The Recognition of Hypothalamo‐NeurohypophysialFunctions by Developing T Cells

Robert, Françoise; Martens, Henri; Cormann, N.; Benhida, Abdellah; Schoenen, Jean; Geenen, Vincent

doi:10.1155/1992/98671

Cited by 31 publications

(16 citation statements)

References 68 publications

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“…As OT and VP differ by only two amino acids, the specific increase of cytokine production by TEC upon antigen recognition confirms that OT is the dominant self-antigen of the neurohypophysial family expressed by TEC. Both 033 and 013 stimulate cytokine production by TEC, although 013 was previously shown not to stain human thymic sections [24,38]. In processing of the OT-precursor, OT must be cleaved from neurophysin before 9gly-OT amidation.…”

Section: Discussionmentioning

confidence: 99%

Cytokine production by human thymic epithelial cells: control by the immune recognition of the neurohypophysial self-antigen

Martens

Malgrange

Robert

et al. 1996

Regulatory Peptides

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Oxytocin (OT) has been shownto be the dominantpeptideof the neurohypophysial familyexpressedby thymicepithelialand nurse cells (TEC/TNC) invmiousspecies. Thymic OT is not secreted but, after translocation of a hybrid neurophysin/MHC class I protein,is integratedwithinthe plasmamembraneof TEC, thus allowing its presentation to pre-T cells. In order to further demonstrate that thymic OT behaves like a membrane antigen, we assessed the effect of rnAbs to OT on cytokine productions by cultures enriched in human TEC. 75-85% pure TEC cultures were prepared tlom human thymic fragments. Using immunofluorescence and confocal microscopy, ir-OT, ir-interleukin-1~(IL-1P), ir-interleukin-6 (IL-6) and ir-leukemia inhibitory factor (LIF) could be detected in these TEC cultures. ir-OT was restricted to TEC, while some ir-IL-6 and ir-LIF were also seen in occasional fibroblasts. In basal conditions, ir-IL-6 and ir-LIF (but not ir-OT and ir-IL-l@) were detected in the supematants of human TEC cultures. MAbs to OT induced a marked increase of ir-IL-6 and ir-LIF secretion in TEC cultures. No significant effect was observed using mAbs against vasopressin, mouse immunoglobulins, or control ascitic fluid controls. These data show that OT is fully processed and recognized by specific mAbs at the outer surface of TEC plasma membrane. They further support that thymic OT behaves as the self-antigen of the nenrohypophysial family.

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Section: Discussionmentioning

confidence: 99%

Cytokine production by human thymic epithelial cells: control by the immune recognition of the neurohypophysial self-antigen

Martens

Malgrange

Robert

et al. 1996

Regulatory Peptides

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“…Glucocorticoids also are synthesised in thymic epithelium and are able to impact on thymocyte development (reviewed in Ashwell et al 2000). The processing of neuroendocrine precursors in the thymus is not coupled to classical secretion but involves constitutive pathways for membrane targeting and presentation by major histocompatibility complex (MHC) proteins (Robert et al 1992, Martens et al 1996a, Vanneste et al 1997. Neuroendocrine selfantigens derive from the processing of precursors dominantly expressed in the thymus and usually correspond to peptide sequences highly conserved during evolution.…”

Section: Physiology Of the Thymusmentioning

confidence: 99%

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

Geenen

Poulin²,

Dion³

et al. 2003

Journal of Endocrinology

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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 selfantigens. 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 and 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 Rec-J TREC or signal joint TREC resulting from Rec-J rearrangement (TCRD deletion) that occurs late during thymopoiesis, before V -J 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.

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“…In 1992, a defect in the process of intrathymic T-cell education to recognize and to tolerate OT was hypothesized to play a pivotal role in the development of hypothalamus-specific autoimmunity leading to 'idiopathic' central diabetes insipidus [71]. The progressive increase in the degree of immune diversity and complexity may explain why failures in self- tolerance are increasingly detected during evolution with most such failures occurring in the human species.…”

Section: Environmental Factorsmentioning

confidence: 99%

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

Geenen

Mottet

Dardenne

et al. 2010

Current Opinion in Pharmacology

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Before being able to react against infectious nonself-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 programing central self-tolerance to pancreatic insulin-secreting islet b cells, leading to the breakdown of immune homeostasis with an enrichment of islet b-cell reactive effector T cells and a deficiency of b-cell specific natural regulatory T cells (nTregs) in the peripheral Tlymphocyte 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 demonstrated in many studies, including the failure of all clinical trials that have attempted immune tolerance to islet b cells via various methods of insulin administration. On the basis of the close homology and crosstolerance 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 selfvaccination', is currently being developed for the prevention and cure of T1D. If this approach were found to be effective for reprograming immunological tolerance in T1D, it could pave the way for the design of other self-vaccines against autoimmune endocrine diseases, as well as other organspecific autoimmune diseases. ''Autoimmune disease can be a depressing subject. In Shakespearian terms, 'it is a tale told by an idiot. . .signifying nothing'. In more modern metaphor, it is an error made at random in an enormous, delicately programmed computer. Nature has no other way of handling genetic error than by eliminating the faulty, and the physician handling autoimmune diseases can expect no help from her.'' Sir F. MacFarlane Burnet, 1972 IntroductionIn 1965, our late Belgian colleague Willy Gepts observed inflammatory infiltrates of mononuclear cells invading Langerhans' islets in the pancreas of deceased young diabetic patients [1]. In a prophetical analysis, he discussed his innovative results with the following words: 'It seems probable that, in the pancreas of acute diabetics, we had the opportunity to catch the final stages of a process which has been going on for an indefinite time, perhaps from birth on'. Since this pioneering work, research conducted worldwide has firmly established that type 1 diabetes (T1D) -previously called juvenile diabetes, and insulin-dependent diabetes -is the final result of a highly selective autoimmune response that generates an inflammation (insulitis), followed by the death of insulin-secreting islet b cells in the pancreas. Incidence of T1D peaks around 10-14 years and this disease affects AE20 million people worldwide (approximately 10%...

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The Recognition of Hypothalamo‐NeurohypophysialFunctions by Developing T Cells

Cited by 31 publications

References 68 publications

Cytokine production by human thymic epithelial cells: control by the immune recognition of the neurohypophysial self-antigen

Cytokine production by human thymic epithelial cells: control by the immune recognition of the neurohypophysial self-antigen

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

Thymic self-antigens for the design of a negative/tolerogenic self-vaccination against type 1 diabetes

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