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Adiko A.C.,French Institute of Health and Medical Research | Adiko A.C.,University Paris Diderot | Babdor J.,French Institute of Health and Medical Research | Babdor J.,University of Paris Descartes | And 5 more authors.
Frontiers in Immunology | Year: 2015

Cross-presentation, in which exogenous antigens are presented via MHC I complexes, is involved both in the generation of anti-infectious and anti-tumoral cytotoxic CD8+ T cells and in the maintenance of immune tolerance. While cross-presentation was described almost four decades ago and while it is now established that some dendritic cell (DC) subsets are better than others in processing and cross-presenting internalized antigens, the involved molecular mechanisms remain only partially understood. Some of the least explored molecular mechanisms in cross-presentation concern the origin of cross-presenting MHC I molecules and the cellular compartments where antigenic peptide loading occurs. This review focuses on MHC I molecules and their intracellular trafficking. We discuss the source of cross-presenting MHC I in DCs as well as the role of the endocytic pathway in their recycling from the cell surface. Next, we describe the importance of the TAP peptide transporter for delivering peptides to MHC I during cross-presentation. Finally, we highlight the impact of innate immunity mechanisms on specific antigen cross-presentation mechanisms in which TLR activation modulates MHC I trafficking and TAP localization. © 2015 Adiko, Babdor, Gutiérrez-Martínez, Guermonprez and Saveanu.


Moriniere V.,APHP | Moriniere V.,Reference Center for Renal Hereditary Disease for Children and Adults | Dahan K.,Institute of Pathology and Genetics | Hilbert P.,Institute of Pathology and Genetics | And 17 more authors.
Journal of the American Society of Nephrology | Year: 2014

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15%and 1% - 5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appearmore frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome. Copyright © 2014 by the American Society of Nephrology.


PubMed | IMAGINE Institute, University of Lausanne, Charité - Medical University of Berlin, University of California at Los Angeles and 8 more.
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

The purpose of the nosology is to serve as a master list of the genetic disorders of the skeleton to facilitate diagnosis and to help delineate variant or newly recognized conditions. This is the 9th edition of the nosology and in comparison with its predecessor there are fewer conditions but many new genes. In previous editions, diagnoses that were phenotypically indistinguishable but genetically heterogenous were listed separately but we felt this was an unnecessary distinction. Thus the overall number of disorders has decreased from 456 to 436 but the number of groups has increased to 42 and the number of genes to 364. The nosology may become increasingly important today and tomorrow in the era of big data when the question for the geneticist is often whether a mutation identified by next generation sequencing technology in a particular gene can explain the clinical and radiological phenotype of their patient. This can be particularly difficult to answer conclusively in the prenatal setting. Personalized medicine emphasizes the importance of tailoring diagnosis and therapy to the individual but for our patients with rare skeletal disorders, the importance of tapping into a resource where genetic data can be centralized and made available should not be forgotten or underestimated. The nosology can also serve as a reference for the creation of locus-specific databases that are expected to help in delineating genotype-phenotype correlations and to harbor the information that will be gained by combining clinical observations and next generation sequencing results.


PubMed | Imagine Institute, University of the Republic of Uruguay, Institute Investigaciones Biologicas Clemente Estable, AB Science and 3 more.
Type: Journal Article | Journal: Journal of neuroinflammation | Year: 2016

In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30mg/kg/day starting after paralysis onset.We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7days after paralysis onset prolonged post-paralysis survival by 40%.These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.


Kurowska M.,Laboratoire du Developpement Normal et Pathologique du Systeme Immunitaire | Kurowska M.,University of Paris Descartes | Kurowska M.,Imagine Institute | Goudin N.,University of Paris Descartes | And 19 more authors.
Blood | Year: 2012

Cytotoxic T lymphocytes kill target cells via the polarized secretion of cytotoxic granules at the immune synapse. The lytic granules are initially recruited around the polarized microtubule-organizing center. In a dynein-dependent transport process, the granules move along micro-tubules toward the microtubule-organizing center in the minus-end direction. Here, we found that a kinesin-1-dependent process is required for terminal transport and secretion of polarized lytic granule to the immune synapse. We show that synaptotagmin-like protein 3 (Slp3) is an effector of Rab27a in cytotoxic T lymphocytes and interacts with kinesin-1 through the tetratricopeptide repeat of the kinesin-1 light chain. Inhibition of the Rab27a/Slp3/kinesin-1 transport complex impairs lytic granule secretion. Our data provide further molecular insights into the key functional and regulatory mechanisms underlying the terminal transport of cytotoxic granules and the latter's secretion at the immune synapse. © 2012 by The American Society of Hematology.


Dittmann M.,Rockefeller University | Hoffmann H.-H.,Rockefeller University | Scull M.A.,Rockefeller University | Gilmore R.H.,Rockefeller University | And 16 more authors.
Cell | Year: 2015

Interferon-stimulated genes (ISGs) act in concert to provide a tight barrier against viruses. Recent studies have shed light on the contribution of individual ISG effectors to the antiviral state, but most have examined those acting on early, intracellular stages of the viral life cycle. Here, we applied an image-based screen to identify ISGs inhibiting late stages of influenza A virus (IAV) infection. We unraveled a directly antiviral function for the gene SERPINE1, encoding plasminogen activator inhibitor 1 (PAI-1). By targeting extracellular airway proteases, PAI-1 inhibits IAV glycoprotein cleavage, thereby reducing infectivity of progeny viruses. This was biologically relevant for IAV restriction in vivo. Further, partial PAI-1 deficiency, attributable to a polymorphism in human SERPINE1, conferred increased susceptibility to IAV in vitro. Together, our findings reveal that manipulating the extracellular environment to inhibit the last step in a virus life cycle is an important mechanism of the antiviral response. © 2015 Elsevier Inc. All rights reserved.


Bader-Meunier B.,Necker Hospital | Bader-Meunier B.,French Institute of Health and Medical Research | Bader-Meunier B.,Imagine Institute | Fraitag S.,Necker Hospital | And 8 more authors.
Pediatrics | Year: 2013

Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis in childhood, associated either with nonmalignant conditions or with subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and often also associated with macrophage activation syndrome (MAS). Discriminating between these 2 conditions is therapeutically important because nonmalignant CHP often improves under cyclosporine and prednisone, whereas most cases of SPLT may be best treated with more aggressive therapy. We report the cases of a 6-month-old boy and a 16-month-old girl who, after viral infection, developed multiple infiltrating skin nodules on the limbs and face, associated with MAS. Histopathologic findings for skin biopsy specimens revealed CHP associated with heavily cellular lobular panniculitis. Hemophagocytosis and immunohistochemical staining features were consistent with typical characteristics of in situ MAS in adipose tissue: the lymphocytes were mostly TCD8+ cells with an activated phenotype (human leukocyte antigen (HLA) -DR+) and expressed interferon-g; CD68+ macrophages expressed tumor necrosis factor-A and interleukin-6. A monoclonal rearrangement of the T-cell receptor g gene was present in skin tissue but not in peripheral blood or bone marrow lymphocytes. Cyclosporine A treatment resulted in the complete remission of cutaneous and systemic manifestations in both patients for 66 and 29 months, respectively. This report suggests that the diagnosis of a reactive T-cell lymphoproliferation should be the treatment of choice in young children with severe CHP, even if there is a SPTCL-like aspect with an in situ T-cell clonality. It also suggests that CSA is the optimal treatment of this condition and postulates the possible pathologic process underlying this efficacy. Pediatrics 2013;132:e545-e549 Copyright © 2013 by the American Academy of Pediatrics.


PubMed | Imagine Institute, National Research Council Italy, University of Modena and Reggio Emilia and Dana-Farber Cancer Institute
Type: Journal Article | Journal: Stem cell reports | Year: 2016

Human skin is maintained by the differentiation and maturation of interfollicular stem and progenitors cells. We used DeepCAGE, genome-wide profiling of histone modifications and retroviral integration analysis, to map transcripts, promoters, enhancers, and super-enhancers (SEs) in prospectively isolated keratinocytes and transit-amplifying progenitors, and retrospectively defined keratinocyte stem cells. We show that >95% of the active promoters are in common and differentially regulated in progenitors and differentiated keratinocytes, while approximately half of the enhancers and SEs are stage specific and account for most of the epigenetic changes occurring during differentiation. Transcription factor (TF) motif identification and correlation with TF binding site maps allowed the identification of TF circuitries acting on enhancers and SEs during differentiation. Overall, our study provides a broad, genome-wide description of chromatin dynamics and differential enhancer and promoter usage during epithelial differentiation, and describes a novel approach to identify active regulatory elements in rare stem cell populations.


PubMed | Imagine Institute, Pediatric Endocrinology, Pediatric Noninvasive Ventilation and Sleep Unit and University of Paris Descartes
Type: | Journal: Sleep medicine | Year: 2016

Central sleep apnea (CSA) syndromes are rare in children and data in children over one year of age are scarce. The aim of the study was to describe the sleep characteristics, underlying disorders, management, and outcome of children with CSA.A retrospective chart review of all children >1 year of age, diagnosed with CSA on a laboratory sleep study during a 20-month period, was performed. CSA was defined by a central apnea index (CAI)>5events/h. The clinical management and the patients outcome were analyzed.Eighteen of 441 (4.1%) patients recorded during the study period had CSA. The median CAI, pulse oximetry, and oxygen desaturation index were 13/h (range 6-146), 96% (93-98%), and 18/h (6-98), respectively. Neurosurgical pathologies represented the most common underlying disorders with Arnold-Chiari malformation in four and ganglioglioma in three patients. Other underlying disorders were Prader-Willi syndrome (N=3), achondroplasia (N=2), and Down syndrome, with one patient having an achondroplasia and a Down syndrome. The remaining six patients had other genetic diseases. The most common investigation was brain magnetic resonance imaging (MRI). Individualized management with neurosurgery and/or chemotherapy, continuous positive airway pressure (in two patients having associated obstructive events), or noninvasive ventilation resulted in an improvement in CSA and the clinical presentation in 11 patients.CSA is rare in children >1 year of age. Underlying disorders are dominated by neurosurgical disorders. Individualized management is able to improve CSA and the clinical condition in most patients.


PubMed | Imagine Institute, French Institute of Health and Medical Research and University of Paris Descartes
Type: | Journal: Molecular & cellular proteomics : MCP | Year: 2017

Cystinosis is a rare autosomal recessive lysosomal storage disorder characterized by intralysosomal accumulation of cystine. The causative gene for cystinosis is CTNS, which encodes the protein cystinosin, a lysosomal proton-driven cystine transporter. Over 100 mutations have been reported, leading to varying disease severity, often in correlation with residual cystinosin activity as a transporter and with maintenance of its protein-protein interactions. In this study, we focus on the ITILELP mutation, the only mutation reported that sometimes leads to severe forms, inconsistent with its residual transported activity. ITILELP is a deletion that eliminates a consensus site on N66, one of the protein seven glycosylation sites. Our hypothesis was that the ITILELP mutant is less stable and undergoes faster degradation. Our dynamic SILAC study clearly showed that wild-type cystinosin is very stable, while ITILELP is degraded three times more rapidly. Additional lysosome inhibition experiments confirmed ITILELP instability and showed that the degradation was mainly lysosomal. We observed that in the lysosome, ITILELP is still capable of interacting with the V-ATPase complex and some members of the mTOR pathway, similar to the wild-type protein. Intriguingly, our interactomic and immunofluorescence studies showed that ITILELP is partially retained at the endoplasmic reticulum (ER). We proposed that the ITILELP mutation causes protein misfolding, ER retention and inability to be processed in the Golgi apparatus, and we demonstrated that ITILELP carries high-mannose glycans on all six of its remaining glycosylation sites. We found that the high turnover of ITILELP, due to its immature glycosylation state in combination with low transport activity, might be responsible for the phenotype observed in some patients. Data are available via ProteomeXchange with identifier PXD004948, PXD005357 and on Panorama Public at https://panoramaweb.org/labkey/Guerrera.url.

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