Immune sensing of nucleic acids in inflammatory skin diseases

Endosomal and cytosolic nucleic acid receptors are important immune sensors required for the detection of infecting or replicating viruses. The intracellular location of these receptors allows viral recognition and, at the same time, avoids unnecessary immune activation to self-nucleic acids that are continuously released by dying host cells. Recent evidence, however, indicates that endogenous factors such as anti-microbial peptides have the ability to break this protective mechanism. Here, we discuss these factors and illustrate how they drive inflammatory responses by promoting immune recognition of self-nucleic acids in skin wounds and inflammatory skin diseases such as psoriasis and lupus

Interleukin-26 activates macrophages and facilitates killing of Mycobacterium tuberculosis

Tuberculosis-causing Mycobacterium tuberculosis (Mtb) is transmitted via airborne droplets followed by a primary infection of macrophages and dendritic cells. During the activation of host defence mechanisms also neutrophils and T helper 1 (TH1) and TH17 cells are recruited to the site of infection. The TH17 cell-derived interleukin (IL)-17 in turn induces the cathelicidin LL37 which shows direct antimycobacterial effects. Here, we investigated the role of IL-26, a TH1- and TH17-associated cytokine that exhibits antimicrobial activity. We found that both IL-26 mRNA and protein are strongly increased in tuberculous lymph nodes. Furthermore, IL-26 is able to directly kill Mtb and decrease the infection rate in macrophages. Binding of IL-26 to lipoarabinomannan might be one important mechanism in extracellular killing of Mtb. Macrophages and dendritic cells respond to IL-26 with secretion of tumor necrosis factor (TNF)-α and chemokines such as CCL20, CXCL2 and CXCL8. In dendritic cells but not in macrophages cytokine induction by IL-26 is partly mediated via Toll like receptor (TLR) 2. Taken together, IL-26 strengthens the defense against Mtb in two ways: firstly, directly due to its antimycobacterial properties and secondly indirectly by activating innate immune mechanisms

Methylated BSA Mimics Amyloid-Related Proteins and Triggers Inflammation

The mechanistic study of inflammatory or autoimmune diseases requires the generation of mouse models that reproduce the alterations in immune responses observed in patients. Methylated bovine serum albumin (mBSA) has been widely used to induce antigen-specific inflammation in targeted organs or in combination with single stranded DNA (ssDNA) to generate anti-nucleic acids antibodies in vivo. However, the mechanism by which this modified protein triggers inflammation is poorly understood. By analyzing the biochemical properties of mBSA, we found that mBSA exhibits features of an intermediate of protein misfolding pathway. mBSA readily interact with a list of dyes that have binding specificity towards amyloid fibrils. Intriguingly, mBSA displayed cytotoxic activity and its binding to ssDNA further enhanced formation of beta-sheet rich amyloid fibrils. Moreover, mBSA is recognized by the serum amyloid P, a protein unanimously associated with amyloid plaques in vivo. In macrophages, we observed that mBSA disrupted the lysosomal compartment, signaled along the NLRP3 inflammasome pathway, and activated caspase 1, which led to the production of IL-1β. In vivo, mBSA triggered rapid and prominent immune cell infiltration that is dependent on IL-1β induction. Taken together, these data demonstrate that by mimicking amyloidogenic proteins mBSA exhibits strong innate immune functions and serves as a potent adjuvant. These findings advance our understanding on the underlying mechanism of how aberrant immune responses lead to autoimmune reactions

The commissioning of the CUORE experiment: the mini-tower run

CUORE is a ton-scale experiment approaching the data taking phase in Gran Sasso National Laboratory. Its primary goal is to search for the neutrinoless double-beta decay in 130Te using 988 crystals of tellurim dioxide. The crystals are operated as bolometers at about 10 mK taking advantage of one of the largest dilution cryostat ever built. Concluded in March 2016, the cryostat commissioning consisted in a sequence of cool down runs each one integrating new parts of the apparatus. The last run was performed with the fully configured cryostat and the thermal load at 4 K reached the impressive mass of about 14 tons. During that run the base temperature of 6.3 mK was reached and maintained for more than 70 days. An array of 8 crystals, called mini-tower, was used to check bolometers operation, readout electronics and DAQ. Results will be presented in terms of cooling power, electronic noise, energy resolution and preliminary background measurements

Results from the Cuore Experiment

The Cryogenic Underground Observatory for Rare Events (CUORE) is the first bolometric experiment searching for neutrinoless double beta decay that has been able to reach the 1-ton scale. The detector consists of an array of 988 TeO2 crystals arranged in a cylindrical compact structure of 19 towers, each of them made of 52 crystals. The construction of the experiment was completed in August 2016 and the data taking started in spring 2017 after a period of commissioning and tests. In this work we present the neutrinoless double beta decay results of CUORE from examining a total TeO2 exposure of 86.3kg yr, characterized by an effective energy resolution of 7.7 keV FWHM and a background in the region of interest of 0.014 counts/ (keV kg yr). In this physics run, CUORE placed a lower limit on the decay half- life of neutrinoless double beta decay of 130Te > 1.3.1025 yr (90% C. L.). Moreover, an analysis of the background of the experiment is presented as well as the measurement of the 130Te 2vo3p decay with a resulting half- life of T2 2. [7.9 :- 0.1 (stat.) :- 0.2 (syst.)] x 10(20) yr which is the most precise measurement of the half- life and compatible with previous results

Place des cellules dendritiques plasmocytoïdes dans l'immunité innée anti-tumorale, de leur activation par des ligands de TLR à leur fonctionnalité en contexte de mélanome

Several innovative therapeutic strategies for the treatment of cancer target Toll-like receptors (TLR) by using synthetic agonists. The most effective therapeutic agonists currently used mainly target TLR7 and -9. These TLRs are predominantly expressed by plasmacytoid dendritic cells (pDC). PDCs are key cells in the early immune response since they produce huge amounts of type I IFN and are able to cross-present antigens during viral infection, linking innate and adaptive immunity. Therefore, these cells constitute a subject of investigation for new antitumor immunotherapies development. The efficacy of treatments targeting TLR7 was demonstrated to involve activated pDCs. However, exact signaling pathways induced after TLR7 triggering and leading to the activation of human pDCs remain to be determined. Hence, we studied in a first part the signaling pathways induced by TLR7 ligands in human blood isolated pDCs and in the pDC cell line, GEN2.2 cells. This study allowed us to define a new signaling pathway leading to the rapid expression of IFN-stimulated genes (ISG) in the absence of type I IFN. In a second part, we determined if this particular pathway could be induced in TLR9-activated pDCs using two kinds of CpGs. We were also interested to identify the signaling factors responsible for the activation of this pathway by targeting the potential role of calcium. Finally, we characterized circulating dendritic cells in melanoma patients in order to verify that these cells are mobilizable and activable for TLR agonists based immunotherapy. This work reinforces the idea that pDCs constitute a target of choice for developing new antitumor therapeutic approaches.Plusieurs stratégies thérapeutiques innovantes dans le traitement du cancer ciblent les Toll-like receptor (TLR) par l'utilisation d'agonistes synthétiques dont les plus utilisés ciblent les TLR7 et -9. Ces TLR sont exprimés de façon prédominante par les cellules dendritiques plasmocytoïdes (pDC). Les pDC produisent de grandes quantités d'IFN de type I et peuvent cross-présenter des antigènes, permettant de faire le lien entre l'immunité innée et adaptative. Ces cellules sont donc un sujet d'investigation pour le développement de nouvelles immunothérapies anticancéreuses. Cependant, les voies de signalisation exactes induites après engagement du TLR7 chez les pDC humaines restent à être déterminées. Pour cela, nous avons étudié dans une première partie les voies de signalisation induites par des ligands de TLR7 dans les pDC humaines. Cette étude nous a permis de mettre en évidence une nouvelle voie de signalisation conduisant à l'expression rapide des gènes induits par l'IFN (ISG) et ce de façon indépendante de l'IFN de type I. Dans une deuxième partie, nous avons déterminé si cette voie particulière peut être induite dans les pDC après stimulation du TLR9 et nous nous sommes intéressés à identifier les facteurs signalétiques responsables de l'activation de cette voie de signalisation. Enfin, nous avons caractérisé les cellules dendritiques circulantes chez les patients porteurs de mélanome afin de savoir si ces cellules sont mobilisables et activables dans l'optique de la mise en place d'une immunothérapie ciblant les TLR. Ces travaux renforcent l'idée que les pDC constituent une cible de choix pour le développement de nouvelles approches thérapeutiques anti-tumorales

Fueling autoimmunity: type I interferon in autoimmune diseases

In recent years, active research using genomic, cellular and animal modeling approaches has revealed the fundamental forces driving the development of autoimmune diseases. Type I IFN (IFN) imprints unique molecular signatures in a list of autoimmune diseases. IFN is induced by diverse nucleic acid-containing complexes, which trigger innate immune activation of plasmacytoid dendritic cells (pDCs). IFN primes, activates or differentiates various leukocyte populations to promote autoimmunity. Accordingly, IFN signaling is essential for the initiation and/or progression of lupus in several experimental models. However, the heterogeneous nature of SLE requires better characterization on how IFN pathways are activated and subsequently promote the advancement of autoimmune diseases. Given the central role of type I IFN, various strategies are devised to target these cytokines or related pathways to curtail the progression of autoimmune diseases

Place des cellules dendritiques plasmocytoïdes dans l'immunité innée anti-tumorale (de leur activation par des ligands de TLR à leur fonctionnalité en contexte de mélanome)

Plusieurs stratégies thérapeutiques innovantes dans le traitement du cancer ciblent les Toll-like receptor (TLR) par l'utilisation d'agonistes synthétiques dont les plus utilisés ciblent les TLR7 et -9. Ces TLR sont exprimés de façon prédominante par les cellules dendritiques plasmocytoïdes (pDC). Les pDC produisent de grandes quantités d'IFN de type I et peuvent cross-présenter des antigènes, permettant de faire le lien entre l'immunité innée et adaptative. Ces cellules sont donc un sujet d'investigation pour le développement de nouvelles immunothérapies anticancéreuses. Cependant, les voies de signalisation exactes induites après engagement du TLR7 chez les pDC humaines restent à être déterminées. Pour cela, nous avons étudié dans une première partie les voies de signalisation induites par des ligands de TLR7 dans les pDC humaines. Cette étude nous a permis de mettre en évidence une nouvelle voie de signalisation conduisant à l'expression rapide des gènes induits par l'IFN (ISG) et ce de façon indépendante de l'IFN de type I. Dans une deuxième partie, nous avons déterminé si cette voie particulière peut être induite dans les pDC après stimulation du TLR9 et nous nous sommes intéressés à identifier les facteurs signalétiques responsables de l'activation de cette voie de signalisation. Enfin, nous avons caractérisé les cellules dendritiques circulantes chez les patients porteurs de mélanome afin de savoir si ces cellules sont mobilisables et activables dans l'optique de la mise en place d'une immunothérapie ciblant les TLR. Ces travaux renforcent l'idée que les pDC constituent une cible de choix pour le développement de nouvelles approches thérapeutiques anti-tumorales.Several innovative therapeutic strategies for the treatment of cancer target Toll-like receptors (TLR) by using synthetic agonists. The most effective therapeutic agonists currently used mainly target TLR7 and -9. These TLRs are predominantly expressed by plasmacytoid dendritic cells (pDC). PDCs are key cells in the early immune response since they produce huge amounts of type I IFN and are able to cross-present antigens during viral infection, linking innate and adaptive immunity. Therefore, these cells constitute a subject of investigation for new antitumor immunotherapies development. The efficacy of treatments targeting TLR7 was demonstrated to involve activated pDCs. However, exact signaling pathways induced after TLR7 triggering and leading to the activation of human pDCs remain to be determined. Hence, we studied in a first part the signaling pathways induced by TLR7 ligands in human blood isolated pDCs and in the pDC cell line, GEN2.2 cells. This study allowed us to define a new signaling pathway leading to the rapid expression of IFN-stimulated genes (ISG) in the absence of type I IFN. In a second part, we determined if this particular pathway could be induced in TLR9-activated pDCs using two kinds of CpGs. We were also interested to identify the signaling factors responsible for the activation of this pathway by targeting the potential role of calcium. Finally, we characterized circulating dendritic cells in melanoma patients in order to verify that these cells are mobilizable and activable for TLR agonists based immunotherapy. This work reinforces the idea that pDCs constitute a target of choice for developing new antitumor therapeutic approaches.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Wrist Splint Effects on Muscle Activity and Force During a Handgrip Task

Wrist splints are commonly prescribed to limit wrist motion and provide support at night and during inactive periods but are often used in the workplace. In theory, splinting the wrist should reduce wrist extensor muscle activity by stabilizing the joint and reducing the need for co-contraction to maintain posture. Ten healthy volunteers underwent a series of 24 10-s gripping trials with surface electromyography on 6 forearm muscles. Trials were randomized between splinted and nonsplinted conditions with three wrist postures (30 ° flexion, neutral, and 30 ° extension) and four grip efforts. Custom-made Plexiglas splints were taped to the dorsum of the hand and wrist. It was found that when simply holding the dynamometer, use of a splint led to a small (<1 % MVE) but significant reduction in activity for all flexor muscles and extensor carpi radialis (all activity <4 % maximum). At maximal grip, extensor muscle activity was significantly increased with the splints by 7.9–23.9 % MVE. These data indicate that splinting at low-to-moderate grip forces may act to support the wrist against external loading, but appears counterproductive when exerting maximal forces. Wrist bracing should be limited to periods of no to light activity and avoided during tasks that require heavy efforts