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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 ▲]

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See detailExpression of growth hormone (GH)/insulin-like growth factor (IGF) axis during Balb/c ontogeny and effects of GH upon ex-vivo T-cell differentiation
Kermani, Hamid; Goffinet, Lindsay ULg; Mottet, Marie ULg et al

in Neuroimmunomodulation (2012), 19

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in ... [more ▼]

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. Effect of GH on T-cell differentiation was explored through thymic organotypic culture. Results: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1, displayed distinct expression profiles depending on the developmental stage. The protein concentration of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and GHR antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. Conclusion: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T-cell differentiation could implicate a different local growth factor or cytokine. [less ▲]

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See detailInvestigations on the mechanisms underlying the thymotropic properties of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis.
Goffinet, Lindsay ULg; Bodart, Gwennaëlle ULg; Renard, Chantal et al

Poster (2011, November 18)

Background. The thymus is responsible for thymopoiesis, i.e. the generation of a diverse and self-tolerant T-cell repertoire including self-antigen specific natural regulatory cells. We have shown that ... [more ▼]

Background. The thymus is responsible for thymopoiesis, i.e. the generation of a diverse and self-tolerant T-cell repertoire including self-antigen specific natural regulatory cells. We have shown that two parameters of thymopoiesis, thymic output of new T cells (estimated by sjTREC frequency) and intrathymic proliferation of T-cell precursors (estimated by sj/Dβ TREC ratio) are severely reduced in adult patients with GH deficiency (AGHD) and are restored by GH injections at physiological doses. In patients with AGHD, there is a very positive correlation between sjTREC frequency and plasma concentrations of IGF-1, the principal mediator of GH action (1). Treatment of HIV+ patients with high pharmacological doses of GH is associated with increased thymic mass and output of circulating naïve and total CD4+ T cells (2). In addition, previous studies have suggested thymic epithelial cells (TEC) and/or thymocytes (thymic T cells) could transcribe the GH gene (3). Objectives and hypothesis. These studies analysed the question of GH transcription and regulation in primary cultures of human (h) TEC. We also investigated the hypothesis that the thymotropic properties of the somatotrope GH/IGF-1 axis could be mediated by thymic interleukin 7 (IL-7), which plays a crucial role in promoting V(D)J recombination at the TCR locus. Results. Primary hTEC cultures were treated with natural secretagogues of pituitary GH, GH releasing hormone (GHRH) and ghrelin. Using sensitive RT-qPCR, we detected neither any transcript of GH or GHV (placental GH variant) in cultured hTEC, nor any transcript of PIT1, the specific transcription factor of pituitary GH. Similarly, the protein GH was detected neither in the cytoplasm nor in the supernatant of cultured hTEC. Only at 1 nM, GH treatment enhanced IGF1 transcription by cultured hTEC. Of high interest, treatment with GH, ghrelin and IGF-1 promoted IL7 transcription by cultured hTEC, but only IGF-1 and epidermal growth factor (EGF) markedly stimulated IL-7 secretion by hTEC in a dose- and time-dependent manner. The specificity of IGF-1 action was demonstrated by its inhibition after treatment with αIR3, a monoclonal antibody against the type 1 IGF receptor. Conclusions and perspectives. Since primary cultures of hTEC neither transcribe nor secrete any significant amount of GH, the thymotropic effects of the GH/IGF-1 axis seem to depend only on systemic endocrine GH. Local thymic IGF-1 could partially mediate GH action within the thymus and act upon thymopoiesis in parallel with systemic IGF-1. Most importantly, thymic IL-7 appears to be an important mediator of the thymotropic properties of the GH/IGF-1 axis. Further knowledge in this domain will be gained with the use and supplementation of Ghrh-/- mice that will be soon available in our laboratory. References 1. Morrhaye G. et al., PLoS ONE 2009, 4:e5668. 2. Napolitano LA et al. J Clin Invest 2008, 118:1085. 3. Smaniotto S et al., Endocrinology 2005, 146:3005. 4. Taub DD, Murphy WJ and Longo DL. Curr Opin Pharmacol 2010, 10:408. (Supported by F.R.S.-FNRS and a Pfizer Independent Research Grant.) [less ▲]

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See detailPreliminary characterisation of a transgenic mouse with selective Igf2 depletion in the thymic epithelium
Mottet, Marie ULg; Martens, Henri ULg; Renard-Charlet, Chantal et al

in Scandinavian Journal of Immunology (2011, April)

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See detailInsulin-like growth factor 1 (IGF-1) promotes interleukin 7 (IL-7) synthesis and secretion by primary cultures of human thymic epithelial cells
Goffinet, Lindsay ULg; Renard-Charlet, Chantal; Martens, Henri ULg et al

in Scandinavian Journal of Immunology (2011, April), 73

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See detailThe role of the thymus in integrated evolution of the recombinase-dependent adaptive immune response and the neuroendocrine system
Mottet, Marie ULg; Goffinet, Lindsay ULg; Beckers, Alisson et al

in Neuroimmunomodulation (2011), 18

Before being able to react against infectious non-self antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process ... [more ▼]

Before being able to react against infectious non-self antigens, the immune system has to be educated in recognition and tolerance of neuroendocrine self-proteins. This sophisticated educational process takes place only in the thymus. The development of an autoimmune response directed to neuroendocrine glands has been shown to result from a thymus dysfunction in programming immunological self-tolerance to neuroendocrine-related antigens. This thymus dysfunction leads to a breakdown of immune homeostasis with an enrichment of ‘forbidden’ self-reactive T cells and a deficiency in self-antigen specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. A large number of neuroendocrine self-antigens are expressed by the thymic epithelium, under the control of the autoimmune regulator (AIRE) gene/protein in the medulla. Based on the close homology and cross-tolerance between thymic type 1 diabetes-related self-antigens and peripheral antigens targeted in β cells by autoimmunity, a novel type of vaccination is currently developed for prevention and cure of type 1 diabetes. If this approach were found to be effective in reprogramming immunological tolerance that is absent or broken in this disease, it could pave the way for the design of negative/tolerogenic self-vaccines against other endocrine and organ-specific autoimmune disorders. [less ▲]

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See detailSerum IL-6 and IGF-1 improve clinical prediction of functional decline after hospitalization in older patients
de Saint-Hubert, Marie; Jamart, Jacques; Morrhaye, Gabriel et al

in Aging Clinical & Experimental Research (2011), 23

Background and aims: Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community-dwelling seniors, these markers have not been studied from this ... [more ▼]

Background and aims: Although inflammatory and hormonal markers have been associated with further functional adverse outcomes in community-dwelling seniors, these markers have not been studied from this perspective in acutely ill older patients. This prospective study was designed to determine whether biological markers can improve the predictive value of a clinical screening tool to assess the risk of functional decline in hospitalized older patients. Methods: Patients aged 75 years and over admitted for hip fracture, acute heart failure or infection (n=118) were recruited. The clinical screening tool SHERPA was filled in on admission, with concomitant measurement of interleukin-6 (IL-6), insulin-like growth factor 1 (IGF-1), C-reactive protein (CRP), white blood cells, urea, albumin, pre-albumin and total cholesterol. Functional decline was defined as a decrease of one point in the activities of daily living scale between pre-admission and 3-month post-discharge status. We compared the discrimination calibration of SHERPA vs SHERPA+, a logistic regression model including SHERPA and selected biomarkers. Results: Three months after discharge, functional decline had occurred in 46 patients. IL-6 and IGF-1 were selected, since their levels were significantly different between decliners and non-decliners, and were included in the new logistic regression model SHERPA+. Areas under the ROC curve [95% CI] for functional decline prediction were 0.73 [0.63-0.81] for SHERPA vs 0.79 [0.69-0.86] for SHERPA+ (p=0.14). However, SHERPA+ was better calibrated, as the average predicted risk of functional decline within subgroups matched the proportion which actually underwent functional decline (Brier score=0.185). Since functional decline was higher in patients with hip fracture, the SHERPA+ model was challenged by including the diagnosis. Only SHERPA, IGF-1 and diagnosis were significantly associated with functional decline. Conclusions: Selected biological markers may marginally improve the clinical prediction of post-discharge functional decline in hospitalized patients, and may allow to stratify them appropriately. The predictive value of these biomarkers is not fully independent of disease status. Further studies are needed to confirm these results in a cohort representative of older patients admitted through the emergency department. (Aging Clin Exp Res 2011; 23: 106-111) [less ▲]

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See detailImpact of the somatotrope Growth Hormone (GH)/Insulin-like Growth Factor 1 (IGF-1) axis upon thymus function: Pharmacological implications in regeneration of immune functions
Goffinet, Lindsay ULg; Mottet, Marie ULg; Kermani, Hamid et al

in Immunology, Endocrine & Metabolic Agents - Medicinal Chemistry (2011), 11

The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic ... [more ▼]

The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as a novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction. [less ▲]

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See detailTranscriptomic biomarkers of the response of hospitalized geriatric patients admitted with heart failure. Comparison to hospitalized geriatric patients with infectious diseases or hip fracture
Vo, Thi Kim Duy; de Saint-Hubert, Marie; Morrhaye, Gabriel et al

in Mechanisms of Ageing & Development (2011), 132

The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart ... [more ▼]

The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart failure and at recovery. This study identified 22 transcripts differentially abundant in acute phase of heart failure versus healthy aged subjects. Transcripts involved in inflammation and oxidative stress weremore abundant. Those associated with T-cell functions were less abundant. The results were compared to two other major acute geriatric issues: infectious diseases and hip fracture. In acute phase, compared to healthy aged subjects, the abundance of 15/22 transcripts was also altered in both geriatric infectious diseases and hip fracture. Many variations had not vanished at the recovery phase. The abundance of CD28, CD69, LCK, HMOX1, TNFRSF1A transcripts, known to be altered in healthy aged versus healthy young subjects, was further affected in acute phase of the three geriatric diseases considered. The transcript levels of BCL2, CASP8, CCL5, DDIT3, EGR3, IL10RB, IL1R2, SERPINB2 and TIMP1 were affected in all three pathological conditions compared to healthy aged, but not versus healthy young subjects. In conclusion, this work provides critical targets for therapeutic research on geriatric heart failure, infectious diseases and hip fracture. [less ▲]

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See detailDifferentially abundant transcripts in PBMC of hospitalized geriatric patients with hip fracture compared to healthy aged controls
Vo, Thi Kim Duy; Godard, Patrice; de Saint-Hubert, Marie et al

in Experimental Gerontology (2011), 46

The abundance of a selection of transcript species involved in in!ammation, immunosenescence and stress response was compared between PBMC of 35 geriatric patients with hip fracture in acute phase (days ... [more ▼]

The abundance of a selection of transcript species involved in in!ammation, immunosenescence and stress response was compared between PBMC of 35 geriatric patients with hip fracture in acute phase (days 2–4 after hospitalization) or convalescence phase (days 7–10) and 28 healthy aged controls. Twenty-nine differentially abundant transcripts were identi"ed in acute phase versus healthy ageing. Twelve of these transcripts remained differentially abundant in convalescence phase, and 22 were similarly differentially abundant in acute phase of geriatric infectious diseases. Seven of these 22 transcripts were previously identi"ed as differentially abundant in PBMC of healthy aged versus healthy young controls, with further alteration for CD28, CD69, LCK, CTSD, HMOX1, and TNFRSF1A in acute phase after geriatric hip fracture and infectious diseases. The next question is whether these alterations are common to other geriatric diseases and/or preexist before the clinical onset of the diseases. [less ▲]

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See detailTranscriptomic biomarkers of human ageing in peripheral blood mononuclear cell total RNA
Duy Vo, Thy Kim; Godard, Patrice; de Saint-Hubert, Marie et al

in Experimental Gerontology (2010), 45

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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 ▲]

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See detailTranscriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases
Duy Vo, Thi Kim; Godard, Patrice; de Saint-Hubert, Marie et al

in Immunity & Ageing : I & A (2010), 17

Background: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response ... [more ▼]

Background: Infectious diseases are significant causes of morbidity and mortality among elderly populations. However, the relationship between oxidative stress, immune function and inflammatory response in acute phase of the infectious disease is poorly understood. Results: Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease (day 2-4 after hospitalization) or in convalescence phase (day 7-10). This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged. For instance, transcripts associated with inflammatory and anti-inflammatory reactions (TNFRSF1A, IL1R1, IL1R2, IL10RB) and with oxidative stress (HMOX1, GPX1, SOD2, PRDX6) were more abundant while those associated with T-cell functions (CD28, CD69, LCK) were less abundant in acute phase. The abundance of seven of these transcripts (CD28, CD69, LCK, CTSD, HMOX1, TNFRSF1A and PRDX6) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase, compromising an efficient response. Conclusion: This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons. [less ▲]

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See detailImpact of growth hormone (GH) deficiency and GH replacement upon thymus function in adult patients.
Morrhaye, Gabriel ULg; Kermani, Hamid; Legros, Jean-Jacques ULg et al

in PLoS ONE (2009), 4(5), 5668

BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 ... [more ▼]

BACKGROUND: Despite age-related adipose involution, T cell generation in the thymus (thymopoiesis) is maintained beyond puberty in adults. In rodents, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and GH secretagogues reverse age-related changes in thymus cytoarchitecture and increase thymopoiesis. GH administration also enhances thymic mass and function in HIV-infected patients. Until now, thymic function has not been investigated in adult GH deficiency (AGHD). The objective of this clinical study was to evaluate thymic function in AGHD, as well as the repercussion upon thymopoiesis of GH treatment for restoration of GH/IGF-1 physiological levels. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-two patients with documented AGHD were enrolled in this study. The following parameters were measured: plasma IGF-1 concentrations, signal-joint T-cell receptor excision circle (sjTREC) frequency, and sj/beta TREC ratio. Analyses were performed at three time points: firstly on GH treatment at maintenance dose, secondly one month after GH withdrawal, and thirdly one month after GH resumption. After 1-month interruption of GH treatment, both plasma IGF-1 concentrations and sjTREC frequency were decreased (p<0.001). Decreases in IGF-1 and sjTREC levels were correlated (r = 0.61, p<0.01). There was also a decrease in intrathymic T cell proliferation as indicated by the reduced sj/beta TREC ratio (p<0.01). One month after reintroduction of GH treatment, IGF-1 concentration and sjTREC frequency regained a level equivalent to the one before GH withdrawal. The sj/beta TREC ratio also increased with GH resumption, but did not return to the level measured before GH withdrawal. CONCLUSIONS: In patients with AGHD under GH treatment, GH withdrawal decreases thymic T cell output, as well as intrathymic T cell proliferation. These parameters of thymus function are completely or partially restored one month after GH resumption. These data indicate that the functional integrity of the somatotrope GH/IGF-1 axis is important for the maintenance of a normal thymus function in human adults. TRIAL REGISTRATION: ClinicalTrials.gov NTC00601419. [less ▲]

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See detailAire and Foxp3 expression in a particular microenvironment for T-cell differentiation
Hansenne, Isabelle; Louis, Céline; Martens, Henri ULg et al

in Neuroimmunomodulation (2009), 16

Detailed reference viewed: 38 (9 ULg)