title: How Does Thymus Infection by Coxsackievirus Contribute to the Pathogenesis of Type 1 Diabetes?
abstract: Through synthesis and presentation of neuroendocrine self-antigens by major histocompatibility complex proteins, thymic epithelial cells (TECs) play a crucial role in programing central immune self-tolerance to neuroendocrine functions. Insulin-like growth factor-2 (IGF-2) is the dominant gene/polypeptide of the insulin family that is expressed in TECs from different animal species and humans. Igf2 transcription is defective in the thymus of diabetes-prone bio-breeding rats, and tolerance to insulin is severely decreased in Igf2 (-/-) mice. For more than 15 years now, our group is investigating the hypothesis that, besides a pancreotropic action, infection by coxsackievirus B4 (CV-B4) could implicate the thymus as well, and interfere with the intrathymic programing of central tolerance to the insulin family and secondarily to insulin-secreting islet β cells. In this perspective, we have demonstrated that a productive infection of the thymus occurs after oral CV-B4 inoculation of mice. Moreover, our most recent data have demonstrated that CV-B4 infection of a murine medullary (m) TEC line induces a significant decrease in Igf2 expression and IGF-2 production. In these conditions, Igf1 expression was much less affected by CV-B4 infection, while Ins2 transcription was not detected in this cell line. Through the inhibition of Igf2 expression in TECs, CV-B4 infection could lead to a breakdown of central immune tolerance to the insulin family and promote an autoimmune response against insulin-secreting islet β cells. Our major research objective now is to understand the molecular mechanisms by which CV-B4 infection of TECs leads to a major decrease in Igf2 expression in these cells.
authors.affiliation: Department of Biomedical and Preclinical Sciences, GIGA-I 3 Center of Immunoendocrinology, GIGA Research Institute, University of Liege , Liege , Belgium.
authors.forename: Hélène
authors.initials: H
authors.lastname: Michaux
authors.affiliation: Department of Biomedical and Preclinical Sciences, GIGA-I 3 Center of Immunoendocrinology, GIGA Research Institute, University of Liege , Liege , Belgium.
authors.forename: Henri
authors.initials: H
authors.lastname: Martens
authors.affiliation: Laboratory of Virology LR99ES27, School of Pharmacy, University of Monastir , Monastir , Tunisia ; Faculty of Sciences of Tunis, University of Tunis El Manar , Tunis , Tunisia.
authors.forename: Hela
authors.initials: H
authors.lastname: Jaïdane
authors.affiliation: Laboratory of Virology LR99ES27, School of Pharmacy, University of Monastir , Monastir , Tunisia ; Faculty of Sciences of Tunis, University of Tunis El Manar , Tunis , Tunisia.
authors.forename: Aymen
authors.initials: A
authors.lastname: Halouani
authors.affiliation: Laboratory of Virology EA3610, Centre Hospitalier Régional Universitaire de Lille, University of Lille 2 , Lille , France.
authors.forename: Didier
authors.initials: D
authors.lastname: Hober
authors.affiliation: Department of Biomedical and Preclinical Sciences, GIGA-I 3 Center of Immunoendocrinology, GIGA Research Institute, University of Liege , Liege , Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Geenen
keywords: coxsackievirus; enterovirus; insulin family; insulin-like growth factor 2; self-tolerance; thymus; type 1 diabetes