Claude Bernard (1813-1878), the father of modern physiology and experimental medicine

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Type 1 diabetes susceptibility loci from genome scans in multiplex families

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The Intrathymic Expression of Insulin-Related Genes: Implications for Pathophysiology and Prevention of Type 1 Diabetes

peer reviewedRecent experimental work has challenged and shattered the old concept of a sequestration of pancreatic islet antigens from developing T-cells within the thymic environment. There is now compelling evidence that the central immunological tolerance of the whole insulin family may be induced during the process of T-cell ontogeny in the thymus. Transcripts of insulin-like growth factor II (IGF-II), IGF-I and insulin genes have been characterized in human, rat and mouse thymuses. At the peptide level, IGF-II was shown to be the dominant polypeptide of the insulin family in the thymus from different species. Data are presented which support a dual role of thymic IGF-II both in T-cell development as well as in T-cell negative selection. Using animal models of autoimmune diabetes, current research is investigating the hypothesis that a defect of thymic T-cell education to the insulin family is implicated in the pathophysiology of human Type 1 diabetes. An efficient and secure prevention of Type 1 diabetes could be designed on the basis of the strong natural tolerogenic properties of the thymus

Thymic Self-Antigen Expression for the Design of a Negative/Tolerogenic Self-Vaccine against Type 1 Diabetes

Before being able to react against infectious non-self-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins, and this critical process essentially takes place in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β cell reactive effector T cells and a deficiency of β cell-specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of negative self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases

Programing of the autoimmune diabetogenic response in the thymus during fetal and perinatal life

The presentation of self-peptides in the thymus is responsible both for negative selection of self-reactive T cells emerging during stochastic TCR recombination in fetal life, as well as positive selection of self-specific regulatory thymic T (tTreg) cells during and after perinatal life. The combination of these two sequential processes programs central self-tolerance, a fundamental property of the adaptive immune system. A defect in intrathymic self-presentation, either genetic or acquired, is the earliest event in the pathogenesis of autoimmunity already during fetal development. This defect is necessary but not sufficient for the appearance of a classical autoimmune disease like type 1 diabetes (T1D). Environmental factors are required for activation of the diabetogenic autoimmune response that targets insulin-secreting β cells in pancreatic Langerhans’ islets. Based on epidemiological studies, viral infections have been suspected for a long time to be one of those environmental factors. In this Debate article, we present a series of experimental data that support the hypothesis that, following vertical transplacental transfer, viruses might infect the fetal thymus and disturb already in utero central self-tolerance orchestrated by this organ