References of "Hober, Didier"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailProgramming of neuroendocrine self in the thymus and its defect in neuroendocrine autoimmunity
Geenen, Vincent ULg; Bodart, Gwennaëlle ULg; Henry, Séverine et al

in Frontiers in Neuroscience (2013), 7

During centuries after its first description by Galen, the thymus has been considered only as a vestigial endocrine organ until the discovery in 1961 by Jacques FAP Miller of its essential role in the ... [more ▼]

During centuries after its first description by Galen, the thymus has been considered only as 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 appeared for the first time in cartilaginous fishes some 500 millions years ago, in 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 latter was a necessity for the survival of species given the potent evolutionary pressure impacted by the high risk of autotoxicity inherent to the stochastic generation of the diversity of immune cell receptors that characterize the adaptive immune response. The new paradigm of neuroendocrine self-peptides has been proposed together with the definition of neuroendocrine self. Neuroendocrine self-peptides are not secreted by thymic epithelial cells (TECs) according to the classic model of neuroendocrine signaling, but processed for a 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 emerging during the random recombination of gene segments that encode variable parts of the T cell receptor for the antigen (TCR). In the same time, self-antigen presentation in the thymus also generates regulatory T (Treg) cells that are able to inhibit in the periphery self-reactive T cells having escaped negative selection in the thymus. Several arguments show that the origin of autoimmunity directed against neuroendocrine glands primarily results from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or acquired during an enteroviral infection, for example. This novel knowledge of normal and pathologic functions of the thymus already constitutes a solid basis for the development of a novel type of tolerogenic/negative self-vaccination against type 1 diabetes (T1D). [less ▲]

Detailed reference viewed: 40 (11 ULg)
Full Text
Peer Reviewed
See detailPersistent infection of thymic epithelial cells with coxsackievirus B4 results in a decreased expression of insulin-like growth factor 2
Jaïdane, Hela; Caloone, Delphine; Lobert, Pierre-Emmanuel et al

in Journal of Virology (2012), 86

It has been hypothesized that a disturbance of central self-tolerance to islet β-cell may play a role in the enteroviral pathogenesis of type 1 diabetes. Whether enteroviruses can induce an impaired ... [more ▼]

It has been hypothesized that a disturbance of central self-tolerance to islet β-cell may play a role in the enteroviral pathogenesis of type 1 diabetes. Whether enteroviruses can induce an impaired expression of β-cell self-antigens in thymic epithelial cells has been investigated in a murine thymic epithelial (MTE) cell line. This cell line was permissive to the diabetogenic strain CV-B4 E2 and spontaneously expressed type 2 insulin-like growth factor (Igf2), the dominant self-antigen of the insulin family. In this model, a persistent replication of CV-B4 E2 was obtained as attested by the prolonged detection of intracellular positive and negative-strand viral RNA by RT-PCR, and capsid protein VP1 by IF and by the release of infectious particles in culture supernatant fluids. The chronic stage of the infection was characterized by a low proportion of VP1-positive cells (1-2%) whereas many cells harbored enteroviral RNA as displayed by RT-PCR without extraction applied directly on a few cells. Igf2 mRNA and IGF-2 protein were dramatically decreased in CV-B4 E2-infected MTE cultures compared with mock-infected cultures, whereas housekeeping and Il6 genes expression were maintained and Igf1 mRNA was decreased but at a lower extent. Inoculation of CV-B3-, CV-B4 JVB- or Echovirus 1 resulted in a low level of IGF-2 in culture supernatant fluids as well, whereas HSV-1 stimulated the production of the protein. Thus, a persistent infection of a thymic epithelial cell line with enteroviruses, like CV-B4 E2 can result in a disturbed production of IGF-2, a protein involved in central self-tolerance towards islet β-cells. [less ▲]

Detailed reference viewed: 46 (10 ULg)
Full Text
Peer Reviewed
See detailImmunology in the clinic review series. Focus on type 1 diabetes and virus: enterovirus, thymus and type 1 diabetes pathogenesis
Jaïdane, H.; Sane, F.; Hiar, R. et al

in Clinical & Experimental Immunology (2012), 168

Thymus dysfunction, especially immune suppression, is frequently associated with various virus infections.Whether viruses may disturb the thymus function and play a role in the pathogenesis of autoimmune ... [more ▼]

Thymus dysfunction, especially immune suppression, is frequently associated with various virus infections.Whether viruses may disturb the thymus function and play a role in the pathogenesis of autoimmune diseases is an open issue. Enteroviruses, especially Coxsackievirus B4 (CV-B4), have been largely suggested as potential inducers or aggravating factors of type 1 diabetes (T1D) pathogenesis in genetically predisposed individuals. Several pathogenic mechanisms of enterovirus-induced T1D have been suggested. One of these mechanisms is the impairment of central self-tolerance due to viral infections. Coxsackievirus-B4 is able to infect murine thymus in vitro and in vivo and to infect human thymus in vitro. Thymic epithelial cells and thymocytes are targets of infection with this virus, and several abnormalities, especially disturbance of maturation/differentiation processes, were observed.Altogether, these data suggest that CV-B infection of thymus may be involved in the pathogenesis of T1D. Further investigations are needed to explore this hypothesis. [less ▲]

Detailed reference viewed: 37 (4 ULg)
Full Text
Peer Reviewed
See detailThymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes.
Geenen, Vincent ULg; Mottet, Marie ULg; Dardenne, Olivier ULg et al

in Current Opinion in Pharmacology (2010), 10

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 takes place only ... [more ▼]

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 takes place only 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 (nTregs) 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. The very low degree of insulin gene transcription in normal murine and human thymus explains why the insulin protein is poorly tolerogenic as evidenced in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet β cells via various methods of insulin administration. 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 being 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 other self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases. [less ▲]

Detailed reference viewed: 46 (17 ULg)
See detailCoxsackievirus B4 and type 1 diabetes
Brilot, Fabienne; Geenen, Vincent ULg; Hober, Didier

in Thebault, Sabine (Ed.) Progress in Virus Research (2005)

Detailed reference viewed: 20 (1 ULg)
Full Text
Peer Reviewed
See detailCoxsackievirus B4 infection of human fetal thymus cells
Brilot, Fabienne; Geenen, Vincent ULg; Hober, Didier et al

in Journal of Virology (2004), 78(18), 9854-9861

The infection of human fetal thymus organ cultures (FTOC) with coxsackievirus B4 E2 (CVB4 E2) was investigated. Both positive- and negative-strand viral RNA were detected by real-time quantitative reverse ... [more ▼]

The infection of human fetal thymus organ cultures (FTOC) with coxsackievirus B4 E2 (CVB4 E2) was investigated. Both positive- and negative-strand viral RNA were detected by real-time quantitative reverse transcription-PCR (RT-PCR) in CVB4 E2-infected FTOC, which supported high yields of virus production (similar to10(6) 50% tissue culture infective doses/ml), and in flow-sorted thymocyte populations for 7 days after inoculation. Cortical CD4(+) CD8(+) thymocytes were found to be the principal targets of infection. Inoculation of human FTOC with CVB4 E2 led to a marked and progressive depletion of immature thymocytes (CD4(+) CD8(+) cells) with no enhancement of Annexin V-positive cells. CVB4 E2 replication caused significant major histocompatibility complex (MHC) class I upregulation on these cells. MHC class I upregulation was correlated with positive- and negative-strand RNA quantitative detection and the release of infectious particles. In addition, chloroquine treatment of FTOC and single-thymocyte suspensions suggested that MHC class I upregulation on thymocytes was the result of direct infection rather than caused by production of soluble factors such as alpha interferon. Thus, CVB4 E2 can infect human fetal thymocytes, which subsequently results in quantitative and qualitative abnormalities of these cells. [less ▲]

Detailed reference viewed: 47 (2 ULg)
Peer Reviewed
See detailHuman thymic epithelial cells are potential targets for the diabetogenic coxsackievirus B4
Brilot, Fabienne; Hober, Didier; Geenen, Vincent ULg

Poster (2000, July)

Detailed reference viewed: 8 (0 ULg)
Peer Reviewed
See detailDiabetogenic coxsackievirus B4 modifies cytokine secretion by human thymic epithelial cells
Brilot, Fabienne; Chehadeh, Wassim; Renard, Chantal et al

in Diabetologia (2000), 43 (Suppl. 1)

Detailed reference viewed: 11 (0 ULg)