IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, ...invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues.
Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We ...investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Exosomes are small vesicles secreted by different immune cells and which display anti‐tumoral properties. Stimulation of RBL‐2H3 cells with ionomycin triggered phospholipase D2 (PLD2) translocation ...from plasma membrane to intracellular compartments and the release of exosomes. Although exosomes carry the two isoforms of PLD, PLD2 was enriched and specifically sorted on exosomes when overexpressed in cells. PLD activity present on exosomes was clearly increased following PLD2 overexpression. PLD2 activity in cells was correlated to the amount of exosome released, as measured by FACS. Therefore, the present work indicates that exosomes can vehicle signaling enzymes.
Aims: The aim of this study was to assess the diagnostic performance of 3‐D contrast‐enhanced power Doppler ultrasonography (3‐D CEPDUS) for differentiating benign and malignant adnexal masses.
...Material and Methods: Consecutive patients with adnexal masses were included prospectively and underwent 2‐D ultrasonography and 3‐D CEPDUS in a tertiary centre in Paris, France. The main outcome measure was the diagnostic accuracy of 3‐D CEPDUS to diagnose malignant and borderline adnexal masses. The reference standard was the final histological examination. Two‐dimensional ultrasonography and 3‐D CEPDUS were compared using semiquantitative scores. Three‐dimensional CEPDUS assessed vessel density, vessel pattern, and three vascular indexes in a 5‐mL region of interest (vascularization index VI, flow index FI, and vascularization flow index VFI). The 2‐D and 3‐D examinations were done by different sonographers who were blinded to the other test. The pathologist was blinded to ultrasonography findings.
Results: Of 99 patients, 88 had benign tumors and were compared to the 11 patients with borderline (n = 5) or malignant (n = 6) tumors. The sensitivity of the subjective 2‐D score was 55% (95% confidence interval CI, 25–84) and specificity 94% (95%CI, 89–99). The sensitivity of the subjective 3‐D score was 82% (95%CI, 58–100) and specificity 90% (95%CI, 83–96). Improvement of detection of malignant or borderline tumors by subjective 3‐D score was 150%. Vessel density and patterns were not more efficient than the subjective 3‐D score. The mean vascular index values were significantly different between benign and borderline/malignant groups: VI, 7.2 versus 35.5 (P < 0.0001); FI, 37.0 versus 48.2 (P = 0.003); and VFI, 2.9 versus 17.6 (P < 0.0001), respectively.
Conclusions: 3‐D CEPDUS improves detection of malignant and borderline adnexal masses.
La bière est la boisson fermentée la plus consommée dans le nord de la France à la fin du Moyen Âge : elle est locale, mais aussi importée et de qualités diverses. Tout en exposant les différentes ...étapes de la fabrication de la bière, cette contribution présente les principaux fours de brasseurs identifiés par l’archéologie dans cette région et alentour. Leurs dimensions permettent d’évaluer les volumes de productions par cuve, de plusieurs centaines à plusieurs milliers de litres brassés. Ceux-ci sont autant de sources de revenus pour les villes qui taxent le commerce de la boisson, en réglementant aussi sa fabrication, notamment pour protéger les consommateurs. Les sources écrites dévoilent l’ampleur de la demande urbaine et la topographie des établissements brassicoles comme leur nombre. En particulier à Douai, en Flandre, la riche documentation permet enfin de saisir la diversité des lieux de consommation, qui parfois coïncident avec ceux de la production de cervoise ou de goudale.
Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 ...and CD16a, the β-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20+ circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies.
KIR3DL2 belongs to the killer immunoglobulin (Ig)-like receptors (KIRs) family and is composed of three extracellular Ig-like domains. KIR3DL2 is naturally expressed on some NK cells and minor ...subpopulations of CD8+ and CD4+ T cells. Physiologically, KIRD3L2 is an inhibitory receptor for human leukocyte antigen (HLA) class I molecules regulating NK cell activation. Remarkably, KIR3DL2 is also aberrantly overexpressed on several subtypes of T lymphomas/leukemias, such as Sezary Syndrome, transformed Mycosis Fungoides and HTLV1+ Adult T Cell Leukemia, making it a unique therapeutic target in cancer. We have generated a series of anti-KIR3DL2 monoclonal antibodies (mAbs) binding selectively to KIR3DL2, spanning epitopes on all three Ig domains. Their efficacy was evaluated in vitro and in vivo against KIR3DL2-expressing tumors and Sezary cell lines as disease model. An autologous assay was set up to evaluate the killing of primary Sezary cells by patients’ NK effectors in the presence of those mAbs. Potent antibody-dependent cell cytotoxicity (ADCC) was found the main mode of action involved in their anti-tumor activity. The most promising candidates were humanized as IgG1 mAbs and the final lead molecule was selected for further development, based on several predefined criteria. In parallel, anti-KIR3DL2 mAbs were also developed as unique and sensitive tools for the detection by immunohistochemistry of KIR3DL2 on tumor biopsies. Owing to the promising efficacy profile of our anti-KIR3DL2 mAb candidate and to the highly restricted expression pattern of the target on some T leukemia/lymphoma cells, an antibody-based therapy targeting KIR3DL2 stands as a potentially unequalled strategy in several orphan diseases with critical unmet medical need.
Studies of dual-tasks (i.e. situations during which an individual performs two tasks simultaneously) and the subsequent inter-task interference have shown that locomotion and posture involves motor ...and cognitive components. Dual-tasks therefore constitute a promising avenue for improving the diagnosis, prevention and management of falls or cognitive impairment in populations at risk. However, tackling these major public health concerns with dual-task interventions requires a better understanding of the mechanisms underlying dual-task interference. In this context, we review (i) the main dual-task theories proposed to date and (ii) the factors that can influence dual-task interference effects in healthy young individuals and might therefore explain the current lack of consensus on the mechanisms of dual-tasks. We also consider cognitive-motor dual-tasks in which the motor task is a less frequently studied transition movement (such as gait initiation or turning), rather than only the often-studied gait and posture tasks. In general, the review focuses on the behavioral effects of dual-tasking.
Surface plasmon (SP) technologies exploit the spectral and spatial properties of collective electronic oscillations in noble metals placed in an incident optical field. Yet the SP local density of ...states (LDOS), which rule the energy transducing phenomena between the SP and the electromagnetic field, is much less exploited. Here, we use two-photon luminescence (TPL) microscopy to reveal the SP-LDOS in thin single-crystalline triangular gold nanoprisms produced by a quantitative one-pot synthesis at room temperature. Variations of the polarization and the wavelength of the incident light redistribute the TPL intensity into two-dimensional plasmonic resonator patterns that are faithfully reproduced by theoretical simulations. We demonstrate that experimental TPL maps can be considered as the convolution of the SP-LDOS with the diffraction-limited Gaussian light beam. Finally, the SP modal distribution is tuned by the spatial coupling of nanoprisms, thus allowing a new modal design of plasmonic information processing devices.
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