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CLEC12B glycan array
No full textWe performed mammalian and microbial glycan arrays to identify CLEC12B ligand(s)
Role of CLEC12B in skin immunity
No full textCLEC12B a été identifié pour la première fois comme étant un récepteur inhibiteur exprimé par les cellules myéloïdes qui neutralise la cytotoxicité médiée par les cellules NK. CLEC12B est un récepteur de lectine de type C (CLR) possédant un domaine ITIM, mais dont la signalisation en aval et le ou les ligands restent en grande partie inconnus. Au cours des 30 dernières années, une fonction de présentation d'antigène des mélanocytes a émergé en raison de leur nature dendritique, de leur position stratégique dans la peau et de leur capacité phagocytaire. Dans un contexte de vitiligo, notre équipe a montré que l'activation de CXCR3B, le récepteur des chimiokines immunitaires CXCL9, CXCL10 et CXCL11, induit l'apoptose des mélanocytes humains en culture. Les mélanocytes restants, activés par la production d'IFNγ, expriment des marqueurs de costimulation, déclenchant ainsi la prolifération des lymphocytes T et l'immunité anti-mélanocytaire qui en résulte. De récents résultats de notre équipe ont montré que CLEC12B est principalement exprimé par les mélanocytes humains et joue un rôle important dans la régulation de la pigmentation cutanée, mais également dans la prolifération du mélanome.Dans ce projet, nous avons cherché à déterminer le rôle de CLEC12B dans l'immunité de la peau en utilisant des mélanocytes humains primaires provenant de donneurs sains. Nous démontrons ici que CLEC12B est essentiel à la production d'IFNγ et des chimiokines innées CXCL9, CXCL10 et CXCL11 par les mélanocytes, comme le montre la modulation de l'expression de CLEC12B à l'aide de techniques de surexpression ou d'extinction génique. Cette régulation se fait via la phosphorylation du domaine ITIM de CLEC12B, comme le montre la forme mutée du gène CLEC12B. De plus, CLEC12B peut non seulement moduler la production de chimiokines mélanocytaires, mais il est également capable d'augmenter directement le chimiotactisme des cellules immunitaires de la peau et donc de déclencher une immunité adaptative à long terme. D'un point de vue signalisation, nous montrons que CLEC12B module la voie de signalisation de l'IFNγ via l'axe STAT1/IRF1. De plus, CLEC12B potentialise l'effet de l'IFNγ dans les mélanocytes activés, induisant ainsi une plus grande production de chimiokines innées et in fine une plus grande chimio-attraction des cellules immunitaires. Nous avons également démontré que CLEC12B interagit directement avec Staphylococcus aureus et Escherichia coli et module une réponse immunitaire innée contre ces bactéries opportunistes présentes sur la peau via l'axe STAT1/IRF1/CXCL9. Enfin, nous avons montré que CLEC12B détecte des motifs présents sur les mélanocytes, les fibroblastes et les macrophages pro- et anti-inflammatoires, mais son ou ses ligands restent encore à être identifiés. Dans l'ensemble, ces résultats démontrent que CLEC12B est un acteur important dans l'immunité cutanée innée en modulant la production d'IFNγ et de chimiokines immunitaires, mais également dans l'immunité adaptative en modulant le chimiotactisme des cellules immunitaires via la phosphorylation de son domaine ITIM. Ce mécanisme présente un grand intérêt car l'IFNγ et le recrutement de cellules immunitaires sont des étapes initiales clés impliquées dans l'inflammation de nombreuses pathologies de la peau, faisant de ce récepteur une cible thérapeutique intéressante pour le traitement de maladies infectieuses, des troubles cutanés inflammatoires et pigmentaires, ainsi que du cancer ; tout cela pouvant être directement immuno-régulé par CLEC12B dans les mélanocytes. Cette nouvelle perspective prometteuse reste encore à être testée dans de futures études.CLEC12B was first identified as an inhibitory receptor on myeloid cells that counteracts NK cells-mediated cytotoxicity. CLEC12B is a C-type Lectin Receptor (CLR) which possesses an ITIM domain, but ligand and downstream signaling are largely unknown. Over the past 30 years, an antigen-presenting function of melanocytes has emerged due to their dendritic nature, their strategic position in the skin and their phagocytic capacity. In a vitiligo context, our team has shown that CXCR3B activation, the receptor for immune chemokines CXCL9, CXCL10 and CXCL11, induces apoptosis of cultured human melanocytes. The remaining melanocytes, activated by the IFNγ production, express co-stimulatory markers which trigger T cell proliferation and subsequent anti-melanocytic immunity. Recent results from our team have shown that CLEC12B is mainly expressed in human melanocytes and plays an important role in the regulation of skin pigmentation, but also in melanoma proliferation.In this project, we set out to determine the role of CLEC12B in skin immunity using primary human melanocytes from healthy donors. We demonstrate that CLEC12B is critical in production of IFNγ and innate chemokines CXCL9, CXCL10 and CXCL11 by melanocytes, as shown by our regulation of CLEC12B expression using silencing or overexpression techniques. This regulation was driven by the phosphorylation of CLEC12B's ITIM domain as shown using CLEC12B mutated form of the gene. Furthermore, not only can CLEC12B drive melanocyte chemokine production, but it is also capable of directly increase chemoattraction of immune cells in the skin and therefore trigger a long-term adaptative immunity. From a signaling point of view, we show that CLEC12B modulates IFNγ signaling pathway through the STAT1/IRF1 axis. Moreover, CLEC12B potentiates the effect of IFNγ in primed melanocytes, thus inducing a larger production of innate chemokines and subsequent greater chemoattraction of immune cells. In addition, we have demonstrated that CLEC12B directly interacts with Staphylococcus aureus and Escherichia coli and modulates an innate immune response against these opportunistic bacteria found on the skin through the STAT1/IRF1/CXCL9 axis. Finally, we have shown that CLEC12B senses motifs present on melanocytes, fibroblasts, and both pro- and anti-inflammatory macrophages, but its exact ligand(s) still remains to be identified. Together, these results demonstrate that CLEC12B is an important player in innate skin immunity by modulating the production of IFNγ and immune chemokines, and in adaptative immunity by modulating the migration ability of immune cells through the phosphorylation of its ITIM domain. This mechanism is of great interest as IFNγ and cellular recruitment are key initial steps involved in inflammation of many skin pathologies, making this receptor an interesting therapeutic target for the treatment of infectious diseases, inflammatory and pigmentary skin disorders, as well as cancer; all which may be able to be directly immuneregulated by CLEC12B on melanocytes. This exciting novel prospect remains to be tested in future studies
Impact of microbiota and its constituent house dust mite (HDM) in Vitiligo skin
No full textLe vitiligo est une dermatose chronique qui induit des dépigmentations acquises de la peau et des poils en entrainant la perte des mélanocytes. Elle affecte environ 0,5 à 2 % de la population mondiale. La pathogénie du vitiligo est complexe. La destruction des mélanocytes par les cellules de l'immunité adaptives est aujourd'hui bien connue. Plus récemment le rôle clef de l'immunité innée mais aussi la perturbation des jonctions au niveau de l'épiderme qui cause un détachement des mélanocytes de la jonction épidermique, ont été mis en évidence. Cependant, les facteurs responsables de ce détachement sont actuellement inconnus. De plus nous savons que des facteurs environnementaux pourraient être aussi impliqués dans l'initiation ou l'exacerbation de cette maladie. En se basant sur ces données et dans le but de trouver de nouvelles cibles thérapeutiques, nous avons comparé le microbiote des patients vitiligo (peau et selles) au microbiote des patients sains et examiné l'implication des facteurs environnementaux « les acariens » dans cette maladie.Dans la première partie de notre étude nous avons obtenu des swabs et des biopsies de la peau lésionnelle et non lésionnelle ainsi que des échantillons de selles et de sang de chaque individu. Nous avons détecté une richesse et une diversité réduite du microbiote dans les selles des patients vitiligo par rapport aux sujets sains. Les swabs cutanés présentaient une plus grande diversité que les biopsies. Les swabs des sites lésionnels étaient principalement appauvris en Staphylococcus par rapport à ceux des sites non lésionnels. L'échantillonnage des couches plus profondes des mêmes patients a montré des différences de diversité α et β entre les échantillons avec diminution de la richesse et de la distribution des espèces dans le site lésionnel. Le microbiote des biopsies de la peau lésionnelle avait une composition distincte, qui était appauvrie en bactéries commensales Bifidobacterium et Bacteroides mais était enrichi en Proteobacteria, Streptococcus, Mycoplasma et mtDNA. Ce dernier augmenté chez les patients avec une immunité innée accrue et des marqueurs de stress dans leur sang.Ces données établissent un lien entre la dysbiose cutanée, les lésions mitochondriales et l'immunité chez les patients atteints de vitiligo.Ensuite, étant donné l'importance des facteurs environnementaux dans le vitiligo, nous nous sommes intéressés à la contribution des acariens (HDM), qui sont des allergènes environnementaux avec une puissante activité protéasique, au détachement des mélanocytes dans le vitiligo. Nous avons montré pour la première fois la présence de Der p1 (allergène majeur de HDM) dans la peau vitiligo. HDM induit une réponse immunitaire de type Th1 Th2 dans les kératinocytes en culture et provoque le clivage spécific de E-cadherine par Der p1, les cysteines protéases et MMP-9. L'inhibition de MMP-9 ou cysteine protéases par E64 restaure l'expression de E-cadherine et inhibe le détachement des mélanocytes. Ces résultats ont été confirmées à l'aide d'un modèle de peau 3D et ex vivo dans les biopsies humaines. Nous rapportons aussi une augmentation du détachement des mélanocytes et de Der p1 dans la peau vitiligo par rapport à une peau saine, ainsi qu'une augmentation de la E-cadhérine soluble dans les biopsies cutanées en culture en présence de HDM. Ensemble, ces résultats mettent en évidence la contribution de HDM dans la perte de mélanocytes chez les personnes ayant une peau fragile et/ou prédisposés génétiquement.En résumé, nos travaux mettent en évidence des facteurs environnementaux potentiellement clefs dans le déclenchement et la progression du vitiligo. Ils ouvrent des perspectives thérapeutiques totalement innovantes.Vitiligo is a chronic dermatosis that induces acquired depigmentation of the skin and hair by loss of melanin-producing cells called melanocytes. It affects approximately 0.5 to 2% of the world population. The pathogenesis of vitiligo is complex. The destruction of melanocytes by adaptive immune cells is now well known. More recently, the key role of innate immunity and the disruption of epidermal junctions, which causes melanocyte detachment from the epidermal junction, have been highlighted as a possible mechanism in melanocyte loss. However, the factors responsible for this trigger are currently unknown. Moreover, we know that the role of environmental factors are likely to be involved in the initiation or exacerbation of this disease. Based on these data and with the aim of finding new therapeutic targets, we were interested in studying the microbiota of vitiligo patients (both stool and skin) compared to healthy microbiota and to examine the impact of environmental factors such as ubiquitous house dust mite (HDM) that may be involved in this disease.In the first part of our study, we obtained swabs and biopsies of lesional and non-lesional skin as well as stool and blood samples from each individual. We detected a reduced richness and diversity of the microbiota in the stools of vitiligo patients compared to healthy subjects. Skin swabs showed a higher diversity than biopsies. Swabs from lesion sites were predominantly depleted of Staphylococcus compared to those from non-lesion sites. Sampling of deeper layers from the same patients showed differences in ᾳ and β diversity between samples with decreased species richness and distribution in the lesional site. The microbiota of lesional skin biopsies had a distinct composition, which was depleted of commensal bacteria such as Bifidobacterium and Bacteroides but was enriched in Proteobacteria, Streptococcus, Mycoplasma, and mitochondrial DNA (mtDNA). The latter increased in patients with increased innate immunity and stress markers in their blood. These data link skin dysbiosis, mitochondrial damage and immunity in patients with vitiligo.In the second part of this theses, given the importance of environmental factors in vitiligo and knowing that the house dust mite (HDM) is a normal component of skin microbiota, we were interested in the contribution of HDM to pathophysiology of vitiligo. HDM are environmental allergens with potent protease activity, known for their trigger in the lungs and onset of allergic disease and asthma. Here we detected the presence of Der p1 (major HDM allergen) in vitiligo skin. We showed HDM to induces a mixed Th1/Th2 immune response in cultured keratinocytes and to cause a specific cleavage of adhesion protein E-cadherin, resulting in melanocyte detachment from the basal membrane. This mechanism was driven by Der p1, cysteine proteases and MMP-9. Inhibition of MMP-9 or cysteine proteases dose-dependently restored E-cadherin expression and inhibited melanocyte detachment in the skin. Our results were confirmed using a 3D skin model and ex vivo using human skin explants. Vitiligo skin was more sensitive to HDM than healthy controls showing increased melanocyte detachment, as well as an increased detection of soluble E-cadherin in cultured supernatants in the presence of HDM. Together, these results highlight the impact of HDM in skin integrity and melanocyte loss which may drive skin depigmentation in people with fragile and/or genetically predisposed skin.Together, our work demonstrates dysbiosis in vitiligo compared to healthy skin and identifies HDM, a microbial component, as a potential important environmental trigger in initiation and/or progression of vitiligo and opens new innovative and new therapeutic perspectives for this debilitating disease
Children with egg allergy have evidence of reduced neonatal CD4+CD25+CD127lo/- regulatory T cell function
No full textBackground: The role of regulatory T (Treg) cells in allergic predisposition is not known.Objective: This study compared the frequency and function of cord blood Treg cells from nonallergic children (n = 18) with those from children who have egg allergy (n = 15) in the first year of life.Methods: CD4+ effector T cells and autologous antigen-presenting cells isolated from cord blood mononuclear cells were cocultured with or without CD4+CD25+CD127lo/? Treg cells, and cytokine responses to staphylococcal endotoxin B were assessed after 48 hours.Results: The addition of Treg cell populations to cord blood mononuclear cell cultures resulted in significant reduction in IL-10 (P = .002), IL-13 (P = .012), and IFN-? (P < .001) production. Consistent with other reports, effector CD4+ T-cell responses (IFN-? and IL-13) tended to be lower in the allergic group. These neonates showed less significant Treg cell–associated suppression of IFN-? (P = .015) compared with that seen in the nonallergic group (P = .001). The allergic group was also less likely (44%) to show Treg cell–associated suppression of IFN-? effector responses compared with that seen in the nonallergic group (78%, P = .015). The magnitude of suppression (change in IFN-? level when CD4+CD25+CD127lo/? Treg cells were added to responding effector T-cell cultures) was significantly lower in the allergic group (P = .004). There were no between-group differences in the circulating CD4+CD25+CD127lo/? Treg cells (as a percentage of cord blood T cells) or in the FOXP3 expression of these cells.Conclusion: This study confirms the presence and activity of Treg cells in cord blood and provides preliminary evidence of differences in neonates who progress to allergic disease in the first year of life.<br/
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
New insights into the pathophysiology of the small airways in asthma
No full textAsthma is a lung disease characterized by inflammation and remodeling of the airways, which leads to airflow obstruction and symptoms of wheeze, chest tightness, cough and dyspnea. It is now widely accepted that airway inflammation and remodeling occur not only in the central airways but also in the small airways and even in the lung parenchyma. Inflammation of the distal lung can be observed even in mild asthmatics with normal or noncompromised lung function. Moreover, the small airways and the lung parenchyma can produce many Th2 cytokines and chemokines involved in initiation and perpetuation of the inflammatory process. In addition, the distal parts of the lung have been recognized as a predominant site of airflow obstruction in asthmatics. In fact, the inflammation at this distal site has been described as more severe when compared to the large airway inflammation, and evidence of remodeling in the lung periphery is emerging. Recognition of asthma as a disease of the entire respiratory tract has an important clinical significance, highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease
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