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See detailLa longue et fascinante épopée de la vaccination
Geenen, Vincent ULiege

E-print/Working paper (2019)

Vaccination is still today the greatest victory of medicine against most of infectious diseases, and this triumph was acquired only after a long history that started hundred of years ago. Nevertheless ... [more ▼]

Vaccination is still today the greatest victory of medicine against most of infectious diseases, and this triumph was acquired only after a long history that started hundred of years ago. Nevertheless, irrational anti-vaccination movements emerged worldwide during recent years and are now one of the ten major threats against public healthcare according to a recent report of the World Health Organization (WHO). More than ever, it is essential to inform with honesty and integrity our citizens about the safety and efficiency of current available vaccines. [less ▲]

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See detailChapter 1 - History of the thymus: from a vestigial organ to the programming of immunological self-tolerance
Geenen, Vincent ULiege

in Passos, Gerald (Ed.) Thymus Transcriptome and Cell Biology (2019)

This introductive chapter presents the most important disruptions of con- cepts concerning the thymus since its discovery in Antique Greece. For centuries, the thymus was considered as a vestigial organ ... [more ▼]

This introductive chapter presents the most important disruptions of con- cepts concerning the thymus since its discovery in Antique Greece. For centuries, the thymus was considered as a vestigial organ, and its role in T-cell differentiation was proposed only in the 1960s. Most recent studies attribute to the thymus an essential and unique role in programming central immunological self-tolerance. The basic mechanism implicated in this function is the transcription in the thymic epithelium of genes encoding precursors of neuroendocrine-related and tissue- restricted self-peptides. Their processing leads to the presentation of self-antigens by the major histocompatibility complex (MHC) machinery expressed by thymic epithelial and dendritic cells. Already during foetal life, this presentation promotes negative selection of T lymphocytes harbouring a receptor with high affinity for MHC/self-peptide complexes. Mainly after birth, this presentation also drives the generation of regulatory T cells specific for these complexes. Numerous studies, as well as the identification of Aire and Fezf2 genes, have shown that a thymus defect plays a crucial role in the development of autoimmunity. The discovery of the cen- tral tolerogenic action of the thymus revolutionized the whole field of immunology, and such knowledge will pave the way for innovative tolerogenic therapies against autoimmunity, the so heavy tribute paid by mankind for the extreme diversity and efficiency of adaptive immunity. [less ▲]

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See detailThe presentation of neuroendocrine self-peptides in the thymus: An essential event for individual life and vertebrate survival
Geenen, Vincent ULiege; Trussart, Charlotte; Michaux, Hélène et al

in Annals of the New York Academy of Sciences (2019)

Confirming Burnet’s early hypothesis, elimination of self-reactive T cells in the thymus was demonstrated in the late 80’s and an important question immediately arose about the nature of the immune self ... [more ▼]

Confirming Burnet’s early hypothesis, elimination of self-reactive T cells in the thymus was demonstrated in the late 80’s and an important question immediately arose about the nature of the immune self expressed in the thymus. Many genes encoding neuroendocrine-related and tissue-restricted antigens (TRAs) are transcribed in thymic epithelial cells (TECs). They are then processed for presentation by proteins of the major histocompatibility complex (MHC) expressed by TECs and thymic dendritic cells (DCs). MHC presentation of self-peptides in the thymus programs self-tolerance by two complementary mechanisms: 1° Negative selection of self-reactive ‘forbidden’ T-cell clones starting already in fetal life, and 2° generation of self-specific thymic T regulatory (tTreg) cells, mainly after birth. Many studies, including the discovery of the AutoImmune REgulator (AIRE) and fasciculation and elongation protein zeta family zinc finger (FEZF2) proteins, have shown that a defect in thymus central self-tolerance is the earliest event promoting autoimmunity. AIRE and FEZF2 control the level of transcription of many neuroendocrine self-peptides and TRAs in thymic epithelium. Furthermore, Aire and Fezf2 mutations are associated with development of autoimmunity in peripheral organs. The discovery of the intrathymic presentation of self-peptides has revolutionized our knowledge of immunology and is opening novel avenues for prevention/treatment of autoimmunity. [less ▲]

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See detailLes géants de la science en Outremeuse
Geenen, Vincent ULiege

Conference given outside the academic context (2019)

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See detailLa Seconde Guerre Mondiale - La science biomédicale qui sauve
Geenen, Vincent ULiege

Conference given outside the academic context (2019)

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See detailRemembering Jean-Pierre Bourguignon, MD, PhD
Parent, Anne-Simone ULiege; Zoeller, R. Thomas; Geenen, Vincent ULiege et al

E-print/Working paper (2019)

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See detailHormones, Neurotransmitters, and T-Cell Development in Health and Disease
Geenen, Vincent ULiege

Book published by Frontiers - Frontiers Research Topic (2019)

Thymus physiology and T-cell development are controlled by a large variety of soluble molecules and their corresponding receptors, which can target both lymphoid and the non-lymphoid compartments. Some of ... [more ▼]

Thymus physiology and T-cell development are controlled by a large variety of soluble molecules and their corresponding receptors, which can target both lymphoid and the non-lymphoid compartments. Some of these molecules include cytokines/chemokines, hormones and neurotransmitters. They modulate the functions of distinct microenvironmental cells, including their maturation, survival, and role in antigen presentation. Additionally, they influence thymocyte survival, migration and selection, determining the pool of mature T-cells in the periphery of the immune system. Importantly, some of these circuits can be affected in specific pathological states. In this context, the aim of this Research Topic is to discuss the control of thymus physiology and T-cell development by hormones and neurotransmitters in health and disease. The Topic will primarily focus on the following themes: • HPA axis, adrenal glands and T-cell development • Thymic adrenergic network • Sympathetic control of regulatory T-cells • Serotonin and intrathymic cytokine production • VIP/PACAP and T-cell development • Brain-derived growth factor and T-cell development • Eph/Ephrin interactions in T-cell development • Semaphorins and human T-cell development in health and disease • Ghrelin and T-cell development • Intrathymic production of glucocorticoids • Sex steroids, thymus ageing and regeneration • T-cell development, acethilcholine receptors and Myasthenia gravis • Hormones and thymus in parasitic diseases • Regulatory T-cells and hormones • T-cell development, diabetes, and insulin [less ▲]

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See detailThyroid dysfunction after Alemtuzumab treatment for multiple sclerosis : a report of four cases
Daniel, Sara ULiege; HANSEN, Isabelle ULiege; Dive, Dominique ULiege et al

in Acta Clinica Belgica (2018, December), 73(2),

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See detailGrowth hormone (GH) deficient mice with GHRH ablation are severely deficient in vaccine and immune responses against Streptococcus pneumoniae
Farhat, Khalil; Bodart, Gwennaëlle ULiege; Moutschen, Michel ULiege et al

in Acta Clinica Belgica (2018, December), 73(6 (Suppl.2)),

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See detailDe la tolérance à l'auto-immunité : l'exemple du diabète de type 1
Geenen, Vincent ULiege

Conference given outside the academic context (2018)

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See detailGrowth hormone (GH) deficient mice with GHRH ablation are severely deficient in vaccine and immune responses against Streptococcus pneumoniae
Farhat, Khalil; Bodart, Gwennaëlle ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Immunology (2018), 9

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene ... [more ▼]

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh−/−) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh−/− mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh−/− mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh−/− mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh−/− mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh−/− mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh−/− mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae. [less ▲]

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See detailHistorical introduction to the history of the thymus and the concept of immune self-tolerance
Geenen, Vincent ULiege; Martens, Henri ULiege

Conference (2018, September)

The name ‘thymus’ first appeared in Galen’s manuscripts (±160 AD) and was so named because of its morphological analogy with the leaf of Thymus cunila. For centuries however, this organ was considered ... [more ▼]

The name ‘thymus’ first appeared in Galen’s manuscripts (±160 AD) and was so named because of its morphological analogy with the leaf of Thymus cunila. For centuries however, this organ was considered only as a vestigial organ that served as a cushion between the sternum and basal blood vessels, and then involuted after puberty. In the late 50’s, JFAP Miller discovered that the thymus was the site for development of a special population of immune cells, the thymo-dependent T lymphocytes. In concordance with P Ehrlich’s early concept of ‘horror autoxicus’, FM Burnet predicted in 1962 that the thymus should play a crucial role in the elimination of developing lymphocytes with potential reactivity against the ‘self’ (‘forbidden’ T cell clones). This theory of intrathymic negative selection of self-reactive T cells was finally demonstrated in late 80’s through the elegant studies in the laboratories of N Le Douarin (Nogent-sur-Marne), P Marrack and J Kappler (Denver), HR Mac Donald (Lausanne) and H von Boehmer (Basel). In the same time, an important question raised about the biochemical nature of the ‘self’ expressed in thymic microenvironment. Our laboratory established that thymic epithelial cells (TECs) from different species transcribe dominant genes of many neuroendocrine families (OT for neurohypophysial family, NKA for tachykinins, NT for neuromedins and IGF-2 for insulin family). However, after transcription, neuroendocrine precursors are not linked to classic (neuro)secretion. Their processing is the source of neuroendocrine self-peptides that are presented by proteins of the major histocompatibility complex (MHC) expressed by TECs and thymic dendritic cells. Through this unique process, already during fetal development, the thymus programs central self-tolerance of the adaptive immune system to neuroendocrine functions and this was an absolute necessity after emergence of this novel form of immunity generating the diversity of antigen recognition some 470 millions years ago. The laboratory of the late B Kyewski further demonstrated the central role of the thymus in central immune tolerance to almost all peripheral tissues. Several laboratories then addressed the logical hypothesis that a defect in the tolerogenic function of the thymus could be a primary event promoting the development of autoimmunity. Several experimental data argued for this assumption and the question was definitively solved with the identification of the AutoImmuneREgulator gene. AIRE controls the level of transcription of many (but not all) tissue specific self-peptides in medullary TECs and AIRE mutations (or Aire ablation) is associated with the development of autoimmunity tackling many peripheral organs. More recently, the Fezf2 gene, already known to be involved in neuronal development, was shown to be expressed in TECs and to regulate the transcription level of Aire-independent genes also coding for tissue specific self-antigens. As stated by several authors, the discovery of the central tolerogenic of the thymus revolutionized the whole field of immunology. Undoubtedly, this novel knowledge will pave the way for innovative tolerogenic therapies aiming to prevent and treat autoimmunity, the so heavy tribute paid by all mankind for the extreme diversity and efficiency of adaptive immunity. (Vincent Geenen is research director at F.S.R.-NFSR of Belgium. Supported by F.S.R.-NFSR, Wallonia, the Federation Wallonia-Brussels, European Union, JDRF, and the Fonds Léon Fredericq of Liège University Hospital.) References 1. Martens H, Goxe B and Geenen V. The thymic repertoire of neuroendocrine self-antigens: physiological implications in, T cell life and death. Immunol Today 1996; 17:312-7. 2. Geenen V et al. Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity. Front Neurosci 2013; 7: article 187 - doi: 10.3389/fnins.2013.00187. 3. Geenen V. Histoire du thymus : d’un organe vestigial à la programmation de la tolérance immunitaire. Med Sci 2017; 33:653-63. [less ▲]

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See detailSession: Presentation of self-peptides in the thymus as an essential event of life.
Geenen, Vincent ULiege

Conference (2018, September)

This session was organized within the framework of RegPep2018. Georg HOLLAENDER(Oxford University), Hiroyuki TAKABA (University of Tokyo) and Vincent GEENEN (University of Liège) presented the latest data ... [more ▼]

This session was organized within the framework of RegPep2018. Georg HOLLAENDER(Oxford University), Hiroyuki TAKABA (University of Tokyo) and Vincent GEENEN (University of Liège) presented the latest data about epigenetic, genetic and cellular mechanisms responsible for the programming of central self-tolerance of the adaptive immune system. [less ▲]

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See detailThe severe deficiency of the somatotrope GHRH/GH/IGF1 axis of Ghrh-/- mice is associated with an important splenic atrophy and relative B lymphopenia
Bodart, Gwennaëlle ULiege; Farhat, Khalil ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Endocrinology (2018), 9(Art. 296),

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this ... [more ▼]

A debate is still open about the precise control exerted by the somatotrope GH-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor 1 axis on the immune system. The objective of this study was to directly address this question through the use of Ghrh−/− mice that exhibit a severe deficiency of their somatotrope axis. After control backcross studies and normalization for the reduced global weight of transgenic mice, no difference in weight and cellularity of the thymus was observed in Ghrh−/− mice when compared with C57BL/6 wild-type (WT) control mice. Similarly, no significant change was observed in frequency and number of thymic T cell subsets. In the periphery, Ghrh−/− mice exhibited an increase in T cell proportion associated with a higher frequency of sjTREC and naïve T cells. However, all Ghrh−/− mice displayed an absolute and relative splenic atrophy, in parallel with a decrease in B cell percentage. GH supplementation of transgenic mice for 6 weeks induced a significant increase in their global as well as absolute and relative splenic weight. Interestingly, the classical thymus involution following dexamethasone administration was shown to recover in WT mice more quickly than in mutant mice. Altogether, these data show that the severe somatotrope deficiency of Ghrh−/− mice essentially impacts the spleen and B compart- ment of the adaptive immune system, while it only marginally affects thymic function and T cell development. [less ▲]

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See detailLes progrès en immunologie sont à la base des plus grands succès médicaux
Geenen, Vincent ULiege

E-print/Working paper (2018)

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See detailBrain imaging and genetics in patients with congenital hypogonadotropic hypogonadism: a multicenter Belgian study.
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; HARVENGT, Julie ULiege et al

in Jorgensen, Jens OL (Ed.) NENEG Abstract Book Communications (2018, April 19)

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See detailGHRH-deleted Mice Are Severely Deficient in Vaccine And Immunological Responses Against Streptococcus Pneumoniae
Farhat, Khalil ULiege; Bodart, Gwennaëlle ULiege; Desmet, Christophe ULiege et al

Conference (2018, March 20)

Background and objective of the work. Ghrh-/- mice with a severe deficiency of their somatotrope GHRH/GH/IGF1 axis (1) are resistant to experimental allergic encephalomyelitis (2). In basal conditions ... [more ▼]

Background and objective of the work. Ghrh-/- mice with a severe deficiency of their somatotrope GHRH/GH/IGF1 axis (1) are resistant to experimental allergic encephalomyelitis (2). In basal conditions, thymus and T-cell development are not severely affected but a marked spleen atrophy and B-cell lymphopenia were constantly observed (3). Therefore, we investigated vaccinal and anti-infectious responses of Ghrh-/- mice against S.pneumoniae, a T-independent pathogen. Results. Transgenic mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, Pnx23) or protein-PPS conjugate (Prev13). GH treatment of Ghrh-/- mice restored IgM response to Pnx23 vaccine but not to Prev13 suggesting that GH exerts a significant impact on the spleen marginal zone that is strongly implicated in T-independent immunological response to pneumococcal polysaccharides. After intranasal instillation of a non-lethal dose of S.pneumoniae, Ghrh-/- mice exhibited a dramatic susceptibility with a time-dependent increase in lung bacterial load, a bacteremia already after 24h, and a survival limit of 48-72h. In marked contrast, WT and heterozygote mice completely cleared S.pneumoniae infection after 24h. Lungs of infected Ghrh-/- mice were massively infiltrated by inflammatory macrophages, while lung B cells were markedly decreased. Transcription of Ifng, Il10, Cd40, and Cxcl9 was highly increased in the lungs of infected Ghrh-/- mice, whereas Tgfb and Iggj transcripts were unchanged. Resistance of Ghrh-/- mice to infection by influenzavirus H1N1 (a T-dependent antigen) was normal or slightly decreased. Conclusion. This animal model shows that the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in the vaccine and immunological defense against S.pneumoniae. [less ▲]

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