance to neuroendocrine principles. This defect may be genetic or acquired, for example during a viral infection. This novel knowledge of normal and pathologic functions of the thymus constitutes a solid scientific basis for the development of a novel type negative self-vaccination against type 1 diabetes.
(Supported by NFSR of Belgium, Wallonia and FP6 Eurothymaide.)