Involvement of Macrophages in the Pathogenesis of Transmissible Spongiform Encephalopathies

Although transmissible spongiform encephalopathies (TSE) or prion diseases are neurodegenerative disorders, the immune system is also involved, at least in the early stages of their pathogenesis. Extensive studies have focused on cells targeted by the TSE agent for its replication but few on the possible involvement of macrophages in its clearance, as in more conventional diseases. This review summarises some of the experiments aimed at demonstrating a role for macrophages in TSE and presents the application to TSE of the macrophage "suicide" technique, which has been used to clarify the implication of these cells in the early steps of TSE pathogenesis

Mechanisms of opsonized HIV entry in normal B lymphocytes

AbstractUsing our in vitro model of normal B cell infection that functions with low doses of HIV but requires virus opsonization by seropositive patient serum, and complement, we analyzed what receptors allowed virus entry. Here, we show that HIV infection of B cells occurs through 2 major receptors: the CD4 antigen and the CR1/CR2 complex. These 2 pathways work independently since a complete inhibition of virus entry requires both CD4 and CD21/CD35 blockade on CD4dim tonsillar B cells whereas only the latter is critical on CD4-negative B cells

Low autocrine interferon beta production as a gene therapy approach for AIDS: Infusion of interferon beta-engineered lymphocytes in macaques chronically infected with SIVmac251

BACKGROUND: The aim of this study was to evaluate gene therapy for AIDS based on the transduction of circulating lymphocytes with a retroviral vector giving low levels of constitutive macaque interferon β production in macaques chronically infected with a pathogenic isolate of SIVmac251. RESULTS: Two groups of three animals infected for more than one year with a pathogenic primary isolate of SIVmac251 were included in this study. The macaques received three infusions of their own lymphocytes transduced ex vivo with the construct encoding macaque IFN-β (MaIFN-β or with a vector carrying a version of the MaIFN-β gene with a deletion preventing translation of the mRNA. Cellular or plasma viremia increased transiently following injection in most cases, regardless of the retroviral construct used. Transduced cells were detected only transiently after each infusion, among the peripheral blood mononuclear cells of all the animals, with copy numbers of 10 to 1000 per 10(6 )peripheral mononuclear cells. CONCLUSION: Long-term follow-up indicated that the transitory presence of such a small number of cells producing such small amounts of MaIFN-β did not prevent animals from the progressive decrease in CD4(+ )cell count typical of infection with simian immunodeficiency virus. These results reveal potential pitfalls for future developments of gene therapy strategies of HIV infection

The Prion Protein Has RNA Binding and Chaperoning Properties Characteristic of Nucleocapsid Protein NCp7 of HIV-1

International audienc

Multi-template approaches for segmenting the hippocampus: the case of the SACHA software

International audienceThe hippocampus has been shown to play a crucial role in memory and learning. Its volumetry is a well-established biomarker of Alzheimer’s Disease (AD) and hippocampal sclerosis in temporal lobe epilepsy (TLE). Manual segmentation being time consuming and suffering from low reproducibility,robust automatic segmentation from routine T1 images is of high interest for studying large datasets. We previously proposed such an approach (SACHA, Chupin et al, 2007, 2009), based on competitive region deformation constrained by both anatomical landmarks and a single probabilistic template of 16 young healthy subjects registered using SPM5. The atlas being introduced as a soft constraint, robust results have been obtained in large series of patients with various pathologies. In recent years, multitemplate approaches have proven to be a powerful mean to increase segmentation robustness (Barnes et al, 2008) (Aljabar et al, 2009) (Heckemann et al 2006), more specifically for subjects with very large atrophy or atypical shapes (such as malrotations (Bernasconi et al, 2005) (Kim et al, 2012)).We propose here to evaluate the introduction of multiple-template constraints in SACHA

Reponses aux questions du directeur general de la sante, du direct ur general de l'alimentation et du directeur general de la consommatio ... adressees au comite en juillet 1996

SIGLEAvailable at La Documentation francaise (FR) Number :96-4-0283 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

(Analyse du risque de transmission)

SIGLEAvailable at La Documentation francaise (FR) Number :96-4-0125 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

PLACE DES ASTROCYTES DANS LA PHYSIOPATHOLOGIE DE L'ENCEPHALOPATHIE A VIH (ETUDE DANS LE MODELE D'INFECTION EXPERIMENTALE DU MACAQUE PAR LE SIVMAC251)

PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Immunobiologie de la sclérose en plaques (une maladie autoimmune du système nerveux central)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Approche in vitro des mécanismes de neurodégénérescence au cours des encéphalopathies subaiguës spongiformes transmissibles

Les encéphalopathies subaiguës spongiformes transmissibles (ESST) sont des maladies dégénératives du système nerveux central caractérisées par l'accumulation d'une protéine normale de l'hôte (la protéine du prion ou PrPc) sous une forme anormale (la PrPsc). Nous nous sommes intéressés aux mécanismes qui conduisent à la mort neuronale selon trois axes : 1) Dans un modèle de cultures primaires de neurones de cortex murins, nous avons testé la toxicité de peptides centrés sur le domaine transmembranaire de la PrPc. Ces peptides induisaient une apoptose neuronale. Leur étude par modélisation moléculaire a montré qu'ils étaient capables de pénétrer et de déstabiliser la membrane plasmique. 2) La PrPc joue un rôle central dans les mécanismes conduisant aux lésions cérébrales. L'hypothèse d'une perte de sa fonction physiologique a été proposée comme le mécanisme central conduisant à la mort neuronale. L'identification d'un récepteur cellulaire de la PrPc constitue donc une étape clef dans la compréhension du processus neurodégénératif. Une interaction entre la PrPc et le précurseur de 37 kD du récepteur à la laminine (LRP) ayant été rapportée, nous avons montré que 1) la PrP se liait aux cellules en culture via le LRP 2) une partie de la PrP était ensuite internalisée 3) la PrP possédait deux domaines de liaison au LRP 4) les différentes formes moléculaires du récepteur sont bien exprimées dans le SNC et capables d'interagir avec une PrP recombinante. 3) Les ESST sont caractérisées par une période d'incubation extrêmement longue. La possibilité d'un renouvellement neuronal dans le cerveau adulte a été mise en évidence. Au cours des maladies neurodégénératives, l'hypothèse selon laquelle une atteinte du renouvellement neuronal participerait à la déplétion neuronale est actuellement envisagée. Nous avons voulu explorer cette piste en testant l'effet de peptides amyloïdes PrP et A-beta sur la survie et les capacités de prolifération de cellules souches embryonnaires murines.Transmissible subacute encephalopathies (TSE)are neurodegenerative disorders that are characterized by the accumulation of an abnormal misfolded isoform (PrPsc) of the host encoded prion protein (PrPc). We studied mechanisms leading to TSE neurodegeneration by three different approaches: 1) We used neuronal cultures of embryonic cortices to study the toxicity of peptides corresponding to the putative transmembrane domain of PrPc. These peptides induced neuronal apoptosis in vitro. Molecular modeling showed that the propensity of these peptides to insert stably into and to destabilize cell membranes could explained their neurotoxic properties. 2) PrPc plays a central role in TSE induced neurodegeneration. A loss of normal PrPc function could explain neuronal death. Therefore, to better understand normal PrPc function and thus the neurogegenerative process involved in TSE, it appears of crucial interest to characterize a PrPc receptor at the membrane. An interaction between PrPc and the precursor of the 67 kD laminine receptor (LRP) has been previously reported. In this study, we showed that 1) PrPc cell binding was LRP dependent 2) part of PrPc was internalised after LRP binding 3) PrPc had two distinct interaction domains with LRP 4) different isoforms of LRP were present in mammalian brains and are able to bind PrPc. 3) A very long incubation period precedes disease onset in TSE. Neuroregeneration in the adult brain of primates have been recently described. It has been proposed that neuroregeneration injuries could contribute to the process leading to the neuronal loss observed in neurodegenerative disorders such as Alzheimer disease and TSE. We investigated this hypothesis by studying the effect of A-beta and PrP amyloid peptides on survival and proliferation of neural precursor cells from embryonic mice cortices.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF