Altered vaccine-induced immunity in children with Dravet syndrome

International audienceDravet syndrome (DS) is a refractory epileptic syndrome. Vaccination is the trigger of the first seizure in about 50% of cases. Fever remains a trigger of seizures during the course of the disease. We compared ex vivo cytokine responses to a combined aluminium-adjuvanted vaccine of children with DS to sex-and age-matched heathy children. Using ex vivo cytokine responses of peripheral-blood mononuclear cells and monocytes, we found that vaccine responsiveness is biased toward a proinflammatory profile in DS with a M1 phenotype of monocytes. We provide new insight into immune mechanisms associated with DS that might guide research for the development of new immunotherapeutic agents in this epilepsy syndrome

The Nrf2-Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma

Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and internal organs and vascular alterations. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of the disease. Indeed, reactive oxygen species (ROS) trigger neoepitopes leading to a breach of immune tolerance and autoimmune responses, activate fibroblasts to proliferate and to produce excess of type I collagen. ROS also alter endothelial cells leading to vascular dysfunction. Glutathione (GSH) is the most potent antioxidant system in eukaryotic cells. Numerous studies have reported a defect in GSH in SSc animal models and humans, but the origin of this defect remains unknown. The transcription factor NRF2 is a key player in the antioxidant defense, as it can induce the transcription of antioxidant and cytoprotective genes, including GSH, through its interaction with the antioxidant response elements. In this work, we investigated whether NRF2 could be implicated in the pathogenesis of SSc, and if this pathway could represent a new therapeutic target in this orphan disease with no curative medicine. Skin biopsies from 11 patients and 10 controls were harvested, and skin fibroblasts were extracted. Experimental SSc was induced both in BALB/c and in nrf2−/− mice by daily intradermal injections of hypochloric acid. In addition, diseased BALB/c mice were treated with an nrf2 agonist, dimethyl fumarate, or placebo. A drop in nrf2 and target genes mRNA levels was observed in skin fibroblasts of SSc patients compared to controls. Moreover, the nrf2 pathway is also downregulated in skins and lungs of SSc mice. In addition, we observed that nrf2−/− mice have a more severe form of SSc with increased fibrosis and inflammation compared to wild-type SSc mice. Diseased mice treated with the nrf2 agonist dimethyl fumarate (DMF) exhibited reduced fibrosis and immune activation compared to untreated mice. The ex vivo treatment of skin fibroblasts from SSc mice with DMF restores GSH intracellular content, decreases ROS production and cell proliferation. These results suggest that the nrf2 pathway is highly dysregulated in human and SSc mice with deleterious consequences on fibrosis and inflammation and that Nrf2 modulation represents a therapeutic target in SSc

Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania

In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam

TGFβ promotes low IL10-producing ILC2 with profibrotic ability involved in skin fibrosis in systemic sclerosis

Objective : Innate lymphoid cells-2 (ILC2) were shown to be involved in the development of lung or hepatic fibrosis. We sought to explore the functional and phenotypic heterogeneity of ILC2 in skin fibrosis within systemic sclerosis (SSc). Methods : Blood samples and skin biopsies from healthy donor or patients with SSc were analysed by immunostaining techniques. The fibrotic role of sorted ILC2 was studied in vitro on dermal fibroblast and further explored by transcriptomic approach. Finally, the efficacy of a new treatment against fibrosis was assessed with a mouse model of SSc. Results : We found that ILC2 numbers were increased in the skin of patients with SSc and correlated with the extent of skin fibrosis. In SSc skin, KLRG1− ILC2 (natural ILC2) were dominating over KLRG1+ ILC2 (inflammatory ILC2). The cytokine transforming growth factor-β (TGFβ), whose activity is increased in SSc, favoured the expansion of KLRG1- ILC2 simultaneously decreasing their production of interleukin 10 (IL10), which regulates negatively collagen production by dermal fibroblasts. TGFβ-stimulated ILC2 also increased myofibroblast differentiation. Thus, human KLRG1- ILC2 had an enhanced profibrotic activity. In a mouse model of SSc, therapeutic intervention-combining pirfenidone with the administration of IL10 was required to reduce the numbers of skin infiltrating ILC2, enhancing their expression of KLRG1 and strongly alleviating skin fibrosis. Conclusion : Our results demonstrate a novel role for natural ILC2 and highlight their inter-relationships with TGFβ and IL10 in the development of skin fibrosis, thereby opening up new therapeutic approaches in SSc

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways

"Trained immunity" and role of macrophage memory in the immunomodulation of fibro-inflammatory diseases

Les maladies fibroinflammatoires sont un groupe hétérogène de pathologies pouvant impacter des organes tels que la peau, le foie, les poumons et l'appareil digestif et engager le pronostic vital. Malgré un large spectre étiologique, la dérégulation de la réponse immune innée avec une inflammation exacerbée et chronique reste l'élément majeur de leur pathogénie. Récemment, il a été démontré que des cellules de l'immunité innée, tels que les macrophages, sont capables d'acquérir une sorte de mémoire immunologique après une première exposition antigénique et de réagir différemment à une deuxième stimulation, soit avec une réponse inflammatoire amplifiée, soit une hyporéponse voire un effet anti-inflammatoire, selon la nature du premier antigène rencontré. Dans ce travail, nous soutenons la thèse que l'induction d'une mémoire macrophagique est capable d'impacter l'évolution d'un processus inflammatoire et donc influer sur l'installation de la fibrose tissulaire. Nous montrons d'abord que la préstimulation in vivo et in vitro des macrophages par du BCG ou du LPS à faibles doses répétées (LPSlow) induit des modifications phénotypiques, métaboliques et épigénétiques singulières, et leur confère des propriétés fonctionnelles opposées. La préstimulation in vivo par du LPSlow réduit l'inflammation précoce et la fibrose chronique dans le modèle murin de sclérodermie systémique (SSc) induite par l'HOCl, tandis que le BCG l'exacerbe. Le transfert adoptif de macrophages mémoires LPSlow ou BCG a également des effets bénéfiques ou aggravants, respectivement. La coculture avec des macrophages mémoires LPSlow atténue le profil fibroinflammatoire des fibroblastes de souris et de patients SSc avec une déviation cytokinique vers un excès d'IL-10. Cet effet immunomodulateur est retrouvé dans le modèle murin d'endométriose (EDT) caractérisé par une inflammation chronique associée à l'implantation des lésions endométriales ectopiques. Outre la réduction du volume et de l'activité glandulaire des lésions, la stimulation des souris EDT avec du LPSlow diminue l'expression des molécules de costimulation et des récepteurs aux chémokines des macrophages péritonéaux et la production de cytokines pro-inflammatoires. La coculture de macrophages LPSlow avec des cellules humaines endométriosiques réduit l'expression des marqueurs de fibrose, d'adhésion et de migration cellulaire, mais augmente la phosphorylation de STAT3 et l'expression de Socs3 et Bcl3, gènes cibles de l'IL-10. Cet effet, aboli par la coculture en présence de siRNA-IL10 ou de l'inhibiteur de pSTAT3, démontre l'effet anti-inflammatoire et antifibrotique IL-10 dépendant. Les macrophages LPSlow sont également capables de moduler la réponse allogénique in vitro dans une réaction lymphocytaire mixte et in vivo dans le modèle murin de la maladie du greffon contre l'hôte via la réduction de l'inflammation initiale responsable du déclenchement et du maintien du processus immun allogénique. Cet effet est associé à une augmentation de la production de l'IL-10, une diminution de la synthèse du TNF-a, de l'IFN-g, de l'IL-6, un remaniement des réseaux de chémokines et de leurs récepteurs, et une réduction du phénotype lymphocytaire mémoire se traduisant par une diminution significative des dommages tissulaires et de la mortalité. Enfin, nous démontrons que le transfert adoptif des macrophages LPSlow n'aggrave pas la croissance des cellules tumorales A20 du lymphome B murin alors que les macrophages BCG en ralentissent la prolifération en favorisant la production du TNF-a et de l'IL-6, l'activation lymphocytaire T CD4+ et CD8+ et l'expression de gènes associés à l'inflammation au niveau splénique et tumoral. Ce travail démontre qu'une stimulation antigénique préalable des macrophages leur confère un phénotype mémoire capable d'immunomoduler l'évolution d'une maladie fibroinflammatoire en agissant sur les voies de l'inflammation et sur l'activation des cellules immunes adaptatives.Fibro-inflammatory diseases are pathologies that affect various organs such as the skin, the liver, the lungs, and the digestive system and thus are life-threatening. Despite a wide etiological spectrum of infectious, toxic or immunological causes, the dysregulation of the innate immune response with an exacerbation and maintenance of the inflammatory process remains the major element of their pathogenesis. Recently, it has been shown that specific innate immune cells such as macrophages can acquire a type of rudimentary immunological memory following a first antigenic exposure and can react differently to a second stimulation, with either a heightened inflammatory response or an anergic/anti-inflammatory status, depending on the type of the first antigen encountered. In this work, we support the reasoning that such memory induction in macrophages can affect the course of the inflammatory process and therefore can influence the proliferation of tissue fibrosis. We first show that macrophages' in vivo and in vitro pre-stimulation with BCG or LPS at low repeated doses (LPSlow) induces singular phenotypic, metabolic, and epigenetic modifications and confer them opposite functional properties. In vivo stimulation with LPSlow alleviates early inflammation and chronic fibrosis in the mouse model of HOCl-induced systemic sclerosis (SSc), while BCG exacerbates it. The adoptive transfer of LPSlow or BCG memory macrophages can also have either beneficial or aggravating effects, respectively. Additionally, co-culture with LPSlow memory macrophages reduces the fibro-inflammatory profile of myofibroblasts in mice and SSc patients with a cytokinic deviation towards an excess of IL-10. This immunomodulatory effect is found in the murine model of endometriosis (EDT) characterized by a chronic inflammation associated with the implantation of ectopic endometrial lesions. Along with the volume and glandular activity reduction of endometriotic lesions, in vivo stimulation of EDT mice with LPSlow leads to an expression decrease of costimulatory molecules and chemokine receptors of peritoneal macrophages, as well as a hypo-production of pro-inflammatory cytokines. The co-culture of LPSlow memory macrophages with human endometriotic cells induces a decrease in markers of fibrosis, adhesion, and cell migration molecules, but an increase in STAT3 phosphorylation and the expression of Socs3 and Bcl3, target genes of the IL-10 cytokine. This effect, abrogated by the coculture with the siRNA-IL10 or the pSTAT3, demonstrates the IL-10 dependent anti-inflammatory and anti-fibrotic mechanism. LPSlow macrophages are also able to modulate the allogeneic response in vitro in a mixed lymphocyte reaction and in vivo in the mouse model of Graft-versus-Host Disease via decrease of the initial inflammation responsible for triggering and maintaining the allogenic immune process. This effect is associated with an increase of IL-10 production, a decrease in the synthesis of TNF-a, IFN-g, IL-6, a change in the chemokine networks and their receptors, and a reduction in the memory lymphocyte phenotype leading to a significant drop in organs damage and mortality rate. Finally, we demonstrate that the adoptive transfer of LPSlow macrophages does not worsen the growth of murine B lymphoma A20 tumor cells, unlike BCG macrophages that slow tumor proliferation by promoting the production of TNF-a and IL-6, CD4+ and CD8+ T cell activation, and the expression of inflammation-associated genes at the splenic and tumor level. Consequently, this work demonstrates that prior antigenic macrophage stimulation induces a memory phenotype that can be expressed in case of a fibro-inflammatory disease and either alleviates or worsens its clinical and biological presentation via the modulation of the inflammation pathways and the adaptive immune cells activation

THE STATUS OF SCIENTIFIC RESEARCH AND PUBLICATION IN MEDIA AND COMMUNICATION SCIENCES AT ARAB UNIVERSITIES: AN ANALYTICAL FIELD STUDY

The present study aims to investigate the reality of scientific publication in media and communication sciences at Arab universities. To this end, an attempt was made to identify the difficulties and pressures hampering the scientific research process in the Arab environment. Furthermore, an effort was made to identify the publication methods and ways adopted in different specialized scientific fields. The study also shed light on such an important issue, namely the scientific publication development processes at Arab universities as well as the demands of professors at those universities. The sample group, which comprised researchers from different Arab universities, was asked to fill out an inventory in order for us to understand their positions regarding the reality of scientific publication in the Arab world. Results revealed it is necessary to attach importance to scientific research in the Arab world by providing the appropriate working and scientific research environment, by considering incentives for those who work in this area, and by providing different tools and technologies of scientific publication development. Such tools and technologies are to adhere to the international standards and to ignore personal relationships and bureaucracy in dealing with studies. To achieve this, all those working in Arab university institutions must work together