Abstract
For centuries after its first description by Galen, the thymus was considered as only a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the development of T (thymo-dependent) lymphocytes. A unique thymus first appeared in cartilaginous fishes some 500 million years ago, at the same time or shortly after the emergence of the adaptive (acquired) immune system. The thymus may be compared to a small brain or a computer highly specialized in the orchestration of central immunological self-tolerance. This was a necessity for the survival of species, given the potent evolutionary pressure imposed by the high risk of autotoxicity inherent in the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. 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 neuroendocrine signaling, but are processed for presentation by, or in association with, the thymic major histocompatibility complex (MHC) proteins. The autoimmune regulator (AIRE) gene/protein controls the transcription of neuroendocrine genes in TECs. The presentation of self-peptides in the thymus is responsible for the clonal deletion of self-reactive T cells, which emerge during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). At the same time, self-antigen presentation in the thymus generates regulatory T (Treg) cells that can inhibit, in the periphery, those self-reactive T cells that escaped negative selection in the thymus. Several arguments indicate that the origin of autoimmunity directed against neuroendocrine glands results primarily from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or acquired, for example during an enteroviral infection. This novel knowledge of normal and pathologic functions of the thymus constitutes a solid basis for the development of a novel type of tolerogenic/negative self-vaccination against type 1 diabetes (T1D).
Highlights
Galen (129–210 AC), who, with Hippocrates, is recognized as one of the fathers of Western medicine, first observed, behind the sternum and before the cardiac area, an organ that he named “thymus” because of its resemblance to the leaf of the thyme plant Thymus vulgaris
Following affinity-chromatography with a mAb against the monomorphic part of human major histocompatibility complex (MHC) class I molecules, we identified, in human thymic epithelial cells (TECs) plasma membrane, a 55-kD protein that was labeled by both anti-MHC class I mAb and a specific anti-neurophysin antiserum
autoimmune regulator (AIRE) encodes a protein with structural characteristics of a transcription factor: its transcription is maximal in thymus epithelium, and Aire−/− mice develop several autoimmune processes associated with a marked decrease in the intrathymic expression of numerous neuroendocrine self-peptides (Anderson et al, 2002)
Summary
Galen (129–210 AC), who, with Hippocrates, is recognized as one of the fathers of Western medicine, first observed, behind the sternum and before the cardiac area, an organ that he named “thymus” because of its resemblance to the leaf of the thyme plant Thymus vulgaris. Later from the bone marrow, T lymphocyte progenitors migrate through the boundary between cortex and medulla into the thymic epithelial rudiment in response to chemoattractant factors (Wilkinson et al, 1999) They undergo many mitotic divisions in the outer cortex, and differentiate after presentation of peptides by major histocompatibility complex (MHC) proteins expressed by thymic antigen-presenting cells (essentially cTECs, mTECs, DCs, and macrophages). In pre-T cells, OT phosphorylates paxillin, a 68-kD protein located at focal adhesion sites and associated with p125FAK (Martens et al, 1998) Together, these data establish the existence of a functional OT-mediated cryptocrine signaling in the thymus network. The OT-mediated promotion of focal adhesion may contribute to the establishment of immunological “synapses” between TECs and immature T cells, which is fundamental for the completion of the T cell differentiation programme
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