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See detailIr-LBP, an ixodes ricinus tick salivary LTB4-binding lipocalin, interferes with host neutrophil function.
Beaufays, Jérôme ULg; Adam, Benoit; Menten-Dedoyart, Catherine ULg et al

in PLoS ONE (2008), 3(12), 3987

BACKGROUND: During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation ... [more ▼]

BACKGROUND: During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: We previously identified 14 new lipocalin genes in the tick Ixodes ricinus. One of them codes for a protein that specifically binds leukotriene B4 with a very high affinity (Kd: +/-1 nM), similar to that of the neutrophil transmembrane receptor BLT1. By in silico approaches, we modeled the 3D structure of the protein and the binding of LTB4 into the ligand pocket. This protein, called Ir-LBP, inhibits neutrophil chemotaxis in vitro and delays LTB4-induced apoptosis. Ir-LBP also inhibits the host inflammatory response in vivo by decreasing the number and activation of neutrophils located at the tick bite site. Thus, Ir-LBP participates in the tick's ability to interfere with proper neutrophil function in inflammation. CONCLUSIONS/SIGNIFICANCE: These elements suggest that Ir-LBP is a "scavenger" of LTB4, which, in combination with other factors, such as histamine-binding proteins or proteins inhibiting the classical or alternative complement pathways, permits the tick to properly manage its blood meal. Moreover, with regard to its properties, Ir-LBP could possibly be used as a therapeutic tool for illnesses associated with an increased LTB4 production. [less ▲]

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See detailProtective effect of prion protein via the N-terminal region in mediating a protective effect on paraquat-induced oxidative injury in neuronal cells.
Dupiereux-Fettweis, Ingrid ULg; Falisse-Poirier, Nandini; Zorzi, Willy ULg et al

in Journal of Neuroscience Research (2008), 86(3), 653-9

Transmissible spongiform encephalopathies are a group of neurodegenerative disorders caused by a posttranslational, conformational change in the cellular isoform of the prion protein (PrP(C)) into an ... [more ▼]

Transmissible spongiform encephalopathies are a group of neurodegenerative disorders caused by a posttranslational, conformational change in the cellular isoform of the prion protein (PrP(C)) into an infectious, disease-associated form (PrP(Sc)). Increasing evidence supports a role for PrP(C) in the cellular response to oxidative stress. We investigated the effect of oxidative stress mediated by paraquat exposure on SH-SY5Y neuroblastoma cells. A loss of mitochondrial membrane potential and subsequent reduction in ATP production were demonstrated in untransfected SH-SY5Y cells, an effect that was ameliorated by the expression of PrP(C). Cells expressing either PrP-DeltaOct, which lacks the octapeptide repeats, or PrP-DA, in which the N-terminus is tethered to the membrane, showed increased sensitivity to paraquat compared with cells expressing wild-type PrP(C) as shown by reduced viability, loss of their membrane integrity, and reduced mitochondrial bioenergetic measurements. Exposure of prion-infected mouse SMB15S cells to paraquat resulted in a reduction in viability to levels similar to those seen in the untransfected SH-SY5Y cells. However, "curing" the cells with pentosan sulfate restored the viability to the level observed in the SH-SY5Y cells expressing PrP(C). These data would indicate that the molecular mechanism promoting cellular resistance to oxidative stress had been compromised in the infected SMB15S cells, which could be reinstated upon curing. Our study supports the hypothesis that PrP(C) expression protects cells against paraquat-induced oxidative injury, demonstrates the significance of the N-terminal region of the protein in mediating this protective effect, and also shows that the biochemical consequences of prion infection may be reversed with therapeutic intervention. [less ▲]

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See detailFollicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8.
Kranich, Jan; Krautler, Nike Julia; Heinen, Ernst ULg et al

in Journal of Experimental Medicine (2008), 205(6), 1293-302

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMphis ... [more ▼]

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMphis). Impairment of this process can contribute to autoimmunity. We show that Mfge8 is identical to the mouse follicular dendritic cell (FDC) marker FDC-M1. In bone-marrow chimeras between wild-type and Mfge8(-/-) mice, all splenic Mfge8 was derived from FDCs rather than TBMphis. However, Mfge8(-/-) TBMphis acquired and displayed Mfge8 only when embedded in Mfge8(+/+) stroma, or when situated in lymph nodes draining exogenous recombinant Mfge8. These findings indicate a licensing role for FDCs in TBMphi-mediated removal of excess B cells. Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8(-/-) mice. Hence, FDCs facilitate TBMphi-mediated corpse removal, and their malfunction may be involved in autoimmunity. [less ▲]

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See detailInfluence of the Ixodes ricinus tick blood-feeding on the antigen-specific antibody response in vivo.
Menten-Dedoyart, Catherine ULg; Couvreur, B.; Thellin, Olivier ULg et al

in Vaccine (2008), 26(52), 6956-64

The blood meal of hard ticks such as Ixodes ricinus lasts several days. This is made possible by tick salivary factors that inhibit inflammation, haemostasis and the host immune response. We assessed the ... [more ▼]

The blood meal of hard ticks such as Ixodes ricinus lasts several days. This is made possible by tick salivary factors that inhibit inflammation, haemostasis and the host immune response. We assessed the latter on a model of immune response in vivo. A significant reduction of specific IgM and IgG levels was observed in BALB/c mice infested 5 days before injection with bovine serum albumin (BSA) and QuilA but not in mice infested 5 days after the immunization. This effect was not observed in mock-infested mice and could not be attributed to the use of anesthetics. The antibody response was not merely delayed and the Th(1)/Th(2) balance appeared not altered. T-dependent zones and germinal centers in lymph nodes draining the tick bite site showed no apparent morphological alterations or shift in T cell subpopulations. However, the spleens of tick-infested mice had also an enlarged red pulp, indicating an increased extramedullary haematopoietic activity. [less ▲]

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See detailAvis n°44 du 23 juin 2008 relatif à l'inhibition de la croissance d'enfants très sévèrement handicapés mentalement
Hiele, M.; Genicot, G.; Mortier, F. et al

Report (2008)

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See detailComité de bioéthique - Avis N° 43 relatif à la commercialisation de parties du corps humain
Heinen, Ernst ULg; Sterckx, S.; Baum, M. et al

Report (2007)

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See detailInteraction between dendritic cells and nerve fibres in lymphoid organs after oral scrapie exposure
Dorban, Gauthier ULg; Defaweux, Valérie ULg; Demonceau, Christine ULg et al

in Virchows Archiv (2007), 451(6), 1057-1065

In transmissible spongiform encephalopathies (TSEs), the infectious agent, called PrPsc, an abnormal isoform of the cellular prion protein, accumulates and replicates in lymphoid organs before affecting ... [more ▼]

In transmissible spongiform encephalopathies (TSEs), the infectious agent, called PrPsc, an abnormal isoform of the cellular prion protein, accumulates and replicates in lymphoid organs before affecting the nervous system. To clarify the cellular requirements for the neuro-invasion of the scrapie agent from the lymphoid organs to the central nervous system, we have studied, by confocal microscopy, the innervations within Peyer's patches, mesenteric lymph nodes and the spleen of mice in physiological conditions and after oral exposure to prion. Contacts between nerve fibres and PrPsc-associated cells, dendritic cells (DCs) and follicular dendritic cells (FDCs), were evaluated in preclinical prion-infected mice. Using a double immunolabelling strategy, we demonstrated the lack of innervation of PrPsc-accumulating cells (FDCs). Contacts between nerve fibers and PrPsc-propagating cells (DCs) were detected in T-cell zones and cell-trafficking areas. This supports, for the first time, the possible implication of dendritic cells in the prion neuroinvasion process. [less ▲]

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See detailDialogue between peripheral nervous system and immunity: a confocal exploration
Dorban, G.; Defaweux, Valérie ULg; Demonceau, C. et al

Poster (2007, November)

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See detailIn Silico tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity
Crowet, Jean-Marc ULg; Lins, Laurence ULg; Dupiereux-Fettweis, Ingrid ULg et al

in Proteins-Structure Function and Bioinformatics (2007), 68(4), 936-947

Alpha-synuclein is a 140 residue protein associated with Parkinson's disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of alpha-synuclein aggregated into amyloid ... [more ▼]

Alpha-synuclein is a 140 residue protein associated with Parkinson's disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of alpha-synuclein aggregated into amyloid fibrils. Other amyloidogenic proteins, such as the beta amyloid peptide involved in Alzheimer's disease and the prion protein (PrP) associated with Creuztfeldt-Jakob's disease, are known to possess "tilted peptides". These peptides are short protein fragments that adopt an oblique orientation at a hydrophobic/hydrophilic interface, which enables destabilization of the membranes. In this paper, sequence analysis and molecular modelling predict that the 67-78 fragment of alpha-synuclein is a tilted peptide. Its destabilizing properties were tested experimentally. The alpha-synuclein 67-78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. The neuronal toxicity, studied using human neuroblastoma cells, demonstrated that the alpha-synuclein 67-78 peptide induces neurotoxicity. A mutant designed by molecular modelling to be amphipathic was shown to be significantly less fusogenic and toxic than the wild type. In conclusion, we have identified a tilted peptide in alpha-synuclein, which could be involved in the toxicity induced during amyloidogenesis of alpha-synuclein. [less ▲]

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See detailOral scrapie infection modifies the homeostasis of Peyer's patches' dendritic cells
Dorban, Gauthier ULg; Defaweux, Valérie ULg; Levavasseur, Etienne et al

in Histochemistry & Cell Biology (2007), 128(3), 243-251

In transmitted prion diseases the immune system supports the replication and the propagation of the pathogenic agent (PrPSc). DCs, which are mobile cells present in large numbers within lymph organs, are ... [more ▼]

In transmitted prion diseases the immune system supports the replication and the propagation of the pathogenic agent (PrPSc). DCs, which are mobile cells present in large numbers within lymph organs, are suspected to carry prions through the lymphoid system and to transfer them towards the peripheral nervous system. In this study, C57Bl/6 mice were orally inoculated with PrPSc (scrapie strain 139A) and sacrificed at the preclinical stages of the disease. Immunolabelled cryosections of Peyer's patches were analysed by confocal microscopy. Membrane prion protein expression was studied by flow cytometry. In Peyer's patches (PP), dissected at day one and day 105 after oral exposure to scrapie, we observed an increased population of DCs localised in the follicular-associated epithelium. On day 105, PrPSc was found in the follicles inside the PP of prion-infected mice. A subset of Peyer's patches DCs, which did not express cellular prion protein on their surface in non-infected mice conditions, was prion-positive in scrapie conditions. Within Peyer's patches oral scrapie exposure thus induced modifications of the homeostasis of DCs at the preclinical stages of the disease. These results give new arguments in favour of the implication of DCs in prion diseases. [less ▲]

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See detailNeuroimmune connections in jejunal and ileal Peyer's patches at various bovine ages: potential sites for prion neuroinvasion
Defaweux, Valérie ULg; Dorban, Gauthier ULg; Antoine, Nadine ULg et al

in Cell & Tissue Research (2007), 329(1), 35-44

During preclinical stages of cattle orally infected with bovine spongiform encephalopathy (BSE), the responsible agent is confined to ileal Peyer's patches (IPP), namely in nerve fibers and in lymph ... [more ▼]

During preclinical stages of cattle orally infected with bovine spongiform encephalopathy (BSE), the responsible agent is confined to ileal Peyer's patches (IPP), namely in nerve fibers and in lymph follicles, before reaching the peripheral and central nervous systems. No infectivity has been reported in other bovine lymphoid organs, including jejunal Peyer's patches (JPP). To determine the potential sites for prion neuroinvasion in IPP, we analyzed the mucosal innervation and the interface between nerve fibers and follicular dendritic cells (FDC), two dramatic influences on neuroinvasion. Bovine IPP were studied at three ages, viz., newborn calves, calves less than 12 months old, and bovines older than 24 months, and the parameters obtained were compared with those of JPP. No differences in innervation patterns between IPP and JPP were found. The major difference observed was that, in calves of less than 12 months, IPP were the major mucosal-associated lymphoid organ that possessed a large number of follicles with extended FDC networks. Using a panel of antibodies, we showed that PP in 24-month-old bovines were highly innervated at various strategic sites assumed to be involved in the invasion and replication of the BSE pathogen: the suprafollicular dome, T cell area, and germinal centers. In PP in calves of less than 12 months old, no nerve fibers positive for the neurofilament markers NF-L (70 kDa) and NF-H (200 kDa) were observed in contact with FDC. Thus, in view of the proportion of these protein subunits present in neurofilaments, the innervation of the germinal centers can be said to be an age-dependent dynamic process. This variation in innervation might influence the path of neuroinvasion and, thus, the susceptibility of bovines to the BSE agent. [less ▲]

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See detailAn immuno-PF2D-MS/MS proteomic approach for bacterial antigenic characterization: To Bacillus and beyond
Ruelle, Virginie ULg; Falisse-Poirier, Nandini; Elmoualij, Benaïssa ULg et al

in Journal of Proteome Research (2007), 6(6), 2168-2175

We are confronted daily to unknown microorganisms that have yet to be characterized, detected, and/ or analyzed. We propose, in this study, a multidimensional strategy using polyclonal antibodies ... [more ▼]

We are confronted daily to unknown microorganisms that have yet to be characterized, detected, and/ or analyzed. We propose, in this study, a multidimensional strategy using polyclonal antibodies, consisting of a novel proteomic tool, the ProteomeLab PF2D, coupled to immunological techniques and mass spectrometry ( i-PF2D-MS/MS). To evaluate this strategy, we have applied it to Bacillus subtilis, considered here as our unknown bacterial model. [less ▲]

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See detailPeculiar hydrophobic properties of the 67-78 fragment of α-synuclein are responsible for membrane destabilization and neurotoxicity
Crowet, Jean-Marc ULg; Lins, Laurence ULg; Dupiereux-Fettweis, Ingrid ULg et al

Poster (2007, March 14)

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ... [more ▼]

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ago, tilted peptides have been detected in two other amyloidogenic proteins : the amyloid β peptide involved in Alzheimer’s disease, and the PrP protein linked to Creuztfeldt-Jakob’s disease. Tilted peptides are short protein fragments that adopt an oblique orientation when inserted into biological membranes. Tilted peptides are able to destabilize membranes. In this study, we predicted by sequence analysis and molecular modelling that the 67-78 fragment of α-synuclein is a tilted peptide. Like most of them, the α-syn 67-78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. A mutant designed by molecular modelling to decrease the destabilizing properties of the peptide was shown to be significantly less fusogenic. The neuronal toxicity was studied using human neuroblastoma cells and we demonstrated that the α-syn 67-78 peptide induces neurotoxicity. In conclusion, we have identified a tilted peptide in α-synuclein which could be involved in the toxicity induced during amyloidogenesis of α-synuclein. [less ▲]

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See detailPeculiar hydrophobic properties of the 67-78 fragment of α-synuclein are responsible for membrane destabilization and neurotoxicity
Crowet, Jean-Marc ULg; Lins, Laurence ULg; Dupiereux-Fettweis, Ingrid ULg et al

Poster (2006, December 18)

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ... [more ▼]

α-synuclein is a 140 residue protein linked to Parkinson’s disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α-synuclein aggregated in amyloid fibrils. Few years ago, tilted peptides have been detected in two other amyloidogenic proteins : the amyloid β peptide involved in Alzheimer’s disease, and the PrP protein linked to Creuztfeldt-Jakob’s disease. Tilted peptides are short protein fragments that adopt an oblique orientation when inserted into biological membranes. Tilted peptides are able to destabilize membranes. In this study, we predicted by sequence analysis and molecular modelling that the 67-78 fragment of α-synuclein is a tilted peptide. Like most of them, the α-syn 67-78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. A mutant designed by molecular modelling to decrease the destabilizing properties of the peptide was shown to be significantly less fusogenic. The neuronal toxicity was studied using human neuroblastoma cells and we demonstrated that the α-syn 67-78 peptide induces neurotoxicity. In conclusion, we have identified a tilted peptide in α-synuclein which could be involved in the toxicity induced during amyloidogenesis of α-synuclein. [less ▲]

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See detailTRANSMISSION ET RÉSISTANCE DES PRIONS : LA PRATIQUE DE LA MÉDECINE DENTAIRE EN SERA T-ELLEAFFECTÉE ?
Elmoualij, Benaïssa ULg; Heinen, Ernst ULg; Zorzi, Willy ULg et al

in Journal de l'Ordre des Dentistes du Québec (2006), 43(9), 461-467

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See detailAdvances in immunoproteomics for serological characterization of microbial antigens
Falisse-Poirier, Nandini; Ruelle, Virginie ULg; Elmoualij, Benaïssa ULg et al

in Journal of Microbiological Methods (2006), 67(3), 593-596

We propose a multi-dimensional strategy, associating immunodetection to a protein fractionating two-dimensional liquid chromatography tool, for serological characterization of microbial antigens. The ... [more ▼]

We propose a multi-dimensional strategy, associating immunodetection to a protein fractionating two-dimensional liquid chromatography tool, for serological characterization of microbial antigens. The originality of such immunoproteomic approaches resides in their application in large-scale studies for rapid serotyping of micro-organisms, evaluation of immunomes and could be proposed in the development and monitoring of vaccines. (c) 2006 Elsevier B.V. All rights reserved. [less ▲]

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See detailImmunoquantitative real-time PCR for detection and quantification of Staphylococcus aureus enterotoxin B in foods
Rajkovic, A.; Elmoualij, Benaïssa ULg; Uyttendaele, M. et al

in Applied and Environmental Microbiology (2006), 72(10), 6593-6599

A real-time immunoquantitative PCR (iqPCR) method for detection of Staphylococcus aureus enterotoxin B (SEB) was developed and evaluated using both pure cultures and foods. The assay consisted of ... [more ▼]

A real-time immunoquantitative PCR (iqPCR) method for detection of Staphylococcus aureus enterotoxin B (SEB) was developed and evaluated using both pure cultures and foods. The assay consisted of immunocapture of SEB and real-time PCR amplification of the DNA probe linked to the detection antibody. iqPCR was compared to an in-house enzyme-linked immunosorbent assay (ELISA) using the same couple of capture-detection antibodies and to commercial kits for detection of S. aureus enterotoxins (SE). The iqPCR was approximately 1,000 times more sensitive (< 10 pg ml(-1)) than the in-house ELISA and had a dynamic range of approximately 10 pg ml(-1) to approximately 30,000 pg ml(-1). iqPCR was not inhibited by any of the foods tested and was able to detect SEB present in these foods. No cross-reactivity with SE other than SEB was observed. Application of iqPCR for detection of SEB in cultures of S. aureus revealed the onset of SEB production after 4 It of incubation at 22, 37, and 42 degrees C, which was in the first half of the exponential growth phase. The total amounts of SEB produced by the two strains tested were larger at 42 degrees C than at 37 degrees C and were strain dependent. [less ▲]

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See detailDistribution of nerve fibres in bovine and human mucosal associated lymphoid tissues
Defaweux, Valérie ULg; Dorban, G.; Antoine, Nadine ULg et al

Poster (2006, October)

Prion cell tropism varies significantly among animal species, depending on both the agent strain and host-specific factors. For example, prions show high lymphotropism in scrapie infected sheep and vCJD ... [more ▼]

Prion cell tropism varies significantly among animal species, depending on both the agent strain and host-specific factors. For example, prions show high lymphotropism in scrapie infected sheep and vCJD, but little, if any, in sCJD or BSE. In particular, the BSE strain is associated with significant PrP-res accumulation in tonsils, spleen and appendix in humans, whereas it is largely confined to the nervous system in infected cattle. Therefore, at least in the case of BSE and vCJD, it appears that host properties can influence the accumulation of the infectious agent in lymphoid organs. Mature FDC play an important role in prion pathogenesis, since neuroinvasion following peripheral challenge is significantly impaired in their absence. The proximity between these FDC and sympathetic nerve endings is known to affect the speed of prion neuroinvasion. In this study, we analysed the mucosal innervation and the interface between nerve fibres and FDC in bovine and human tonsils and in ileal and jejunal bovine Peyer’s patches using a panel of antibodies observed by confocal microscopy. Since differences in the innervation of lymphoid organs depending on age have been reported, we analysed three categories of bovine ages (new born calves, calves less than 12 months old and bovines older than 24 months) and two categories of human ages (patients less than 5 years old and patients older than 25 years). In both species, hypothetical ways of innervation by-passing germinal centre could be postulated: nerve fibres are widely distributed in antigens/cells traffic area (the lamina propria, the interfollicular zone, the suprafollicular dome in Peyer’s patches and the lymphoepithelial area in tonsils). We pointed out that, only in ileal and jejunal Peyer’s patches and in tonsils of bovines older than 24 months, nerve fibres are observed to be in contact with FDC. In contrast, in human tonsils, no nerve fibres established contact with FDC, whatever the age. Thus, innervation of germinal centres can be said to be an age-dependent dynamic process in bovines and a weak innervation of the secondary lymphoid organs could thus be a rate-limiting step to neuroinvasion in humans. This variation could influence the way of neuroinvasion and thus, the differences of susceptibility of bovines and humans to the BSE agent. [less ▲]

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