Arf6: a new player in FcγRIIIA lymphocyte-mediated cytotoxicity

AbstractThe activation of phosphoinositide metabolism represents a critical step in the signaling pathways leading to the activation of cytolytic machinery, but its regulation is partially understood. We report here that the stimulation of the low-affinity receptor for immunoglobulin G (IgG) (FcγRIIIA, CD16) on primary human natural killer (NK) cells induces a phosphatidylinositol 3-kinase (PI3K)–dependent activation of the small G protein Arf6. We first demonstrate a functional role for Arf6-dependent signals in the activation of the antibody-dependent cellular cytotoxicity (ADCC) attributable to the control of secretion of lytic granule content. We also show that Arf6 couples CD16 to the lipid-modifying enzymes phosphatidylinositol4phosphate 5-kinase type I alpha (PI5KIα) and phospholipase D (PLD) that are involved in the control of granule secretion; Arf6, but not Rho family small G proteins RhoA and Rac1, is required for receptor-induced PI5KIα membrane targeting as well as for PI5KIα and PLD activation. Our findings suggest that Arf6 plays a crucial role in the generation of a phosphatidylinositol4,5-bisphosphate (PIP2) plasma membrane pool required for cytolytic granule-mediated target cell killing

Differential Requirements for Vav Proteins in DAP10- and ITAM-mediated NK Cell Cytotoxicity

Natural killer (NK) cells express multiple activating receptors that initiate signaling cascades through DAP10- or immunoreceptor tyrosine-based activation motif–containing adapters, including DAP12 and FcRγ. Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation. However, whether Vav1 regulates only some or all NK cell–activating pathways is matter of debate. It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation. Here, we examine the relative contribution of each of these exchange factors to NK cell–mediated cytotoxicity using mice lacking one, two, or all three Vav proteins. We found that Vav1 deficiency is sufficient to disrupt DAP10-mediated cytotoxicity, whereas lack of Vav2 and Vav3 profoundly impairs FcRγ- and DAP12-mediated cytotoxicity. Our results provide evidence that these three Vav proteins function specifically in distinct pathways that trigger NK cell cytotoxicity

TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS) triggered by autoimmune mechanisms. Microglia are critical for the clearance of myelin debris in areas of demyelination, a key step to allow remyelination. TREM2 is expressed by microglia and promotes microglial survival, proliferation, and phagocytic activity. Herein we demonstrate that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects with TREM2 genetic deficiency displayed a defect in phagocytic pathways. Treatment with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity. These results are relevant as they propose TREM2 on microglia as a potential new target to promote remyelination

Operationalizing mild cognitive impairment criteria in small vessel disease: The VMCI-Tuscany Study

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD

Appunti sull'uso ludico delle tecnologie

Il testo, scritto a pi\uf9 mani, vuole essere una tavolozza di diverse voci sull\u2019unico argomento del rapporto tra gioco e tecnologie; tali termini possano congiungersi ed integrarsi in modo proficuo ed efficace ed entrare anche nel mondo dei pi\uf9 piccoli. Il saggio si propone quindi come una finestra su teorie e pratiche aventi ad oggetto il rapporto tra gioco e tecnologie in contesti sia scolastici sia extrascolastici e nasce come condivisione dello stato delle ricerche avviate dal gruppo degli autori dei contributi qui presentati. Si avvale dell\u2019apporto di alcune coautrici che hanno affrontato nel proprio lavoro di tesi aspetti aventi a tema proprio tale rapporto, che ora condividono in questo testo. Dal punto di vista dei contenuti si possono intravvedere due nuclei: nel primo il focus \ue8 centrato sul rapporto fra gioco, tecnologie, infanzia; nel secondo, prendendo spunto dalla letteratura, si punta l\u2019attenzione sull\u2019influenza che le tecnologie esercitano, sia sulle nuove generazioni, sia sugli adulti

Determination of glycerol carbon stable isotope ratio for the characterization of Italian balsamic vinegars

The gas chromatographic-combustion-isotopic ratio mass spectrometry (GC-C-IRMS) approach was applied to determine the compound-specific 13C/12C isotopic ratio of glycerol in balsamic vinegars of Modena (Italy). In particular, Italian Protected Designation of Origin and Protected Geographical Indication balsamic vinegars, namely the traditionally made Aceto Balsamico Tradizionale di Modena (ABTM) and the industrial Aceto Balsamico di Modena (ABM) products, were analyzed and a first attempt at classification was carried out. The carbon isotopic ratio of the glycerol polyalcohol varies on the basis of origin, varietal or provenance; therefore the discriminating potentiality of this species might be useful to elucidate the balsamic vinegar production process. To do this, a preliminary study was conducted and several marketable products, ABTM and ABM type, were subjected to measurements in addition to samples coming from three ABTM cask series (batteria). Experimental results highlighted the peculiarities of the two different production processes, suggesting the use of the carbon isotopic ratio of glycerol as an additional tool for balsamic vinegar authentication

Long-term outcomes of patients with preeclampsia, a review of the literature

Hypertensive pregnancy disorders affect up to 10% of all pregnancies and are associated with an increased future risk of heart disease, chronic hypertension, kidney dysfunction, diabetes, and thromboembolism. Although mechanisms are not yet well understood, endothelial dysfunction, pro-inflammatory and procoagulant states seem to persist in women with a history of preeclampsia many years after a pregnancy complicated by HDP. Moreover, the number and severity of these complications differs according to the type of disorder developed during pregnancy. Lifestyle modifications and long-term follow-up are essential to reduce the risk of developing a disease later in life

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

DC recognize microbial components through an array of receptors known as PRR. PRR initiate intracellular signals, which engender DC with the capacity to stimulate T‐cell responses. Dectin‐1 is a PRR that recognizes β‐glucan, a major constituent of many fungi's outer cell wall. Here we show that Dectin‐1 activates DC through phospholipase (PLC)γ2 signaling. PLCγ2‐deficient DC were unable to expand antigen‐specific T cells and induce TH1 and TH17 differentiation in response to β‐glucan. Mechanistically, PLCγ2‐deficiency impaired the capacity of DC to secrete polarizing cytokines following exposure to β‐glucan. Dectin‐1 required PLCγ2 to activate MAPK, AP‐1 and NF‐κB, which induce cytokine gene expression. Moreover, PLCγ2 controlled Dectin‐1‐mediated NFAT activation and induction of NFAT‐dependent genes such as IL‐2, cyclooxigenase‐2 and Egr transcription factors. We conclude that PLCγ2 is a crucial signaling mediator that modifies DC gene expression program to activate DC responses to β‐glucan‐containing pathogens