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See detailVoyage[s] à travers le thymus
Geenen, Vincent ULg

Book published by Presses Universitaires de Liège (2016)

Cet ouvrage concis s'intéresse au thymus, un organe dont la fonction a échappé si longtemps au monde de la science que d'aucuns le considèrent encore aujourd'hui comme un vestige de l'évolution. Vous le ... [more ▼]

Cet ouvrage concis s'intéresse au thymus, un organe dont la fonction a échappé si longtemps au monde de la science que d'aucuns le considèrent encore aujourd'hui comme un vestige de l'évolution. Vous le connaissez néanmoins très bien car vous avez certainement consommé de très savoureux 'ris de veau' qui sont la dénomination culinaire du thymus de cet animal. Ce n'est qu'au cours des 60 dernières années environ que cet organe a livré un à un ses secrets les plus intimes jusqu'à occuper la place essentielle de 'petit cerveau' de notre système de défenses immunitaires. Cet essai concerne donc aussi l’immunologie, la science qui étudie les mécanismes de notre système de défenses, contre les agressions infectieuses surtout, en un mot l’immunité. Dès la fondation de cette nouvelle science à la fin du XIXe siècle, les immunologistes ont été confrontés à cet important paradoxe: comment notre système immunitaire, capable de réagir contre une multitude d’agents étrangers (ce qui est désigné comme le ‘non-soi’), est-il heureusement incapable en conditions normales d’agresser l’organisme qui l’héberge (le ‘soi’) ? Cette impossibilité du système immunitaire de réagir contre le ‘soi’ s’appelle la ‘tolérance immunitaire’ et elle est devenue aujourd’hui la pierre angulaire du fonctionnement normal de ce système. La rupture de cette tolérance est à l’origine des maladies dites ‘auto-immunes’. Il en existe environ 70 dont les plus connues sont le diabète juvénile insulino-dépendant (diabète de type 1) qui frappe les enfants et les jeunes adolescents, la plupart des affections de la glande thyroïde, la sclérose en plaques, le psoriasis et la polyarthrite rhumatoïde. J’ai souhaité inviter le lecteur à pénétrer dans un monde qui était encore presque inconnu il y a moins de soixante ans, celui du thymus qui peut être qualifié aujourd’hui sinon de ‘cerveau’, au moins de programmeur central de la tolérance immunitaire. Les travaux menés par mon groupe à l’Université de Liège ont établi que le thymus constitue un carrefour crucial entre les trois grands systèmes de communication intercellulaire des espèces vivantes, les systèmes nerveux, endocrine et immunitaire. Ils ont démontré que le thymus joue un rôle unique dans la programmation de la tolérance immunitaire vis-à-vis des systèmes nerveux et endocrine. Ces études ont aussi établi qu’un dysfonctionnement du thymus joue un rôle moteur dans le développement des maladies auto-immunes spécifiques des glandes endocrines. En un mot, c’est d’abord le thymus qui est malade et non les organes touchés par le processus auto-immun pathogène qui résulte de cette pathologie du thymus. Mon plus vif espoir aujourd’hui est que la découverte de ce nouveau concept se traduise un jour par l’invention d’un nouveau type de vaccination contre le diabète des enfants et des adolescents. Quelles sont les raisons qui ont motivé ma candidature au Prix littéraire Prince Alexandre de Belgique 2014. 1° La première était de témoigner ma reconnaissance à l’égard de la Fondation cardiologique Princesse Lilian qui a joué un rôle déterminant dans l’orientation de ma carrière de médecin-chercheur. En effet, cette Fondation a organisé en 1984 à Bruxelles un symposium international consacré au contrôle exercé par le système nerveux sur le système immunitaire. Mon promoteur, le regretté Pr Paul Franchimont, avait assisté à ce symposium et me conseilla vivement d’essayer de développer des activités de recherches dans ce tout nouveau domaine. C’est dans ce même esprit de reconnaissance à la Fondation Princesse Lilian que j’ai proposé que la chaire internationale du même nom soit confiée en 2015 à mon confrère allemand, lui aussi spécialiste du thymus, le Pr Bruno Kyewski de l’Institut allemand de la recherche contre le cancer à Heidelberg en Allemagne. Cette proposition a été acceptée et la leçon inaugurale de cette chaire a eu lieu le 16 mars 2015 en la Grande Salle Académique de l’Université de Liège. 2° Mon goût pour la littérature, qu’elle soit romancière, historique, scientifique ou philosophique, constitue incontestablement la deuxième raison de ma candidature au Prix Prince Alexandre. Combien de fois n’ai-je lu une œuvre littéraire en m’interrogeant si je serais capable moi-même d’écrire un jour un livre ? C’est aussi en me plongeant dans la littérature que j’ai vécu les plus beaux voyages initiatiques de la pensée. 3° Une autre raison essentielle qui m’a poussé à rédiger mes « Voyage(s) à travers le thymus » est la suivante. L’équipe de recherche que j’anime au Centre d’Immunologie du GIGA de Liège a contribué à mettre au jour un phénomène essentiel de la vie qui est apparu avec le premier thymus il y a environ 450 millions d’années chez les poissons cartilagineux comme la raie ou le requin. Cette ‘découverte’ d’un secret inouï de la vie suscite alors en vous une sensation d’émerveillement du même ordre que l’émotion qui vous étreint quand vous écoutez l’Oratorio de Noël ou la Passion selon Saint-Mathieu de Jean-Sébastien Bach, quand vous regardez un tableau de Piero de la Francesca, ou quand vous contemplez une merveille de la Nature comme le Grand Canyon du Colorado ou le lever du soleil sur Massif du Hoggar depuis l’ermitage du Père de Foucault à l’Assekrem. Vous pouvez très bien vivre seul un pareil émerveillement mais le premier désir que vous ressentez au fond de vous-même est de le partager avec vos proches. Ce désir irrésistible a joué lui aussi un rôle déterminant dans ma décision de consacrer la majeure partie de mes soirées de l'été 2014 à écrire ce texte et, surtout, à le rédiger de manière compréhensible pour toutes et tous. Et c’est là que réside la plus grande difficulté car, comme le disait Albert Einstein, « Si vous ne pouvez expliquer un concept à un enfant de six ans, c'est que vous ne le comprenez pas complètement ». 4° Enfin, les trente-cinq années de ma vie de médecin engagé dans la recherche ont exercé un impact considérable sur ma propre conception de la vie et de ses innombrables mystères. Mon essai se clôture par un témoignage personnel décrivant comment ces différents voyages ont nourri ma réflexion à propos des rapports entre la science et la foi. J’ai tenté d’expliquer qu’il était encore possible aujourd’hui de rester chrétien en devenant un scientifique quelque peu écouté, comment mes vies professionnelle et spirituelle pouvaient se nourrir l’une de l’autre tout en respectant leur indépendance. [less ▲]

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See detailDrug-induced thyroid dysfunction
Geenen, Vincent ULg

Conference (2016, April 16)

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See detailThymus and Type 1 diabetes: Where are we now?
Geenen, Vincent ULg

Scientific conference (2016, March 24)

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 ... [more ▼]

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. [less ▲]

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See detailVoyage[s] through the thymus, the small central 'brain' of the adaptive immune system
Geenen, Vincent ULg

Scientific conference (2016, March 24)

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 ... [more ▼]

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. [less ▲]

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See detailTreg, Th17 and γδ T cells during normal and abortive pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Munaut, Carine ULg et al

Poster (2016, January 25)

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See detailSwitch from Hashimoto Thyroiditis (HT) to Graves Basedow (GB) disease : a controlled study in a series of 15 patients
Maiga, I; BETEA, Daniela ULg; Geenen, Vincent ULg et al

in Abstract book - 20th Annual Congress of the Belgian Society of Internal Medicine (2015, December)

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See detailThe central role of the thymus in the programming of immunological tolerance to neuroendocrine self: Implications for the pathogenesis of autoimmune diseases.

Geenen, Vincent ULg

Conference (2015, June)

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 ... [more ▼]

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. [less ▲]

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See detailL'école liégeoise de physiologie aux 19e et 20e siècles
Geenen, Vincent ULg

in Histoire des Sciences Médicales (2015), XLIX(2), 209-218

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See detailAdditional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: An open trial.
Scantamburlo, Gabrielle ULg; Hansenne, Michel ULg; Geenen, Vincent ULg et al

in European psychiatry : the journal of the Association of European Psychiatrists (2015), 30(1), 65-68

The aim of this open trial was to assess the antidepressant/anxiolytic effects of oxytocin used as an adjunct to antidepressant in treatment-resistant depression. Fourteen patients, who have not responded ... [more ▼]

The aim of this open trial was to assess the antidepressant/anxiolytic effects of oxytocin used as an adjunct to antidepressant in treatment-resistant depression. Fourteen patients, who have not responded to 40mg of escitalopram, received intranasal synthetic oxytocin during 4 weeks, in association with antidepressant. This is the first open trial study suggesting OT in association with escitalopram significantly reduced scores on Hamilton Depression Rating Scale. [less ▲]

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See detailIntroduction à l'embryologie animale
Geenen, Vincent ULg

Learning material (2015)

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See detailNeuroimmunomodulation in Health and Disease
Geenen, Vincent ULg

Book published by Wiley Company (2015)

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See detailSomatotrope GHRH/GH/IGF-1 axis at the crossroad between immunosenescence and elder frailty
Bodart, Gwennaëlle ULg; Goffinet, Lindsay; Morrhaye, Gabriel et al

in Annals of the New York Academy of Sciences (2015), 1351

Immunosenescence as complex modifications of immunity with age could be related to the so-called frailty syndrome of elderly leading to an inadequate response to minimal aggression. Functional decline ... [more ▼]

Immunosenescence as complex modifications of immunity with age could be related to the so-called frailty syndrome of elderly leading to an inadequate response to minimal aggression. Functional decline, the loss of ability to perform activities of daily living, is related to the decrease in physiological reserves and frailty and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty were explored and 20 immunological parameters were affected in seniors with functional decline. IGF-1, thymopoeisis and telomere length were part of these markers. A strong relationship between insulin-like growth factor-1 (IGF-1) and thymic ouput was evidenced. IGF-1, mediator of GH, was subsequently shown to induce IL-7 secretion in cultured primary human thymic epithelial cells (TECs). We are also exploring the ‘stress hypothesis’ according which an acute stress is the discriminator revealing a frailty susceptility. GH can counteract the deleterious immunosuppressive effect of stress-induced steroids. Under non-stressing conditions, the immunosenescent system preserves physiological responses, while in stressing conditions, the combination of immunosenescence and a defect in somatotrope axis might lead to functional decline. [less ▲]

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See detailHow does thymus infection by coxsackievirus contribute to the pathogenesis of type 1 diabetes?
Michaux, Hélène ULg; Martens, Henri ULg; Jaïdane, Hela et al

in Frontiers in Immunology (2015), 6(Article 338), 1-6

Through synthesis and presentation of neuroendocrine self-antigens by major histocom- patibility complex proteins, thymic epithelial cells (TECs) play a crucial role in programing central immune self ... [more ▼]

Through synthesis and presentation of neuroendocrine self-antigens by major histocom- patibility 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. [less ▲]

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See detailEnterovirus persistence as a mechanism in the pathogenesis of type 1 diabetes
Alidjinou, Enagnon Kazali; Sané, Famara; Engelmann, Ilka et al

in Discovery Medicine (2014), 18

Beyond acute clinical conditions, the role of enteroviruses (EVs) in chronic human diseases has been described. Although they are considered as highly cytolytic viruses, EVs can persist in various tissues ... [more ▼]

Beyond acute clinical conditions, the role of enteroviruses (EVs) in chronic human diseases has been described. Although they are considered as highly cytolytic viruses, EVs can persist in various tissues. The persistence is believed to play a major role in the pathogenesis of EV related chronic dis- eases such as type 1 diabetes (T1D). T1D is charac- terized by an autoimmune destruction of pancreatic beta cells, and results from interplay between a genetic predisposition, the immune system, and environmental factors. EVs and especially group B coxsackieviruses (CVB) have been the most incrimi- nated as exogenous agents involved in the develop- ment of T1D. Enteroviral persistence is the result of a virus-host coevolution combining a cell resistance to lysis through mutations or down-regulation of viral receptor, and a decrease of the viral replication by genomic modifications or the production of a sta- ble double-stranded RNA form. CVB can persist in pancreatic cells and therefore could trigger, in genet- ically predisposed individuals, the autoimmune destruction of beta cells mainly through an activa- tion of inflammation. The persistence of the virus in other tissues such as intestine, blood cells, and thy- mus has been described, and could also contribute to some extent to the enteroviral pathogenesis of T1D. The molecular and cellular mechanisms of CVB per- sistence and the link with the development of T1D should be investigated further. [less ▲]

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See detailTreg/Th17 balance during murine embryo implantation and pregnancy
Polese, Barbara ULg; Gridelet, Virginie ULg; Araklioti, Eleni et al

Poster (2014, November)

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See detail9th Congress of the International Society of NeuroImmunoModulation (ISNIM)
Geenen, Vincent ULg

Scientific conference (2014, September 25)

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