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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymic epithelium, including nurse cells (TEC/TNC), as well as other thymic stromal cells (macrophages and dentritic cells), express a repertoire of polypeptide belonging to various neuroendocrine protein families (such as the neurophypophysial, tachykinin, neurotensin and insulin families). A hierarchy of dominance exists in the organization of the thymic repertoire of neuroendocrine precursors. Oxytocin (OT) is more expressed in the TEC/TNC than vasopressin (VP); insulin-like growth factor 2 (IGF-2) thymic expression predominates over IGF-1, and much more over (pro)insulin. Thus, OT was proposed to be the self antigen of the neurohypophysial family, and IGF-2 the self antigen precursor of the insulin family. The dual role of the thymus in T-cell life and death is recapitulated at the level of the thymic neuroendocrine protein repertoire. Indeed, thymic polypeptides behave as accessory signals involved in T-cell development and positive selection according to the cryptocrine model of signaling. Moreover, thymic neuroendocrine polypeptides are the source of self antigens presented by thymic MHC molecules to developing pre-T cells. This presentation might induce the negative selection of T cells bearing a randomly rearranged antigen receptor (TCR) oriented against neuroendocrine families. Using an animal model of autoimmune type 1 diabetes (BB rat), we have shown a defect in intrathymic expression of the self antigen of the insulin family (IGF-2) and in IGF-2-mediated T-cell education to recognize and tolerate the insulin family. Altogether these studies have enlightened the crucial role played by the thymus in the induction of the central self tolerance of neuroendocrine families. The tolerogenic properties of thymic self peptides could be used in a novel type of vaccination for the prevention of autoimmune diseases.
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PMID:The thymic repertoire of neuroendocrine-related self antigens: biological role in T-cell selection and pharmacological implications. 987 42

The repertoire of thymic neuroendocrine precursors plays a dual role in T-cell differentiation as the source of either cryptocrine accessory signals in T-cell development or neuroendocrine self-antigens presented by the thymic major histocompatibility complex (MHC) machinery. Thymic neuroendocrine self-antigens usually correspond to peptide sequences highly conserved during the evolution of one family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Oxytocin (OT) is the dominant peptide of the neurohypophysial family. It is expressed by thymic epithelial and nurse cells (TEC/TNCs) of different species. Ontogenetic studies have shown that the thymic expression of the OT gene precedes the hypothalamic one. Both OT and VP stimulate the phosphorylation of p125FAK and other focal adhesion-related proteins in murine immature T cells. These early cell activation events could play a role in the promotion of close interactions between thymic stromal cells and developing T cells. It is established that such interactions are fundamental for the progression of thymic T-cell differentiation. Insulin-like growth factor 2 (IGF-2) is the dominant thymic polypeptide of the insulin family. Using fetal thymic organ cultures (FTOCs), the inhibition of thymic IGF-2-mediated signaling was shown to block the early stages of T-cell differentiation. The treatment of FTOCs with an mAb anti-(pro)insulin had no effect on T-cell development. In an animal model of autoimmune type 1 diabetes (BB rat), thymic levels of (pro)insulin and IGF-1 mRNAs were normal both in diabetes-resistant and diabetes-prone BB rats. IGF-2 transcripts were clearly identified in all thymuses from diabetes-resistant adult (5-week) and young (2- and 5-days) BB rats. In marked contrast, the IGF-2 transcripts were absent and the IGF-2 protein was almost undetectable in +/- 80% of the thymuses from diabetes-prone adult and young BB rats. These data show that a defect of the thymic IGF-2-mediated tolerogenic function might play an important role in the pathophysiology of autoimmune Type 1 diabetes.
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PMID:Thymic neuroendocrine self-antigens. Role in T-cell development and central T-cell self-tolerance. 1126 99

Insulin expression in the thymus has been implicated in regulating the negative selection of autoreactive T cells and in mediating the central immune tolerance towards pancreatic beta-cells. To further explore the function of this ectopic insulin expression, we knocked out the mouse Ins2 gene specifically in the Aire-expressing medullary thymic epithelial cells (mTECs), without affecting its expression in the beta-cells. When further crossed to the Ins1 knockout background, both male and female pups (designated as ID-TEC mice for insulin-deleted mTEC) developed diabetes spontaneously around 3 weeks after birth. beta-cell-specific autoimmune destruction was observed, as well as islet-specific T cell infiltration. The presence of insulin-specific effector T cells was shown using ELISPOT assays and adoptive T cell transfer experiments. Results from thymus transplantation experiments proved further that depletion of Ins2 expression in mTECs was sufficient to break central tolerance and induce anti-insulin autoimmunity. Our observations may explain the rare cases of type 1 diabetes onset in very young children carrying diabetes-resistant HLA class II alleles. ID-TEC mice could serve as a new model for studying this pathology.
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PMID:Thymus-specific deletion of insulin induces autoimmune diabetes. 1975 22