The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of Type 1 diabetes

Geenen, Vincent; Lefèbvre, Pierre

doi:10.1002/(sici)1099-0895(199803)14:1<95::aid-dmr200>3.0.co;2-w

Cited by 20 publications

(17 citation statements)

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“…Though the autoimmune nature of type 1 diabetes is well established, animal experiments and human clinical studies have failed to determine the specific origin of the immunological self-reactivity against insulin-secreting islet b-cells. It has been hypothesized, however, that specific self-reactivity of the immune system may develop from a defect in the thymic establishment of central self-tolerance [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

Kecha-Kamoun

Achour

Martens

et al. 2001

Diabetes Metab. Res. Rev.

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Background Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet b-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell selftolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat.

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Section: Introductionmentioning

confidence: 99%

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

Kecha-Kamoun

Achour

Martens

et al. 2001

Diabetes Metab. Res. Rev.

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“…It is also the case for the whole insulin family, since transcripts of insulin-like growth factor 2 (Igf2), Igf1, and insulin (Ins) genes have been characterized in human, rat, and mouse thymuses (21,22,33,34,61). At the peptide level, IGF-2 was shown to be the dominant polypeptide of the insulin family in the thymus epithelial network from different species (17,18,34).…”

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confidence: 99%

Persistent Infection of Thymic Epithelial Cells with Coxsackievirus B4 Results in Decreased Expression of Type 2 Insulin-Like Growth Factor

Jaïdane

Caloone

Lobert

et al. 2012

J Virol

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“…Igf2 transcripts were also present in the thymus from all BBDR rats, but were not detected in the thymus from more than 80% of BBDP rats, in close concordance with the incidence (86%) of autoimmune diabetes in those rats. This defect in Igf2 transcription in BBDP thymus could contribute to both their lymphopenia (including CD8+ T cells and suppressor/regulatory RT6+ T cells) and to the absence of central self-tolerance to insulin-secreting islet b cells [74,75]. Other authors have shown that susceptibility to autoimmune diabetes is correlated with the level of Ins2 transcription in the mouse thymus [76].…”

Section: Environmental Factorsmentioning

confidence: 97%

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

Geenen

Mottet

Dardenne

et al. 2010

Current Opinion in Pharmacology

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Before being able to react against infectious nonself-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins and this critical process takes place only in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programing central self-tolerance to pancreatic insulin-secreting islet b cells, leading to the breakdown of immune homeostasis with an enrichment of islet b-cell reactive effector T cells and a deficiency of b-cell specific natural regulatory T cells (nTregs) in the peripheral Tlymphocyte 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. The very low degree of insulin gene transcription in normal murine and human thymus explains why the insulin protein is poorly tolerogenic as demonstrated in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet b cells via various methods of insulin administration. On the basis of the close homology and crosstolerance 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 selfvaccination', is currently being developed for the prevention and cure of T1D. If this approach were found to be effective for reprograming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organspecific autoimmune diseases. ''Autoimmune disease can be a depressing subject. In Shakespearian terms, 'it is a tale told by an idiot. . .signifying nothing'. In more modern metaphor, it is an error made at random in an enormous, delicately programmed computer. Nature has no other way of handling genetic error than by eliminating the faulty, and the physician handling autoimmune diseases can expect no help from her.'' Sir F. MacFarlane Burnet, 1972 IntroductionIn 1965, our late Belgian colleague Willy Gepts observed inflammatory infiltrates of mononuclear cells invading Langerhans' islets in the pancreas of deceased young diabetic patients [1]. In a prophetical analysis, he discussed his innovative results with the following words: 'It seems probable that, in the pancreas of acute diabetics, we had the opportunity to catch the final stages of a process which has been going on for an indefinite time, perhaps from birth on'. Since this pioneering work, research conducted worldwide has firmly established that type 1 diabetes (T1D) -previously called juvenile diabetes, and insulin-dependent diabetes -is the final result of a highly selective autoimmune response that generates an inflammation (insulitis), followed by the death of insulin-secreting islet b cells in the pancreas. Incidence of T1D peaks around 10-14 years and this disease affects AE20 million people worldwide (approximately 10%...

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The intrathymic expression of insulin-related genes: implications for pathophysiology and prevention of Type 1 diabetes

Cited by 20 publications

References 60 publications

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

Thymic expression of insulin-related genes in an animal model of autoimmune type 1 diabetes

Persistent Infection of Thymic Epithelial Cells with Coxsackievirus B4 Results in Decreased Expression of Type 2 Insulin-Like Growth Factor

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

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