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Voyage[s] through the thymus, the small central 'brain' of the adaptive immune system
Geenen, Vincent
2016
 

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Keywords :
Thymus; Self-tolerance; Autoimmunity
Abstract :
[en] Our studies have demonstrated that the thymus programs central self-tolerance to neuroendocrine functions through transcription of neuroendocrine-related genes in thymic epithelial cells (TECs). However, thymic neuroendocrine precursors are not secreted but processed as the source of neuroendocrine self-antigens that are presented by thymic proteins of the major histocompatibility complex (MHC). This process, highly specific of the thymus, has allowed an integrated and harmonious coevolution of the neuroendocrine and immune systems when recombination-activating genes and the subsequent adaptive immune response have emerged in cartilaginous fishes some 450-500 millions years ago. All the members of the insulin gene family are expressed in murine TECs under the control of AutoImmune Regulator (AIRE) according a precise hierarchy: Igf2 >Igf1>Ins2>Ins1. Igf2 transcription is defective in TECs of autoimmune diabetes-prone BB rats, and tolerance to insulin is severely impaired in Igf2-/- mice as well as in Igf2-loxP/Foxn1-cre mice with Igf2 deletion targeted in TECs. In addition, the diabetogenic coxsackievirus B4 (CV-B4) is able to persistently infect human and murine TECs and to inhibit Igf2 transcription and IGF-2 synthesis in a murine medullary TEC line (coolaboration with D. Hober, Laboratory of Virology, CHRU and University of Lille 2, France). These studies show that: 1° IGF-2 is the dominant tolerogenic precursor of the family and mediates cross-tolerance to insulin; 2° a thymus dysfunction plays a crucial role in the development of the diabetogenic autoimmune response; and 3° a thymic infection by CV-B4 is implicated in type 1 diabetes (T1D) pathogenesis. Most probably due to its very low level of expression in the thymus, the protein insulin is highly immunogenic and is the primary autoantigen tackled in T1D. On the basis of the tolerogenic properties of IGF-2, we are currently working on the development of a negative/tolerogenic self-vaccine against T1D.
Research center :
CIML
Disciplines :
Immunology & infectious disease
Endocrinology, metabolism & nutrition
Author, co-author :
Geenen, Vincent ;  Université de Liège > Centre d'immunologie
Language :
English
Title :
Voyage[s] through the thymus, the small central 'brain' of the adaptive immune system
Publication date :
24 March 2016
Event name :
Biotrail training and tutorial
Event organizer :
Philippe Naquet
Event place :
Marseille, Centre d'Immunologie Marseille-Luminy (CIML), France
Event date :
24 mars 2016
Audience :
International
Funders :
INSERM - Institut National de la Santé et de la Recherche Médicale [FR]
CNRS - Centre National de la Recherche Scientifique [FR]
Available on ORBi :
since 19 January 2016

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