Pattern of DAP12 Expression in Leukocytes from Both Healthy and Systemic Lupus Erythematosus Patients

DAP12 is an ITAM-bearing transmembrane adaptor originally identified on the surface of Natural Killer cells. A broad expression among other immune cells was later found in myeloid and lymphoid cells. However, data on DAP12 expression pattern rely only on immunoblot and microarray analysis. Here, we describe the generation and the characterization of an anti-DAP12 monoclonal antibody. Using this novel reagent, we show that DAP12 expression is restricted to innate immune cells in basal condition. Since a decreased expression of DAP12 has been suggested in NK cells of systemic lupus erythematosus patients, we have further investigated the NK cell receptor repertoire and leukocyte expression of DAP12 in these patients and no major changes were detectable when compared to controls

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Investigation of the regulatory mechanisms of natural killer cell activation

Les cellules Natural Killer (NK) sont des cellules lymphoïdes innées cytotoxiques impliquées dans la réponse anti-microbienne et anti-tumorale. Elles distinguent les cellules saines des cellules stressées grâce à des récepteurs de surface inhibiteurs et activateurs, dont l’engagement conditionne l’activation des fonctions effectrices.Nous avons d’abord mesuré les capacités effectrices des cellules NK de patients présentant des déficiences pour le récepteur à l’IL-12 et montré que l’IL-12 participe à l’acquisition des réponses effectrices des cellules NK chez l’Homme. Nous avons aussi étudié les mécanismes de tolérance en combinant des modèles murins à l’analyse de la mobilité latérale des récepteurs de surface des cellules NK. Dans les cellules NK non éduquées, nous avons observé que les récepteurs activateurs sont confinés dans un réseau d’actine, peu propice à l’activation, qui conduit à l’hyporéactivité. Cette organisation des récepteurs activateurs constitue un mécanisme fondamental de la tolérance. Nous avons également conçu un essai clinique de phase I pour évaluer la sécurité d'une perfusion de cellules NK activées par l'IL-2 chez des patients atteints d'hémopathies malignes. Cet essai montre des résultats encourageants chez les patients traités. Enfin, nous travaillons à identifier des ligands tumoraux des récepteurs activateurs NKp44 et NKp46 exprimés par les cellules NK. Nous avons réalisé un crible fonctionnel basé sur la résistance à la lyse des cellules cibles mutantes par les cellules NK. La collection de mutants a été générée par une librairie pan-génomique de guides ARN CRISPR/Cas9. Les gènes candidats sont en cours d’évaluation.Natural Killer (NK) cells are cytotoxic innate lymphoid cells involved in the anti-microbial and anti-tumor response. They distinguish the healthy cells from stressed cells through a set of inhibitory and activating surface receptors, whose engagement conditions the activation of their effector functions.We first measured the effector capacities of NK cells from patients with IL-12 receptor deficiencies and showed that IL-12 is involved in the acquisition of effector responses of NK cells in humans. We also studied the mechanisms of tolerance by combining mouse models with the analysis of the lateral mobility of NK cell surface receptors. In uneducated NK cells, we observed that the activating receptors are confined in an actin network, which is not very conducive to activation and leads to hyporeactivity. This organization of activating receptors is a fundamental mechanism of tolerance. We have also designed a Phase I clinical trial to evaluate the safety of an infusion of IL-2 activated NK cells in patients with hematological malignancies. This trial is showing encouraging results in treated patients. Finally, we are working to identify tumor ligands for the activating receptors NKp44 and NKp46 expressed by NK cells. We performed a functional screen based on the resistance to lysis of mutant target cells by NK cells. The mutant collection was generated by a pan-genomic CRISPR/Cas9 library. Candidate genes identified as a tumor ligand of NKp44 are being evaluated

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Helper-like Innate Lymphoid Cells in Humans and Mice

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Die Politik der Entwicklungszusammenarbeit

Nach den Impulsen des Gipfels von Fontainebleau im Jahr 1984 und dem Amtsantritt von Jacques Delors, der sich auf eine wiedererstarkte deutsch-französische Allianz stützen konnte, beschleunigte sich der europäische Integrationsprozess rasch. Die Kommission war der Motor dieses Integrationsprozesses. Unter Jacques Delors wurden drei große Projekte angestoßen: die Vollendung des Binnenmarkts, die Wirtschas- und Währungsunion und die Öffnung der Gemeinschaft für die Länder Mittel- und Osteuropas nach dem Fall der Berliner Mauer. Unter Jacques Santer und Romano Prodi hat die Kommission die Umsetzung dieser Vorhaben betrieben bzw. ihre Fortführung gewährleistet. Sie führte die Verhandlungen sowohl zur Errichtung der Wirtschas- und Währungsunion als auch zur Vorbereitung der größten Erweiterung in der Geschichte der Union und trieb die Vertiefung sowie die Überlegungen über die Weiterentwicklung der europäischen Institutionenlandscha angesichts des Beitritts neuer Mitgliedstaaten voran. Auch wurden neue Verträge geschlossen, mit denen die Kompetenzen der Gemeinscha erheblich ausgeweitet wurden. Aber die Schwierigkeiten bei der Ratifizierung des Vertrags von Maastricht zeigten auch, dass um die öff entliche Meinung geworben werden musste und die Gemeinscha über ihre Anliegen besser und nachhaltiger in der Öffentlichkeit informieren musste. 52 Professoren und Forscher von über 30 Universitäten oder Forschungszentren in Europa, den Vereinigten Staaten und 15 weiteren Ländern haben an diesem Band mitgearbeitet. Dabei hatten sie Zugang zu bislang unveröff entlichtem Archivmaterial der Kommission. Darüber hinaus wurden zahlreiche Zeitzeugen befragt, unter ihnen ehemalige Beamte, Mitglieder und Präsidenten der Kommission. All diese unveröffentlichten mündlichen oder schrilichen Quellen ergaben eine reichhaltige Dokumentation, die es den Forschern erlaubte, die Tätigkeit der Kommission in den Jahren 1986-2000 in neuem Licht zu sehen. Die Veröff entlichung der beiden ersten Bände dieser Reihe, die den Jahren 1958-1972 bzw. 1973-1986 gewidmet sind, war das Ergebnis ähnlicher Forschungsprojekte. Das vorliegende Werk ist der dritte Band einer Reihe. Band 1, Die Europäische Kommission 1958-1972 – Geschichte und Erinnerungen einer Institution, wurde 2007 veröffentlicht, Band 2, Die Europäische Kommission 1973-1986 – Geschichte und Erinnerungen einer Institution, folgte im Jahr 2014. Dem ging eine Ausschreibung der Kommission voraus, deren Gegenstand diesmal die Untersuchung der Jahre 1986-2000 wa

La politique de coopération au développement

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