Institute National Of La Sante Et Of La Recherche Medicale

La Chaux-de-Fonds, Switzerland

Institute National Of La Sante Et Of La Recherche Medicale

La Chaux-de-Fonds, Switzerland
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Falace A.,University of Genoa | Falace A.,Institute National Of La Sante Et Of La Recherche Medicale | Buhler E.,Institute National Of La Sante Et Of La Recherche Medicale | Buhler E.,Aix - Marseille University | And 19 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.

Araujo L.M.,French National Center for Scientific Research | Araujo L.M.,University of Paris Descartes | Chauvineau A.,University of Poitiers | Chauvineau A.,French Institute of Health and Medical Research | And 28 more authors.
Journal of Immunology | Year: 2011

Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide- induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA-/- mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI. Copyright © 2011 by The American Association of Immunologists, Inc.

Ouederni M.,Pediatric Hematology Immunology Unit | Ouederni M.,Tunis el Manar University | Sanal O.,Ankara University | Ikinciogullari A.,Hacettepe University | And 51 more authors.
Clinical Infectious Diseases | Year: 2014

Background. Interleukin 12Rβ1 (IL-12Rβ1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rβ1 deficiency.Results. Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin.Conclusions. Patients who are deficient in IL-12Rβ1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients. © The Author 2013.

Fava V.M.,McGill University | Cobat A.,McGill University | Van Thuc N.,Hospital for Dermato Venerology | Latini A.C.P.,Lauro Of Souza Lima Institute | And 15 more authors.
Journal of Infectious Diseases | Year: 2015

Background. Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R. Methods. We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects. Results. In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R. Conclusions. Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Beurze S.M.,Radboud University Nijmegen | Toni I.,Radboud University Nijmegen | Pisella L.,Institute National Of La Sante Et Of La Recherche Medicale | Pisella L.,University Claude Bernard Lyon 1 | Medendorp W.P.,Radboud University Nijmegen
Journal of Neurophysiology | Year: 2010

To plan a reaching movement, the brain must integrate information about the spatial goal of the reach with positional information about the selected hand. Recent monkey neurophysiological evidence suggests that a mixture of reference frames is involved in this process. Here, using 3T functional magnetic resonance imaging (fMRI), we tested the role of gaze-centered and body-centered reference frames in reach planning in the human brain. Fourteen human subjects planned and executed arm movements to memorized visual targets, while hand starting position and gaze direction were monitored and varied on a trial-by-trial basis. We further introduced a variable delay between target presentation and movement onset to dissociate cerebral preparatory activity from stimulus- and movement-related responses. By varying the position of the target and hand relative to the gaze line, we distinguished cerebral responses that increased for those movements requiring the integration of peripheral target and hand positions in a gaze-centered frame. Posterior parietal and dorsal premotor areas showed such gaze-centered integration effects. In regions closer to the primary motor cortex, body-centered hand position effects were found. These results suggest that, in humans, spatially contiguous neuronal populations operate in different frames of reference, supporting sensorimotor transformations according to gaze-centered or body-centered coordinates. The former appears suited for calculating a difference vector between target and hand location, whereas the latter may be related to the implementation of a joint-based motor command. Copyright © 2010 The American Physiological Society.

Nebor D.,Institute National Of La Sante Et Of La Recherche Medicale | Nebor D.,CEA DAM Ile-de-France | Nebor D.,University Antilles Guyane | Bowers A.,University of the West Indies | And 19 more authors.
PLoS ONE | Year: 2014

High plasma level of microparticles (MPs) deriving mainly from erythrocytes and platelets has been detected in sickle cell anemia (SCA) patients. Flow cytometry was used to determine the concentration of MPs in two groups of SCA patients exhibiting marked differences in painful vaso-occlusive crisis rates [a non-severe group (n = 17) and a severe group (n = 12)], and in a control group composed of healthy subjects (n = 20). A 3- to 4-fold increase of total MP plasma concentration was detected in SCA patients. Higher platelet-derived MPs concentration was detected in the severe SCA group while erythrocyte-derived MPs concentration was increased in the non-severe SCA patient group only. Our results suggest that plasma concentration of MPs shed by platelets is a biomarker of the vaso-occlusive phenotype-related severity. © 2014 Nebor et al.

Van Maele L.,Institute Pasteur Of Lille | Van Maele L.,Institute National Of La Sante Et Of La Recherche Medicale | Van Maele L.,French National Center for Scientific Research | Van Maele L.,University of Lille Nord de France | And 39 more authors.
Journal of Infectious Diseases | Year: 2014

Mucosal sites are continuously exposed to pathogenic microorganisms and are therefore equipped to control respiratory infections. Type 3 innate lymphoid cells (ILC3) are key players in antimicrobial defense in intestinal mucosa, through interleukin 17 and interleukin 22 (IL-22) production. The present study aimed at analyzing the distribution and function of ILC3 in the respiratory tract. We first observed that lung mucosa harbors a discrete population of ILC3 expressing CD127, CD90, CCR6, and the transcriptional factor RORγt. In addition, lung ILC3 were identified as a major source of IL-22 in response to interleukin 23 stimulation. During Streptococcus pneumoniae infection, ILC3 rapidly accumulated in the lung tissue to produce IL-22. In response to S. pneumoniae, dendritic cells and MyD88, an important adaptor of innate immunity, play critical functions in IL-22 production by ILC3. Finally, administration of the Toll-like receptor 5 agonist flagellin during S. pneumoniae challenge exacerbated IL-22 production by ILC3, a process that protects against lethal infection. In conclusion, boosting lung ILC3 might represent an interesting strategy to fight respiratory bacterial infections. © The Author 2014.

Fauriat C.,Institute National Of La Sante Et Of La Recherche Medicale | Olive D.,Institute National Of La Sante Et Of La Recherche Medicale
Blood | Year: 2014

In this issue of Blood, Nanbakhsh et al show that leukemic cell lines rendered resistant to cytarabine display a higher expression of the natural killer (NK) group 2, member D (NKG2D) ligands (NKG2DL) UL-16 binding proteins 1-3 (ULBP1-3). This expression is c-Myc dependent as it is abrogated by c-Myc inhibitors or small interfering RNA. Consequently, upregulation of NKG2DL renders the cell lines more sensitive to NK-cell-mediated lysis. © 2014 by The American Society of Hematology.

PubMed | Institute National Of La Sante Et Of La Recherche Medicale
Type: | Journal: Emerging health threats journal | Year: 2013

Should an emerging infectious disease outbreak or an environmental disaster occur, the collection of epidemiological data must start as soon as possible after the events onset. Questionnaires are usually built de novo for each event, resulting in substantially delayed epidemiological responses that are detrimental to the understanding and control of the event considered. Moreover, the public health and/or academic institution databases constructed with responses to different questionnaires are usually difficult to merge, impairing necessary collaborations. We aimed to show that e-commerce concepts and software tools can be readily adapted to enable rapid collection of data after an infectious disease outbreak or environmental disaster. Here, the customers are the epidemiologists, who fill their shopping baskets with standardised questions.For each epidemiological field, a catalogue of questions is constituted by identifying the relevant variables based on a review of the published literature on similar circumstances. Each question is tagged with information on its source papers. Epidemiologists can then tailor their own questionnaires by choosing appropriate questions from this catalogue. The software immediately provides them with ready-to-use forms and online questionnaires. All databases constituted by the different EpiBasket users are interoperable, because the corresponding questionnaires are derived from the same corpus of questions.A proof-of-concept prototype was developed for Knowledge, Attitudes and Practice (KAP) surveys, which is one of the fields of the epidemiological investigation frequently explored during, or after, an outbreak or environmental disaster. The catalogue of questions was initiated from a review of the KAP studies conducted during or after the 2003 severe acute respiratory syndrome epidemic.Rapid collection of standardised data after an outbreak or environmental disaster can be facilitated by transposing the e-commerce paradigm to epidemiology, taking advantage of the powerful software tools already available.

PubMed | CNRS Institute of Pharmacology and Structural Biology, University of Nantes and Institute National Of La Sante Et Of La Recherche Medicale
Type: Journal Article | Journal: Journal of immunology (Baltimore, Md. : 1950) | Year: 2014

The structural rules governing peptide/MHC (pMHC) recognition by T cells remain unclear. To address this question, we performed a structural characterization of several HLA-A2/peptide complexes and assessed in parallel their antigenicity, by analyzing the frequency of the corresponding Ag-specific naive T cells in A2(+) and A2(-) individuals, as well as within CD4(+) and CD8(+) subsets. We were able to find a correlation between specific naive T cell frequency and peptide solvent accessibility and/or mobility for a subset of moderately prominent peptides. However, one single structural parameter of the pMHC complexes could not be identified to explain each peptide antigenicity. Enhanced pMHC antigenicity was associated with both highly biased TRAV usage, possibly reflecting favored interaction between particular pMHC complexes and germline TRAV loops, and peptide structural features allowing interactions with a broad range of permissive CDR3 loops. In this context of constrained TCR docking mode, an optimal peptide solvent exposed surface leading to an optimal complementarity with TCR interface may constitute one of the key features leading to high frequency of specific T cells. Altogether our results suggest that frequency of specific T cells depends on the fine-tuning of several parameters, the structural determinants governing TCR-pMHC interaction being just one of them.

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