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See detailCentral self-tolerance by thymic presentation of self-antigens and autoimmunity
Geenen, Vincent ULg; Martens, Henri ULg; Hansenne, Isabelle et al

in Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents (2001), 1

Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the ... [more ▼]

Before reacting against non-self infectious agents, the immune system is educated 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 inactivating 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, and then bone marrow) enter the thymus and undergo a program of proliferation, T cell receptor (TCR) gene rearrangement, maturation and selection. Close interactions between thymocytes (pre-T cells) and the thymic cellular environment are crucial both for T cell development and induction of central self-tolerance. Thymic epithelial and stromal cells synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors transposes 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 peptides 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 thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens often correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Following the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T cell system might be educated to tolerate main hormone families. Recent experiments argue that a defect in the thymic essential tolerogenic function is implicated as an important factor in the pathophysiology of many autoimmune diseases. [less ▲]

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See detailThymic Expression of Insulin-Related Genes in an Animal Model of Autoimmune Type 1 Diabetes
Kecha-Kamoun, Ouafae; Achour, Imane; Martens, Henri ULg et al

in Diabetes/Metabolism Research & Reviews (2001), 17(2, Mar-Apr), 146-52

BACKGROUND: Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against ... [more ▼]

BACKGROUND: Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet beta-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell self-tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat. METHODS: The expression of the mammalian insulin-related genes (Ins, Igf1 and Igf2) was analysed in the thymus of inbred Wistar Furth rats (WF), diabetes-resistant BB (BBDR) and diabetes-prone BB (BBDP) rats. RESULTS: RT-PCR analyses of total RNA from WF, BBDP and BBDR thymi revealed that Igf1 and Ins mRNAs are present in 15/15 thymi from 2-day-old, 5-day-old and 5-week-old WF, BBDR and BBDP rats. In contrast, a complete absence of Igf2 mRNA was observed in more than 80% of BBDP thymi. The absence of detectable Igf2 transcripts in the thymus of BBDP rats is tissue-specific, since Igf2 mRNAs were detected in all BBDP brains and livers examined. Using a specific immunoradiometric assay, the concentration of thymic IGF-2 protein was significantly lower in BBDP than in BBDR rats (p<0.01). CONCLUSIONS: The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats. This tissue-specific defect in gene expression could contribute both to the lymphopenia of these rats (by impaired T-cell development) and the absence of central T-cell self-tolerance of the insulin hormone family (by defective negative selection of self-reactive T-cells). [less ▲]

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See detailThymic neurohypophysial peptide-mediated signaling and T-cell differentiation
Geenen, Vincent ULg; Martens, Henri ULg; Hansenne, Isabelle

in FASEB Journal (2001), 15

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See detailInvolvement of Insulin-Like Growth Factors in Early T Cell Development: A Study Using Fetal Thymic Organ Cultures
Kecha, O.; Brilot, F.; Martens, Henri ULg et al

in Endocrinology (2000), 141(3), 1209-17

The expression of insulin-like growth factor (IGF) and IGF receptor genes was investigated by RT-PCR during ontogeny of the murine thymus. IGF-1, IGF-1R, M6P/IGF-2R genes are expressed in the thymus both ... [more ▼]

The expression of insulin-like growth factor (IGF) and IGF receptor genes was investigated by RT-PCR during ontogeny of the murine thymus. IGF-1, IGF-1R, M6P/IGF-2R genes are expressed in the thymus both in fetal and postnatal life, whereas IGF-2 messenger RNAs (mRNAs) decline after birth but are still detectable on the seventh week. By in situ hybridization, IGF-2 transcripts were located in the outer cortex and medulla of the postnatal thymus, and on the whole surface ofthe epithelial-like network in the fetal thymus. The effects of anti-IGFs and IGF-receptors neutralizing Abs on the generation of pre-T cell subpopulations were then investigated using fetal thymic organ cultures (FTOC). FTOC treatment with an anti-IGF-2 mAb, an anti-IGF-1R mAb, or an anti-M6P/IGF-2R polyclonal Ab induced a blockade of T cell differentiation at the CD4-CD8- stage, as shown by a significant increase in the percentage of CD4-CD8- cells and a decrease in the percentage of CD4+CD8+ cells. Moreover, anti-IGF-2 Ab treatment induced an increase in CD8+ cells suggesting that thymic IGF-2 might have a role in determining differentiation into the CD4 or CD8 lineage. Anti-IGF-1 Ab treatment decreased the proportion in CD4-CD8- cells and increased the frequency in CD4+CD8+. FTOC treatment with anti-(pro)insulin did not exert any significant effect on T cell development. These data indicate that the intrathymic IGF-mediated signaling plays an active role in the early steps of T cell differentiation during fetal development. [less ▲]

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See detailThymic neuroendocrine self-antigens. Role in T-cell development and central T-cell self-tolerance
Geenen, Vincent ULg; Martens, Henri ULg; Brilot, Fabienne et al

in Annals of the New York Academy of Sciences (2000), 917

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See detailThymic neurohypophysial peptide-mediated signalling in T-cell differentiation
Martens, Henri ULg; Hansenne, Isabelle; Kecha, Ouafae et al

in Pflügers Archiv : European Journal of Physiology (2000), 440

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See detailThymic insulin-related genes: role in T-lymphocyte development and self-tolerance of the insulin family
Kecha, Ouafae; Martens, Henri ULg; Brilot, Fabienne et al

in Pflügers Archiv : European Journal of Physiology (2000), 440

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See detailTumor Necrosis Factor Alpha Decreases, and Interleukin-10 Increases, the Sensitivity of Human Monocytes to Dexamethasone: Potential Regulation of the Glucocorticoid Receptor
Franchimont, Denis; Martens, Henri ULg; Hagelstein, Marie-Thérèse ULg et al

in Journal of Clinical Endocrinology and Metabolism (1999), 84(8), 2834-9

Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ... [more ▼]

Resistance to glucocorticoid therapy has been observed in patients with autoimmune/inflammatory diseases and may be related to the inflammatory process itself. The aim of this study was to examine the ability of tumor necrosis factor alpha (TNFalpha, a proinflammatory cytokine) and interleukin (IL)-10 (an anti-inflammatory cytokine) to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. To accomplish this, we first analyzed the pattern of TNFalpha and IL-10 inhibition by dexamethasone in LPS-stimulated whole-blood cell cultures. Second, we studied the modulation of the sensitivity of these cells to dexamethasone by preincubation with TNFalpha or IL-10 and measurement of LPS-stimulated IL-6 secretion. In addition, we evaluated the effect of dexamethasone on phorbolmyristate-acetate-stimulated IL-1 receptor antagonist secretion by the human monocytic cell line U937. Finally, we investigated whether the modulation of corticosensitivity in TNFalpha- and IL-10-pretreated U937 cells was related to a change of the glucocorticoid receptor concentration and affinity. Dexamethasone had different effects on LPS-induced TNFalpha and IL-10 secretion; whereas it suppressed TNFalpha in a dose-dependent fashion, its effect on IL-10 secretion was biphasic, producing stimulation at lower, and inhibition at higher doses. The concentration of LPS employed influenced the effect of dexamethasone on IL-10 secretion (P < 0.001). Pretreatment with TNFalpha diminished, and with IL-10 improved, the ability of dexamethasone to suppress IL-6 secretion in whole-blood cell cultures (P < 0.01 for both) and to enhance IL-1 receptor antagonist secretion by U937 cells (P < 0.05 for both). TNFalpha decreased (P < 0.001), while IL-10 increased (P < 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. We conclude that glucocorticoids differentially modulate TNFalpha and IL-10 secretion by human monocytes in a LPS dose-dependent fashion and that the sensitivity of these cells to glucocorticoids is altered by TNFalpha or IL-10 pretreatment; TNFalpha blocks their effects, whereas IL-10 acts synergistically with glucocorticoids. This is accompanied by opposite glucocorticoid receptor changes, respectively opposing and favoring glucocorticoid actions. This study suggests that the pattern of pro-/antiinflammatory cytokine secretion may alter the response of patients to glucocorticoid therapy. [less ▲]

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See detailCharacterization of the Insulin-Like Growth Factor Axis in the Human Thymus
Kecha, Ouafae; Martens, Henri ULg; Franchimont, Nathalie et al

in Journal of Neuroendocrinology (1999), 11(6), 435-40

The components of the insulin-like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF-II transcripts were detected in the normal ... [more ▼]

The components of the insulin-like growth factor (IGF) axis have been investigated in the normal human thymus. Using ribonuclease protection assays (RPA), IGF-II transcripts were detected in the normal human thymus. By reverse transcriptase polymerase chain reaction (RT-PCR) analyses, promoters P3 and P4 were found to be active in the transcription of IGF2 gene within human thymic epithelial cells (TEC). No IGF-II mRNA could be detected in human lymphoid Jurkat T cells with 30 cycles of RT-PCR. By Northern blot analyses, IGFBP-2 to -6 (but not IGFBP-1) were found to be expressed in TEC with a predominance of IGFBP-4. Interestingly, Jurkat T cells only express IGFBP-2 but at high levels. The type 1 IGF receptor was detected in Jurkat T cells but not in human TEC. The identification of the components of the IGF axis within separate compartments of the human thymus adds further evidence for a role of this axis in the control of T-cell development. The precise influence of thymic IGF axis upon T-cell differentiation and immunological self-tolerance however needs to be further investigated. [less ▲]

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See detailThe thymic repertoire of neuroendocrine-related self-antigens: Biological role in T-cell selection and pharmacological implications
Geenen, Vincent ULg; Kecha, Ouafae; Brilot, Fabienne et al

in Savino, Wilson (Ed.) Neuroendocrine Control of the Thymus (1999)

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See detailThymic insulin-related polypeptides in diabetes-prone Bio-Breeding rats
Kecha, Ouafae; Winkler, Rose ULg; Martens, Henri ULg et al

in Diabetologia (1999), 42 (Suppl. 1)

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See detailThymic insulin-related polypeptides: role in T cell selection and in central self-tolerance of the insulin family
Kecha, Ouafae; Brilot, Fabienne; Martens, Henri ULg et al

in The Endocrine Society (Ed.) Proceedings of the 81st Annual Meeting of the Endocrine Society (1999)

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See detailDe nouveaux acteurs dans la physiopathologie du metabolisme de l'eau: les aquaporines
Pequeux, Christel ULg; Brilot, Fabienne; Martens, Henri ULg et al

in Revue Médicale de Liège (1999), 54(11), 867-74

Aquaporins are transmembrane proteins mediating water transport across plasma membrane of animal, vegetal or bacterial cells. Among the ten aquaporins known in mammals, six are located in kidney and take ... [more ▼]

Aquaporins are transmembrane proteins mediating water transport across plasma membrane of animal, vegetal or bacterial cells. Among the ten aquaporins known in mammals, six are located in kidney and take part in urine concentration. AQP2 is vasopressin regulated, it is the only family member to be implicated in human pathology, such as nephrogenic diabetes insipidus, congestive heart failure, hepatic cirrhosis, nephrotic syndrome or SIADH. Aquaporins are expressed in a wide variety of tissues, such as brain or gastrointestinal tractus, and suggest a role in water tissue exchange, but their real function is still not define. To know the physiological impact of aquaporins, AQP1, AQP3, AQP4 and AQP5 knockout mice have been created and their phenotype analysed. [less ▲]

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See detailThymus gland, Neuroendocrine-Immunology
Geenen, Vincent ULg; Wiemann, Martin; Martens, Henri ULg

in Adelman, George; Smith, Barry H. (Eds.) Encyclopedia of Neuroscience, 2nd enlarged and revised edition (1999)

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See detailEffects of Dexamethasone on the Profile of Cytokine Secretion in Human Whole Blood Cell Cultures
Franchimont, Denis; Louis, Edouard ULg; Dewé, Walthère ULg et al

in Regulatory Peptides (1998), 73(1), 59-65

EXPERIMENTAL OBJECTIVES: The interaction between the endocrine and immune systems is a very intriguing area. Endogenous glucocorticoids, as end-effectors of the hypothalamo-pituitary-adrenal axis, inhibit ... [more ▼]

EXPERIMENTAL OBJECTIVES: The interaction between the endocrine and immune systems is a very intriguing area. Endogenous glucocorticoids, as end-effectors of the hypothalamo-pituitary-adrenal axis, inhibit the immune and inflammatory responses and are used as immunosuppressive drugs in many inflammatory, autoimmune and allergic diseases. The aims of this study were to investigate the effects of dexamethasone on the profile of cytokine secretion in whole blood cell cultures from healthy subjects and to analyse the gender-related sensitivity to dexamethasone on each cytokine secretion. RESULTS: There was a significant inhibition by dexamethasone (from 1 to 100 nM) on the secretion of monokines (IL-1beta, IL-6, IL-8 and TNF alpha) and lymphokines (IL-2, IL-4, IL-10 and IFN gamma), either after LPS or PHA stimulation (P < 0.01). Interleukin 4 and IL-10 were less inhibited than IFN gamma (P < 0.05 at 1 nM, P < 0.01 at 10 nM and P < 0.001 from 100 nM to 10 microM). No gender difference was observed in the rate of inhibition of the secretion of each cytokine. CONCLUSION: This study shows that the inhibition of cytokine secretion by dexamethasone is more marked on Th1-type cytokines than on Th2-type cytokines. These data support the idea that glucocorticoids may induce a shift from the Th1 to Th2 profile of cytokine secretion. [less ▲]

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See detailNeurohypophysial peptides stimulate the phosphorylation of pre-T cell focal adhesion kinases
Martens, Henri ULg; Kecha, Ouafae; Charlet-Renard, Jeanne de Chantal ULg et al

in Neuroendocrinology (1998), 67(4), 282-289

Thymic oxytocin (OT) behaves as a cryptocrine signal targeted at the outer surface of thymic epithelial cell plasma membrane from where OT is able to interact with neurohypophysial peptide receptors ... [more ▼]

Thymic oxytocin (OT) behaves as a cryptocrine signal targeted at the outer surface of thymic epithelial cell plasma membrane from where OT is able to interact with neurohypophysial peptide receptors expressed by pre-T cells. Immature T cells bear a receptor of the V1 subtype, while OT receptors are predominantly expressed by cytotoxic CD8+ lymphocytes. In both T cell types, neurohypophysial peptide receptors transduce OT via the phosphoinositide pathway. Protein tyrosine phosphorylation is an early event of T cell activation. Western blots of murine pre-T cells (RL12-NP line) proteins probed with anti-phosphotyrosine (PY-20) revealed a great number of proteins the phosphorylation of which increased either with OT or vasopressin treatment. Two were immunoprecipitated with anti-focal adhesion kinase (FAK) mAb 2A7 and were identified one as p125FAK and the other as a coprecipitating 130-kDa protein. The p125FAK is connected to the Ras/MAPK pathway and is also implicated in TCR/CD3 signalling in T cell. Another protein phosphorylated by OT in RL12-NP was identified as paxillin, a 68-kDa protein localised at focal adhesion sites and associated with p 125FAK. These results indicate that phosphorylation of focal adhesion kinase may be induced in pre-T cell by thymic OT. [less ▲]

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See detailCellular and molecular aspects of thymic T-cell education to neuroendocrine self principles: implications in autoimmunity
Geenen, Vincent ULg; Martens, Henri ULg; Kecha, Ouafae et al

in Annals of the New York Academy of Sciences (1998), 840

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See detailThymic expression of neuroendocrine self-peptide precursors: role in T-cell survival and self-tolerance
Geenen, Vincent ULg; Kecha, Ouafae; Martens, Henri ULg

in Journal of Neuroendocrinology (1998), 10

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See detailPhosphorylation of Proteins Induced in a Murine Pre-T Cell Line by Neurohypophysial Peptides
Martens, Henri ULg; Kecha, O.; Charlet-Renard, C. et al

in Advances in Experimental Medicine and Biology (1998), 449

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See detailPhosphorylation of proteins induced in a murine pre-T cell line by neurohypophysial peptides
Martens, Henri ULg; Kecha, Ouafae; Brilot, Fabienne et al

in Zingg, Hans H.; Bourque, Charles W.; Bichet, Daniel (Eds.) Vasopressin and Oxytocin: Molecular, Cellular, and Clinical Advances (1998)

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