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V Geenen

Publications and source records attributed to V Geenen.

At least 19 recordsLinked to original sources
PubMed2006

[What's new at the maternal-foetal interface: role of the hCG/LH-hCG receptor couple during embryo implantation].

Implantation of the embryo into the maternal endometrium represents a unique biological process, combining an immunological (tolerance of an allograft) and biological (adhesion of two epitheliums) paradox. The success of implantation depends on a receptive endometrium, a functionally normal blastocyst and a synchronized cross-talk between embryonic and maternal tissues. Though sexual steroids control the process, a cascade of growth factors or cytokines are the prime paracrine mediators of the dialogue at the maternal-embryonic interface. HCG is one of the molecules most precociously produced by the embryo and is the most specific marker of its presence. HCG is a luteotropic factor which relays the inadequate support provided by the reduced rates of LH, but also influences the pregnancy on a paracrine mode by a local action on implantation process, probably by interacting with its receptor, the LH/hCG-R that we have evidenced on endometrial epithelium. We demonstrate that embryo actively participate into its implantation, tolerance and placentation.

Chorionic Gonadotropin↗
PubMed2005

[Role of the thymus in the physiopathology and in the prevention of type 1 diabetes].

There is now accumulating experimental evidence that, much more than a breakdown of peripheral immunological self-tolerance, the development of the diabetogenic autoimmune response (in type 1 diabetes) first results from a thymus dysfunction in the establishment of central beta-cell self-tolerance. Based on the homology between dominant thymic self-antigens and peripheral autoantigens, on the one hand, and the difference between the immune responses elicited by these antigens (respectively, tolerance vs immunity), a novel strategy is proposed for the development of a "negative" self-vaccine able to (re)install the state of immune self-tolerance to pancreatic islet beta cells and prevent type 1 diabetes.

Antibody Formation↗
PubMed2005

Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network.

Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.

Analysis of Variance↗
PubMed2004

Human chorionic gonadotropin and growth factors at the embryonic-endometrial interface control leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) secretion by human endometrial epithelium.

BACKGROUND: The elucidation of the molecular mechanisms by which the embryo contributes to its implantation is an area of extensive research. The main objective of this study was to investigate the pattern of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) secretion by human endometrial epithelium, and their regulation by human chorionic gonadotropin (hCG) and other growth factors present at the embryonic-endometrial interface. METHODS: Endometrial epithelial cells (EEC) were isolated from biopsies collected at both proliferative and secretory phases of fertile women. RESULTS: HCG (1-50 IU/ml) increased LIF secretion by EEC cultures derived from follicular phase (up to 285+/-75%) or from secretory phase (up to 212+/-16%). In contrast, hCG reduced IL-6 secretion by EEC in both phases. The hCG/LH receptor gene was transcribed by EEC as evidenced by RT-PCR. Insulin-like growth factors 1 and 2 increased LIF secretion by EEC. Transforming growth factor beta1 stimulated LIF and reduced IL-6 secretion. CONCLUSIONS: Through hCG, the blastocyst may be involved in the control of its implantation (via an increase of proimplantatory LIF) and tolerance (via an inhibition of proinflammatory IL-6). Other growth factors present at the embryonic-endometrial interface are also involved in the control of LIF and IL-6 endometrial secretion.

Adolescent↗
PubMed2004

Neurohypophysial receptor gene expression by thymic T cell subsets and thymic T cell lymphoma cell lines.

Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes, OTR, V1R, V2R and V3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147. OTR is transcribed in all thymic T cell subsets and T cell lines, while V3R transcription is restricted to CD4+CD8+ and CD8+ thymic cells. Neither V1R nor V2R transcripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data, OTR and V3R are differentially expressed during T cell ontogeny. Moreover, the restriction of OTR transcription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment.

Animals↗
PubMed2004

An insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8+ type 1 diabetic adolescents: preliminary design of a thymus-based tolerogenic self-vaccination.

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 diabetes (T1D) prevention. This evaluation was primarily based on cytokine profile driven by MHC presentation of insulin and IGF-2-derived antigens to PBMC cultures derived from 16 T1D DQ8(+) adolescents. Insulin B9-23, one dominant beta-cell autoantigen, and the homologous sequence B11-25 of IGF-2 display the same affinity and fully compete for binding to DQ8, a MHC-II allele conferring major genetic susceptibility to type 1 diabetes (T1D). However, compared to insulin B9-23, presentation of IGF-2 B11-25 elicits a suppressive/regulatory cytokine profile with a higher number of IL-10-secreting cells (P < 0.05), a much higher ratio of IL-10/IFN-gamma (P < 0.01), as well as a lower number of IL-4-secreting cells (P < 0.05). Thus, with regard to T1D prevention, administration of IGF-2-derived self-antigen(s) seems to be an efficient approach that combines both antagonism for binding to a major susceptibility MHC-II allele, as well as downstream promotion of an antigen-driven tolerogenic response.

Adolescent↗
PubMed2004

Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway.

Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT- and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90RSK). Pre-incubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca2+ chelator significantly reduced OT- and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT- and VP-induced p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, PKC and ERK1/2 are absolutely required for the OT- and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT- and VP-induced mitogenic effects on SCLC are respectively mediated by OTR and V1aR signalling and that this mitogenic signalling passes through the phosphorylation of ERK1/2 and p90RSK in a PLC-, Ca2+-, PKC- and MEK1/2-dependent pathway.

Calcium↗
PubMed2003

Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology.

Although the thymus constitutes a target organ for most protein and steroid hormones, it has been quite difficult to determine the precise control exerted in vivo by the endocrine system upon thymic function. The biological role of the thymus is to ensure the generation of a diversified population of peripheral T cells able to respond to non-self-antigens but nevertheless tolerant to self-antigens. For a long time, thymic function could not be monitored, as a consequence of the absence of adequate technology to differentiate recent thymic emigrants from naive T cells. The generation of T cell receptor (TCR) diversity occurs in the thymus through recombination of gene segments encoding the variable parts of the TCR alpha and beta chains. During these processes, by-products of the rearrangements are generated in the form of TCR excision circles (TRECs). As these molecules are lost upon further cell division, their quantification is actually considered as a very valuable tool to estimate thymic function. The most appropriate TREC is deltaRec-Psi(J)alpha TREC or signal joint TREC resulting from deltaRec-Psi(J)alpha rearrangement (TCRD deletion) that occurs late during thymopoiesis, before V(alpha)-J(alpha) rearrangement. Here we describe how TREC quantification is a powerful and reliable method to evaluate the impact of hormones and endocrine disorders upon thymic function.

Aged↗
PubMed2002

Human endometrial epithelial cells modulate the activation of gelatinase a by stromal cells.

Metalloproteinases (MMPs) are central effectors in endometrial physiology. Their production is tightly regulated by ovarian steroids and cytokines. Using zymography, we investigated MMP-2 production by human endometrial cells treated with estradiol-17beta + progesterone (E(2)+P) and by various key cytokines in endometrial physiology (IL-1beta, LIF, TGF-beta, and TNF-alpha). No gelatinase activity was detected in the culture media of epithelial cells. In basal conditions, stromal cells produced the pro form of MMP-2. MMP-2 production/activation was not directly affected by cytokine treatment. Interestingly, activated MMP-2 was only detected after treatment of stromal cells with culture medium from epithelial cells. Cytokine treatment of epithelial cells increased the capacity of conditioned medium to stimulate stromal cells to activate MMP-2. As the tissue inhibitor of MMP-2 (TIMP-2) is a regulator of gelatinase A activity, its concentration was measured by ELISA. TIMP-2 production by stromal cells was not affected by cytokines or by epithelial cell-conditioned medium. These results strongly suggest that regulation of stromal MMP-2 activation involves soluble factor(s) derived from the epithelial compartment.

Cytokines↗
PubMed2002

[The implantation window].

BACKGROUND: Embryo implantation is a complex event involving apposition followed by adhesion of the blastocyst to the maternal endometrium, and finally invasion of this endometrium. Though implantation could occur in any human tissue, the endometrium is the only tissue where embryo implantation cannot occur except during a restricted period called the implantation window. During this window, the endometrium is highly receptive to the embryo. MATERIAL: and methods. We reviewed the literature concerning the different factors involved in improved endometrial receptivity and implantation. RESULTS: Maternal - embryo crosstalk is favored by the implantation window. Endometrial receptivity results from the acquisition of ligands or receptors facilitating apposition, then adhesion of the embryo, or from the loss of components preventing it. The molecular basis of the implantation window remains to be defined. CONCLUSION: Despite progress in assisted reproduction technologies, the lack of control of implantation remains a major obstacle to successful pregnancy. It is of prime importance to determine the characteristic features of a receptive endometrium and, among the many markers proposed by in vitro studies, to analyze in humans those demonstrated by knock-out experiments to play a crucial role in mice.

Animals↗
PubMed2002

[Pharma clinics how I treat ... autoimmune thyroiditis].

Autoimmune thyroiditis represents an important percentage of diseases encountered by an endocrinologist and by any hospital division of Endocrinology. The classification of autoimmune thyroid diseases used in Liege University Hospital is the one proposed by T.F. Davies on the basis of their pathophysiology and the continuum of their clinic phenotype determined by the functional status of the thyroid. The management and therapeutic monitoring of these thyroid disorders completely differ depending on the type of autoimmune thyroiditis affecting the patient.

Humans↗
PubMed2002

[Autoimmunity in endocrinology: general principles].

The thymus is a crucial meeting place between the major systems of cell-to-cell communication, the nervous, the endocrine and the immune systems. More specifically, the thymus is the site for establishment of central T cell self-tolerance of neuroendocrine principles. The different factors--genetic, environmental, sexual--that intervene in the pathogenesis of autoimmune endocrinopathies are briefly reviewed here. Current research try to evidence that a thymic dysfunction, a defect in central self-tolerance could play an important role in the development of organ-specific autoimmune diseases, or cell-specific such as type 1 diabetes.

Antigens↗
PubMed2002

[Autoimmune polyendocrine syndrome (APS)].

As a complement to basic research, thorough clinical investigation of rare diseases may provide fundamental elements which improve our understanding of still obscure pathophysiologic mechanisms. This is the case with immunoendocrinopathy syndromes. Since Addison's pioneer observations in the 19th century, physicians have known that some individuals and their families may be affected by several spontaneous endocrine insufficiencies that are associated with autoimmune extra-endocrine processes. APS-I or APECED syndrome appears in children firstly affected by recurrent muco-cutaneous candidiasis and hypoparathyroidism, followed by adrenocortical insufficiency and by other autoimmune processes. APS-I is a monogenic disorder resulting from one mutation in the AIRE gene. The protein encoded by AIRE is a nuclear transcription factor the precise target of which is still not known. AIRE is mainly expressed by cells playing a crucial role in the establishment of central T cell self-tolerance (medullary epithelium, macrophages and dendritic cells of the thymus). APS-I must be considered in children affected with recurrent candidiasis without any sign of primary immune deficiency. Scientific investigation of the biological nuclear events controlled by AIRE has to be pursued. Undoubtedly, their deciphering will increase our knowledge of the mechanisms responsible for the establishment of central T cell self-tolerance and will open novel strategies for managing many autoimmune diseases. APS-II is a more common syndrome characterized by adrenocortical insufficiency spontaneously occurring in non tuberculous adults and associated with autoimmune thyroiditis and/or type 1 diabetes. Contrary to APS-I, APS-II is linked to genetic loci of the major histocompatibility complex. There is no adrenal insufficiency in APS-III which includes autoimmune thyroiditis, type 1 diabetes, and other autoimmune extra-endocrine processes (like pernicious anemia and vitiligo).

Adrenal Glands↗
PubMed2001

Novel plasma extraction procedure and development of a specific enzyme-immunoassay of oxytocin: application to clinical and biological investigations of small cell carcinoma of the lung.

Paraneoplastic secretion of the lactation-inducing hormone oxytocin (OT) has been reported in about 30% of cases of small cell carcinoma of the lung (SCCL). In order to investigate the role of OT in the biology of SCCL tumours, a specific enzyme-immunoassay (EIA) for OT, which can be applied to both human plasma and culture medium, has been developed. OT EIA is performed on 96-well microtiter plates coated with a rabbit polyclonal antibody (Ab) anti-OT (04). This antibody does not exhibit any significant cross-reactivity either with vasopressin (VP) or with vasotocin (VT). The immunological reaction involving Ab anti-OT is a competition between the tracer (biotinylated OT) and synthetic OT (standard curve) or OT present in biological samples. In order to limit interference induced by plasma proteins, plasma samples are filtrated by a one-step centrifugation on centricon YM-3 (cut-off 3000 Da). After plasma filtration, 90.7 +/- 5.1 (SD) % (n = 22) immunoreactive (IR) OT is recovered. The sensitivity of OT EIA is 1 pmol/L, while intra- and inter-assay coefficients of variation (CV) are around 3.41% and 2.84%, respectively. In healthy volunteers, plasma IR OT is 7.28 +/- 4.49 (SD) pmol/L (n = 32) with no gender difference. As shown by the data both from plasma of SCCL patients and from supernatants and cell contents of SCCL cell lines, this EIA procedure offers a novel, reproducible, specific and sensitive method for the measurement of IR OT.

Adult↗
PubMed2001

[Is it reasonable to prescribe growth hormones in the elderly?].

During normal aging, there is a +/- 60% decrease of the endogenous GH secretion ("somatopause"). However it is safe to prescribe GH therapy only to those people who show a clear cut decrease of GH release as evidenced by low integrated 24 hr secretion and/or low plasma IGF-1. In our view, a complete clinical check up must also show, on the one hand, an abnormal decrease of the optimal quality of life and, on the other hand a willing to maintain a reasonable intellectual and physical activity in the absence of major clinical and biological abnormalities. The benefits are likely to be an increase of muscular strength and of exercise tolerance, a decrease of trabecular osteopenia, a decrease of abdominal obesity, an increase of immunocompetence and a general improvement of the "quality of life". A "pharmacological" prescription is contra-indicated whereas very low dose regimen could induce, through feed back mechanism, a putative decrease of endogenous GH-RH (and GHRPs?) function whose deleterious psychoneuroendocrine effects remain to be demonstrated.

Activities of Daily Living↗
PubMed2001

Thymic T-cell tolerance of neuroendocrine functions: physiology and pathophysiology.

Intimate interactions between the two major systems of cell-to-cell communication, the neuroendocrine and immune systems, play a pivotal role in homeostasis and developmental biology. During phylogeny as well as during ontogeny, the molecular foundations of the neuroendocrine system emerge before the generation of diversity within the system of immune defenses. Before reacting against non-self infectious agents, the immune system has to be educated in order to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves anergizing mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T-cells. During ontogeny, T-cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, then bone marrow) enter the thymus and undergo a program of proliferation, T-cell receptor (TCR) gene rearrangement, maturation and selection. Intrathymic T-cell maturation proceeds through discrete stages that can be traced by analysis of their cluster differentiation (CD) surface antigens. It is well established that close interactions between thymocytes (pre-T-cells) and the thymic cellular environment are crucial both for T-cell development and for induction of central self-tolerance. Particular interest has focused on the ability of thymic stromal cells to synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors recapitulates at the molecular level the dual role of the thymus in T-cell negative and positive selection. Thymic precursors not only constitute a source of growth factors for cryptocrine signaling between thymic stromal cells and pre-T-cells, but are also processed in a way that leads to the presentation of self-antigens by (or in association with) thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens usually correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens does not seem to be restricted by MHC alleles. Through the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T-cell system might be educated to tolerate main hormone families. More and more recent experiments support the concept that a defect in thymic tolerogenic function is implicated as an important factor in the pathophysiology of autoimmunity.

Animals↗
PubMed2001

[Autoimmune thyroiditis].

The continuum of clinical phenotype between different autoimmune thyroid diseases and mainly the common pathophysiological mechanisms have lead to a novel classification of these disorders into three types: (1) Type 1 autoimmune thyroiditis (euthyroidism associated with the presence of anti-thyroglobulin and anti-thyroperoxydase autoantibodies); (2) Type 2 autoimmune thyroiditis or Hashimoto's disease (hypothyroidism with anti-thyroglobulin and anti-thyroperoxydase autoantibodies). Postpartum thyroiditis falls into this category and is characterized by transient hyperthyroidism followed by hypothyroidism; and (3) Type 3 autoimmune thyroiditis or Graves-Basedow's disease (hyperthyroidism with anti-TSH receptor "stimulating" auto-antibodies, often associated with anti-thyroglobulin and anti-thyroperoxydase autoantibodies). Thyroid orbitopathy often complicates Type 3 autoimmune thyroiditis and is thought to result from an autoimmune response against an autoantigen common to thyroid and orbital fibroblasts/adipose cells. We present the actualized knowledge about the immunological parameters that can be detected and quantified in autoimmune thyroid diseases, about the pathophysiological mechanisms involved in these disorders, and about the options of their treatment that are currently offered to the medical community.

Biomarkers↗