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

Kecha-Kamoun, Ouafae; Achour, Imane; Martens, Henri; Collette, Julien; Lefèbvre, Pierre; Greiner, Dale L.; Geenen, Vincent

doi:10.1002/dmrr.182

Cited by 35 publications

(16 citation statements)

References 47 publications

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“…Transplantation of the thymus and thymic epithelium from the NOD mouse (an animal model of type 1 diabetes) was shown to induce insulitis in recipient athymic ÔnudeÕ mice (47,48). A defect of Igf2 transcription was also demonstrated in the thymus of more than 80% of diabetesprone BB rats (another animal model of type 1 diabetes), in close accordance with the incidence (86%) of autoimmune diabetes in this rat strain (49). The influence of VNTR on IGF2 expression has been analysed in leucocytes, and no difference in IGF2 mRNA levels was observed between protective class III and susceptible class I VNTR alleles (50).…”

Section: Implications For Pathogenesis Of Type 1 Diabetessupporting

confidence: 62%

Thymic Transcription of Neurohypophysial and Insulin‐Related Genes: Impact Upon T‐Cell Differentiation and Self‐Tolerance

Hansenne¹

2005

J Neuroendocrinology

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The thymus is the unique lymphoid organ responsible for the generation of a diverse repertoire of T lymphocytes that are competent against non self-antigens while being tolerant to self-antigens. A vast repertoire of neuroendocrine-related genes is transcribed in the nonlymphoid cellular compartment of the thymus (thymic epithelial cells, dendritic cells and macrophages). The precursors encoded by these genes engage two types of interactions with developing T cells (thymocytes). First, they are not processed in a classical neuroendocrine way but as the source of self-antigens that are presented to pre-T cells by the major histocompatibility complex proteins of the thymus. This presentation could be responsible for the establishment of central T-cell self-tolerance to neuroendocrine functions. Second, they also deliver signal ligands that are able to bind to neuroendocrine-type receptors expressed by thymocytes. This interaction activates several types of intracellular signalling pathways implicated in the developmental process of T lymphocytes. Several experimental arguments support a role for thymic dysfunction as a crucial factor in the development of organ-specific autoimmune endocrinopathies, such as 'idiopathic' central diabetes insipidus and type 1 diabetes mellitus. The rational use of tolerogenic neuroendocrine self-antigens for the prevention/treatment of autoimmune endocrinopathies is currently under investigation.

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Section: Implications For Pathogenesis Of Type 1 Diabetessupporting

confidence: 62%

Thymic Transcription of Neurohypophysial and Insulin‐Related Genes: Impact Upon T‐Cell Differentiation and Self‐Tolerance

Hansenne¹

2005

J Neuroendocrinology

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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 also explain both their lymphopenia (including CD8+ T cells and RT6+ Treg) and the absence of central self-tolerance to insulin-secreting islet β cells [41, 42]. As already mentioned, we have shown that susceptibility to autoimmune diabetes is correlated with the level of Ins2 transcription in the mouse thymus [6].…”

Section: The Central Role Of a Thymus Dysfunction In T1d Pathogenementioning

confidence: 78%

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

Chentoufi

Geenen

2011

Clinical and Developmental Immunology

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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.

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“…Ins and Igf1 transcripts were detected in all BBDP and BBDR thymi whereas Igf2 transcripts were also detected in all BBDR thymi but in only in 4 of 15 BBDP thymi. Such a defect of Igf2 transcription in BBDP thymus could contribute both to their lymphopenia (including CD8+ T and RT6+ Treg cells) and to the absence of central tolerance to islet β cells (Kecha-Kamoun et al, 2001). In humans, INS transcripts are measured at a lower level in the thymus from fetuses with short class I variable number of tandem repeat (VNTR) alleles, the second genetic trait ( IDDM2 ) of T1D susceptibility (Pugliese et al, 1997; Vafiadis et al, 1997).…”

Section: A Defect Of Central Self-tolerance As the Primary Event Drivmentioning

confidence: 99%

“…In this context, infusion of a strongly active insulin mimetope was recently shown to convert naïve T cells into Foxp3+ Treg cells in vivo and to prevent autoimmune diabetes in NOD mice (Daniel et al, 2011). We proposed that IGF-2 could be a safer and more valuable basis for developing a specific “negative/tolerogenic self-vaccination,” on the basis that Igf2 transcription is defective in the thymus of BBDP rats (Kecha-Kamoun et al, 2001) and that IGF-2 mediates significant cross-tolerance to insulin (Hansenne et al, 2006). The concept of negative self-vaccination implies both the competition between IGF-2 and insulin-derived epitopes for presentation by DQ2 and DQ8 alleles, as well as a tolerogenic response—including recruitment of Treg cells–induced by MHC-presentation of IGF-2 self-peptides (Geenen et al, 2004, 2010).…”

Section: The Concept Of “Negative/tolerogenic Self-vaccination”mentioning

confidence: 99%

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

et al. 2013

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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).

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

Cited by 35 publications

References 47 publications

Thymic Transcription of Neurohypophysial and Insulin‐Related Genes: Impact Upon T‐Cell Differentiation and Self‐Tolerance

Thymic Transcription of Neurohypophysial and Insulin‐Related Genes: Impact Upon T‐Cell Differentiation and Self‐Tolerance

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

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

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