Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

Mélanomes familiaux (intérêt du test et résultats de la surveillance chez 28 familles porteuses d'une mutation de CDKN2A)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Simulation de mesure polarimétrique du ciel

National audienceDans le cadre du développement d’une boussole optique bio-inspirée basée sur la lecture des propriétés de polarisation de la lumière diffusée par l’atmosphère, nous avons été amenés à développer un simulateur complet d’une caméra polarimétrique observant le ciel. Cela comprend le phénomène de diffusion multiple, la répartition de l’énergie lumineuse, l’optique utilisée, les caractéristiques des polariseurs et du capteur (matrice de pixels), ainsi que tous paramètres réglables en entrée. Ce simulateur a l’avantage d’être modulaire et évolutif. Il est constitué de plusieurs blocs élémentaires, facilement remplaçables, pour une amélioration constante et une bonne adaptabilité quels que soient les systèmes optiques et de détection étudiés. Ce simulateur sera disponible en "open source" sous Matlab et Python pour les besoins de la recherche et de la formation. Ce simulateur permettra ainsi de dimensionner les systèmes d’acquisition et surtout des algorithmes de traitement d’images à partir de données variées difficilement accessibles par l’expérimentation (conditions météorologiques, matériels couteux, éphémérides en zone géographique spécifique)

Simulation de mesure polarimétrique du ciel

International audienceDans le cadre du développement d’une boussole optique bio-inspirée basée sur la lecture des propriétés de polarisation de la lumière diffusée par l’atmosphère, nous avons été amenés à développer un simulateur complet d’une caméra polarimétrique observant le ciel. Cela comprend le phénomène de diffusion multiple, la répartition de l’énergie lumineuse, l’optique utilisée, les caractéristiques des polariseurs et du capteur (matrice de pixels), ainsi que tous paramètres réglables en entrée. Ce simulateur a l’avantage d’être modulaire et évolutif. Il est constitué de plusieurs blocs élémentaires, facilement remplaçables, pour une amélioration constante et une bonne adaptabilité quels que soient les systèmes optiques et de détection étudiés. Ce simulateur sera disponible en "open source" sous Matlab et Python pour les besoins de la recherche et de la formation. Ce simulateur permettra ainsi de dimensionner les systèmes d’acquisition et surtout des algorithmes de traitement d’images à partir de données variées difficilement accessibles par l’expérimentation (conditions météorologiques, matériels couteux, éphémérides en zone géographique spécifique)

OpenSky: a modular and open-source simulator of sky polarization measurements

International audienceAutonomous navigation requires robust strategies, particularly in GPS-denied environments. Of great interest for geolocation or to estimate North is the measurement and processing of polarized skylight patterns. In this study, we fully describe an open source and easily upgradable simulator, named OpenSky, which can simulate the measurement of sky polarization properties, i.e., the light intensity, the angle of polarization and the degree of linear polarization of light seen through a polarimetric camera. OpenSky is an open source simulator available on open repositories (Github and Open Science Framework). It structured around 5 blocks, each of which can easily be improved, replaced or completed by users. These blocks individually simulate sky polarization properties, skylight intensity, optical conjugation, polarizing filters and sensors. The high fidelity of OpenSky was assessed by comparing the simulated camera captures to experimental raw images, from which both the angle and the degree of polarization were extracted by image processing. OpenSky will be useful for developing novel celestialbased sensors and estimating their potential relevance to scientific communities (fundamental or applied sciences). OpenSky could also become a powerful tool to train or validate deep neural networks. One major interest is the ability of the OpenSky simulator to generate many sky conditions at various positions on Earth, which can be difficult and costly to obtain in real world

Targeted Skin Overexpression of the Mineralocorticoid Receptor in Mice Causes Epidermal Atrophy, Premature Skin Barrier Formation, Eye Abnormalities, and Alopecia

The mineralocorticoid receptor (MR) is a transcription factor of the nuclear receptor family, activation of which by aldosterone enhances salt reabsorption in the kidney. The MR is also expressed in nonclassical aldosterone target cells (brain, heart, and skin), in which its functions are incompletely understood. To explore the functional importance of MR in mammalian skin, we have generated a conditional doxycycline-inducible model of MR overexpression, resulting in double-transgenic (DT) mice [keratin 5-tTa/tetO-human MR (hMR)], targeting the human MR specifically to keratinocytes of the epidermis and hair follicle (HF). Expression of hMR throughout gestation resulted in early postnatal death that could be prevented by antagonizing MR signaling. DT mice exhibited premature epidermal barrier formation at embryonic day 16.5, reduced HF density and epidermal atrophy, increased keratinocyte apoptosis at embryonic day 18.5, and premature eye opening. When hMR expression was initiated after birth to overcome mortality, DT mice developed progressive alopecia and HF cysts, starting 4 months after hMR induction, preceded by dystrophy and cycling abnormalities of pelage HF. In contrast, interfollicular epidermis, vibrissae, and footpad sweat glands in DT mice were normal. This new mouse model reveals novel biological roles of MR signaling and offers an instructive tool for dissecting nonclassical functions of MR signaling in epidermal, hair follicle, and ocular physiology

Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I

Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-γ, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1β, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-β, tumor necrosis factor [α], or transforming growth factor β). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I