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Abstract Background Racehorses commonly develop evidence of mild asthma in response to dust exposure. Diets deficient in omega‐3 polyunsaturated fatty acids (Ω‐3) might exacerbate this response. Hypothesis To compare dust exposure, bronchoalveolar lavage fluid (BALF) cytology, and plasma Ω‐3 and specialized pro‐resolving mediators (SPM) concentrations amongst racehorses fed dry hay, steamed hay, and haylage. Animals Forty‐three Thoroughbred racehorses. Methods Prospective clinical trial. Horses were randomly assigned to be fed dry hay, steamed hay, or haylage for 6 weeks. Measures of exposure to dust in the breathing zone were obtained twice. At baseline, week‐3, and week‐6, BALF cytology was examined. Plasma lipid profiles and plasma SPM concentrations were examined at baseline and week 6. Generalized linear mixed models examined the effect of forage upon dust exposure, BALF cytology, Ω‐3, and SPM concentrations. Results Respirable dust was significantly higher for horses fed hay (least‐square mean ± s.e.m. 0.081 ± 0.007 mg/m3) when compared with steamed hay (0.056 ± 0.005 mg/m3, P = .01) or haylage (0.053 ± 0.005 mg/m3, P

Ibrahim Traore,1 Guillaume Eberst,1– 3 Fréderic Claudé,1 Lucie Laurent,1 Aurelia Meurisse,2,3 Sophie Paget-Bailly,2,3 Pauline Roux-Claudé,1 Pascale Jacoulet,1 Cindy Barnig,1 Rachel Martarello,1 Bastien Poirson,4 Kevin Bouiller,5 Catherine Chirouze,5 Julien Behr,6 Franck Grillet,6 Ophélie Ritter,1 Sébastien Pili-Floury,7 Hadrien Winiszewski,8 Emmanuel Samain,7,9 Gilles Capellier,8– 10 Virginie Westeel1– 3 1Respiratory Medicine Department, University Hospital of Besançon, Besançon, France; 2Methodology and Quality of Life in Oncology Unit, University Hospital, Besançon, France; 3UMR 1098, University of Franche-Comté, Besançon, France; 4Department of Geriatrics, University Hospital of Besançon, Besançon, France; 5Department of Infectious Disease, University Hospital of Besançon, Besançon, France; 6Department of Radiology, University Hospital of Besançon, Besançon, France; 7Anesthesia and Intensive Care Unit, University Hospital of Besançon, Besançon, France; 8Medical Intensive Care Unit, University Hospital of Besançon, Besançon, France; 9Research Unit EA3920, Université de Franche Comté, Besançon, France; 10Australian and New Zealand Intensive Care Research Center, Department of Epidemiology and Preventive Medicine, Monash University, Monash, AustraliaCorrespondence: Ibrahim Traore, Respiratory Medicine Department, University Hospital of Besançon, Besançon, France, Email traore.ibrahim180@gmail.comBackground: Sleep apnea (SA) was reported as possibly exacerbating symptoms of COVID-19, a disease induced by SARS-CoV-2 virus. The same comorbidities are common with both pathologies. This study aimed to estimate the prevalence, characteristics of SA and variation in AHI three months after severe COVID-19 requiring intensive care unit (ICU) admission.Methods: A prospective cohort of patients admitted to ICU for severe COVID-19 underwent an overnight home polygraphy 3 months after onset of symptoms, as part of a comprehensive follow-up program (pulmonary function tests, 6-minute walk tests and chest CT-scan). Patients with an apnea hypopnea index (AHI) ≥ 5 were considered as having SA. We performed a comparative descriptive analysis of 2 subgroups according to the existence, severity of SA and indication for effective SA treatment: patients with absent or mild SA (AHI < 15) vs patients with moderate to severe SA (AHI ≥ 15).Results: Among 68 patients included, 62 (91%) had known comorbidities (34 hypertension, 21 obesity, 20 dyslipidemia, 16 type 2 diabetes). It has been observed a preexisting SA for 13 patients (19.1%). At 3 months, 62 patients (91%) had SA with 85.5% of obstructive events. Twenty-four patients had no or a mild SA (AHI < 15) and 44 had moderate to severe SA (AHI ≥ 15). Ischemic heart disease exclusively affected the moderate to severe SA group. Except for thoracic CT-scan which revealed less honeycomb lesions, COVID-19 symptoms were more severe in the group with moderate to severe SA, requiring a longer curarization, more prone position sessions and more frequent tracheotomy.Conclusion: SA involved 91% of patients in our population at 3 months of severe COVID-19 and was mainly obstructive type. Although SA might be a risk factor as well as consequences of ICU care in severe COVID-19 infection, our results underline the importance of sleep explorations after an ICU stay for this disease.Keywords: SARS-CoV-2, pneumonia, obstructive sleep apnea syndrome, intensive care unit

Abstract Deep neural networks (DNNs) are widely used to handle many difficult tasks, such as image classification and malware detection, and achieve outstanding performance. However, recent studies on adversarial examples, which have maliciously undetectable perturbations added to their original samples that are indistinguishable by human eyes but mislead the machine learning approaches, show that machine learning models are vulnerable to security attacks. Though various adversarial retraining techniques have been developed in the past few years, none of them is scalable. In this paper, we propose a new iterative adversarial retraining approach to robustify the model and to reduce the effectiveness of adversarial inputs on DNN models. The proposed method retrains the model with both Gaussian noise augmentation and adversarial generation techniques for better generalization. Furthermore, the ensemble model is utilized during the testing phase in order to increase the robust test accuracy. The results from our extensive experiments demonstrate that the proposed approach increases the robustness of the DNN model against various adversarial attacks, specifically, fast gradient sign attack, Carlini and Wagner (C&W) attack, Projected Gradient Descent (PGD) attack, and DeepFool attack. To be precise, the robust classifier obtained by our proposed approach can maintain a performance accuracy of 99% on average on the standard test set. Moreover, we empirically evaluate the runtime of two of the most effective adversarial attacks, i.e., C&W attack and BIM attack, to find that the C&W attack can utilize GPU for faster adversarial example generation than the BIM attack can. For this reason, we further develop a parallel implementation of the proposed approach. This parallel implementation makes the proposed approach scalable for large datasets and complex models.

Background: Although asthma mortality declined sharply until the mid-2000s, a stagnation in mortality has been observed over the past decade in different countries. Objective: The objective of this study is to describe healthcare resource consumption for patients who died from asthma in France. Method: This study was conducted using data from the French National Health Data System. Patients who died from asthma between 2013 and 2017 were identified by the ICD10 codes J45 and J46. Health care consumption data were collected. Patients were categorized into four categories according to age: ⩾75, (18–75), (12–18), (0–12). Daily doses of ICS were categorized according to GINA guidelines. Results: A total of 3829 patients were included. No ICS or an inadequate ICS dose was observed in 43.8%, 50.6%, 48.1%, and 54.0% of patients aged ⩾75, (18–74), (12–18), and (0–12) years, respectively. Dispensation of six or more SABA canisters was observed in 37.2%, 49.0%, and 70.3% of patients aged of ⩾75, (18–75), and (12–18) years, respectively. Omalizumab dispensation rate was very low [1.1% and 2.8% in patients aged ⩾75 and (18–75) years)]. The proportion of patients with a pulmonologist office visit was 13.8% and 14.6% in patients ⩾75 and (18–75) years, respectively. A lung function test was noted in only 18.6%, 28.3%, and 25.9% of patients ⩾75, (18–75) and (12–18) years, respectively. Conclusion: Half of the patients who died from asthma received inadequate ICS doses and only a small proportion had access to biological therapies. Less than 15% were referred to a specialist.

Equine bronchoalveolar lavage (BAL) is usually performed with 250–500 mL of isotonic saline at pH 5.5. The acidic pH of saline may cause an increase in airway neutrophil count 48 h after BAL. Other isotonic solutions such as Ringer’s solution, phosphate-buffered saline (PBS) or Plasma-Lyte 148® have a neutral pH of 7.4 and might be a better choice for BAL by not provoking inflammation and the influx of neutrophils into airways. BAL was performed in four healthy horses in four different lung lobes using four different solutions in a randomized crossover design. In each lobe, BAL was performed twice with a 48 h interval using 250 mL of solution. Automated total nucleated cell counts (TNCs) were recorded, and differential cell counts in lavage fluid were determined by two investigators blinded to treatments. The mean volume of BAL fluid retrieved was 51 ± 14%. The mean neutrophil percentage (%N) increased from 1.5 ± 0.9% to 14.7 ± 9.6% at 48 h (p < 0.001) but was not significantly affected by the solution used or the lung lobe sampled. In conclusion, in this study, the influx of neutrophils into airways after BAL was independent of the type of isotonic solution used and the lung lobe sampled. Saline remains an appropriate solution for BAL in horses.

Asthma is caused by hyperreactivity to benign antigens, with humoral immunity orchestrated by interleukin-4 (IL-4) and IL-13 being the key etiological factor. Here the authors show, in humanized mouse models, that dual vaccination against IL-4 and IL-13 induces their durable suppression ameliorate experimental asthma, and to hint clinical translation.

Abstract Background The autologous nerve graft, despite its donor site morbidity and unpredictable functional recovery, continues to be the gold standard in peripheral nerve repair. Rodent research studies have shown promising results with cell transplantation of human adipose-derived stem cells (hADSC) in a bioengineered conduit, as an alternative strategy for nerve regeneration. To achieve meaningful clinical translation, cell therapy must comply with biosafety. Cell extraction and expansion methods that use animal-derived products, including enzymatic adipose tissue dissociation and the use of fetal bovine serum (FBS) as a culture medium supplement, have the potential for transmission of zoonotic infectious and immunogenicity. Human-platelet-lysate (hPL) serum has been used in recent years in human cell expansion, showing reliability in clinical applications. Methods We investigated whether hADSC can be routinely isolated and cultured in a completely xenogeneic-free way (using hPL culture medium supplement and avoiding collagenase digestion) without altering their physiology and stem properties. Outcomes in terms of stem marker expression (CD105, CD90, CD73) and the osteocyte/adipocyte differentiation capacity were compared with classical collagenase digestion and FBS-supplemented hADSC expansion. Results We found no significant differences between the two examined extraction and culture protocols in terms of cluster differentiation (CD) marker expression and stem cell plasticity, while hADSC in hPL showed a significantly higher proliferation rate when compared with the usual FBS-added medium. Considering the important key growth factors (particularly brain-derived growth factor (BDNF)) present in hPL, we investigated a possible neurogenic commitment of hADSC when cultured with hPL. Interestingly, hADSC cultured in hPL showed a statistically higher secretion of neurotrophic factors BDNF, glial cell-derived growth factor (GDNF), and nerve-derived growth factor (NFG) than FBS-cultured cells. When cocultured in the presence of primary neurons, hADSC which had been grown under hPL supplementation, showed significantly enhanced neurotrophic properties. Conclusions The hPL-supplement medium could improve cell proliferation and neurotropism while maintaining stable cell properties, showing effectiveness in clinical translation and significant potential in peripheral nerve research.

Thibaud Soumagne,1 Alicia Guillien,2 Nicolas Roche,3 Isabella Annesi-Maesano,4 Pascal Andujar,5,6 Lucie Laurent,1 Stéphane Jouneau,7,8 Martial Botebol,9 Jean-Jacques Laplante,10 Jean-Charles Dalphin,1,11 Bruno Degano12,13 1Service de Pneumologie, Oncologie Thoracique et Allergologie Respiratoire, CHU de Besançon, Besançon, France; 2Equipe d’Epidémiologie Environnementale, Institute for Advanced Biosciences, Centre de Recherche UGA, INSERM U1209, CNRS UMR 5309, Grenoble, France; 3Service de Pneumologie, Groupe Hospitalier Cochin, Site Val de Grâce, AP-HP and Université Paris Descartes (EA2511), Sorbonne-Paris-Cité, Paris, France; 4Epidemiology of Allergic and Respiratory Diseases UMR-S 707 Inserm/UPMC, Université Paris 6, Paris, France; 5Centre Hospitalier Intercommunal de Créteil, Service de Pathologie Professionnelle et de l’Environnement, Créteil, France; 6Université Paris-Est Créteil, Faculté de Médecine, Créteil, France; 7Service de Pneumologie, CHU de Rennes, Rennes, France; 8Univ Rennes, CHU Rennes, Inserm, EHESP, Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) – UMR-S 1085, Rennes, France; 9Fédération des Maisons de Santé Comtoises (FéMaSaC), Beure, France; 10Mutualité Sociale Agricole (MSA), Besançon, France; 11UMR CNRS Chrono Environnement, Université de Franche-Comté, Besançon, France; 12Service Hospitalier Universitaire Pneumologie Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble, Alpes, France; 13Université Grenoble Alpes, INSERM U 1042, Grenoble, FranceCorrespondence: Thibaud Soumagne Email thibaud_soumagne@live.frBackground: Comorbidities including cardiovascular diseases are very common in chronic obstructive pulmonary disease (COPD) secondary to tobacco smoking and contribute to the overall severity of the disease. In non-smoking COPD, which accounts for about 25% of COPD cases worldwide, current knowledge on the frequency and determinants of comorbidities remains scarce. The aims of the current study were to assess the frequency of major comorbidities and to evaluate their determinants in a group of non-selected patients with mild-to-moderate COPD who were exposed to organic dust (dairy farmers), to tobacco smoking, or to both, and in controls without COPD who were exposed to organic dust (dairy farmers), or to tobacco smoking, or to both, or who were without exposure.Patients and Methods: A total of 4665 subjects (2323 dairy farmers and 2342 non-farmers) including 355 patients with COPD and 4310 controls with normal spirometry were recruited through a large COPD screening program. Self-reported physician-diagnosed diseases with plausible links to COPD were recorded in this cross-sectional study.Results: Whatever the exposure, cardiovascular comorbidities were not more frequent in patients with COPD than their counterparts without airflow limitation. A higher risk of major cardiovascular comorbidities was associated with tobacco smoking and a lower risk was associated with exposure to organic dusts.Conclusion: Tobacco smoking (but not COPD) is associated with higher frequency of cardiovascular comorbidities. By contrast, being a dairy farmer exposed to organic dusts is associated with a lower frequency of the same comorbidities. This reinforces the crucial need for controlling established cardiovascular risk factors even in patients with mild-to-moderate COPD.Keywords: cardiovascular diseases, chronic obstructive pulmonary disease, comorbidity, diabetes mellitus, tobacco smoking

Neutrophils are the most abundant leukocytes in human blood and critical actors of the immune system. Many neutrophil functions and facets of their activity in vivo were revealed by studying genetically modified mice or by tracking fluorescent neutrophils in animals using imaging approaches. Assessing the roles of neutrophils can be challenging, especially when exact molecular pathways are questioned or disease states are interrogated that alter normal neutrophil homeostasis. This review discusses the main in vivo models for the study of neutrophils, their advantages and limitations. The side-by-side comparison underlines the necessity to carefully choose the right model(s) to answer a given scientific question, and exhibit caveats that need to be taken into account when designing experimental procedures. Collectively, this review suggests that at least two models should be employed to legitimately conclude on neutrophil functions.

Alicia Guillien,1 Lucie Laurent,2 Thibaud Soumagne,3 Marc Puyraveau,4 Jean-Jacques Laplante,5 Pascal Andujar,6 Isabella Annesi-Maesano,7 Nicolas Roche,8,9 Bruno Degano,1,* Jean-Charles Dalphin3,* 1Research Unit EA 3920, Franche-Comté University, Besançon, France; 2Department of Clinical Physiology, University Hospital, Besançon, France; 3Department of Respiratory Diseases, University Hospital, Besançon, France; 4Clinical Methodology Center, University Hospital, Besançon, France; 5Department of Occupational Diseases, Mutualité sociale agricole, Besançon, France; 6University of Medical Sciences, Paris-est Créteil University, Créteil, France; 7Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Saint-Antoine Medical School, Paris, France; 8Respiratory and Intensive Care Medicine, Cochin Hospital (AP-HP), University Paris Descartes, Paris, France; 9Research Unit EA 2511, University Paris Descartes, Paris, France *These authors contributed equally to this work Background: Chronic obstructive pulmonary disease (COPD) and farming are two conditions that have been associated with an increased risk of anxiety and depression. Dairy farming is an independent risk factor for COPD.Objective: To test the hypotheses that the prevalence of anxiety and/or depression is higher in dairy farmers with COPD than in farmers without COPD, and higher in dairy farmers with COPD than in non-farmers with COPD.Methods: Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale in 100 dairy farmers with COPD (DF-COPD), 98 dairy farmers without COPD (DF-controls), 85 non-farming patients with COPD (NF-COPD) and 89 non-farming subjects without COPD (NF-controls), all identified by screening in the Franche-Comté region of France. Anxiety and depression were considered present when the Hospital Anxiety and Depression Scale score was ≥8. COPD was defined by a post-bronchodilator forced expiratory volume in 1 second/forced vital capacity ratio

Plant competition and deer browsing are two main factors which limit tree recruitment. We examined natural tree-recruitment processes under continuous-tree-cover management. Changes in plant communities and tree regeneration were monitored over an eight-year period at two different sites in a temperate hardwood forest in the North-East of France. We used paired control plot (unfenced areas, free access to deer) and exclosures (fenced areas, excluding deer) at both sites. Shade-tolerant browsing-tolerant opportunistic species (beech, Fagus sylvatica at site 1 and bramble, Rubus spp. at site 2) were present in low numbers at the beginning of the study. We found that these species used a sit-and-wait strategy, waiting for opportunities to proliferate (thinning and deer exclusion). In the exclosure at site 1, beech proliferate slowly. In the exclosure at site 2, bramble proliferated enough during the first two growing seasons to prevent tree recruitment. Thus, fencing encouraged beech sapling or bramble growth, and this growth in turn was detrimental to the richness and diversity of the plant community. The two study cases presented show that both plant competition and deer browsing can be problematic for tree recruitment. Our results further suggest that excluding deer is not sufficient to enhance the growth of browse-sensitive and moderately shade-tolerant tree species such as oaks (Quercus petraea and Q. robur).

Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

TNFSF14 (LIGHT) contributes to airway inflammation and remodelling. Here the authors show that TNFSF14 acting on its receptor TNFRSF14 on mast cells enhances their IgE-dependent activation and that interference with this pathway attenuates features of asthma pathology in mice.

Contact hypersensitivity (CHS) is a common T cell-mediated skin disease induced by epicutaneous sensitization to haptens. Mast cells (MCs) are widely deployed in the skin and can be activated during CHS responses to secrete diverse products, including some with pro-inflammatory and anti-inflammatory functions. Conflicting results have been obtained regarding pathogenic versus protective roles of MCs in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products in vivo. Notably, fluorescent avidin-based two-photon imaging approaches enable in vivo selective labeling and simultaneous tracking of MC secretory granules (e.g., during MC degranulation) and MC gene activation by real-time longitudinal intravital microscopy in living mice. The combination of such genetic and imaging tools has shed new light on the controversial role played by MCs in mouse models of CHS. On the one hand, they can amplify CHS responses of mild severity while, on the other hand, can limit the inflammation and tissue injury associated with more severe or chronic models, in part by representing an initial source of the anti-inflammatory cytokine IL-10.

Gouty arthritis is caused by the deposition of monosodium urate (MSU) crystals in joints. Despite many treatment options for gout, there is a substantial need for alternative treatments for patients unresponsive to current therapies. Tyrosine kinase inhibitors have demonstrated therapeutic benefit in experimental models of antibody-dependent arthritis and in rheumatoid arthritis in humans, but to date, the potential effects of such inhibitors on gouty arthritis has not been evaluated. Here we demonstrate that treatment with the tyrosine kinase inhibitor imatinib mesylate (imatinib) can suppress inflammation induced by injection of MSU crystals into subcutaneous air pouches or into the ankle joint of wild type mice. Moreover, imatinib treatment also largely abolished the lower levels of inflammation which developed in IL-1R1-/- or KitW-sh/W-sh mice, indicating that this drug can inhibit IL-1-independent pathways, as well as mast cell-independent pathways, contributing to pathology in this model. Imatinib treatment not only prevented ankle swelling and synovial inflammation when administered before MSU crystals but also diminished these features when administrated after the injection of MSU crystals, a therapeutic protocol more closely mimicking the clinical situation in which treatment occurs after the development of an acute gout flare. Finally, we also assessed the efficiency of local intra-articular injections of imatinib-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles in this model of acute gout. Treatment with low doses of this long-acting imatinib:PLGA formulation was able to reduce ankle swelling in a therapeutic protocol. Altogether, these results raise the possibility that tyrosine kinase inhibitors might have utility in the treatment of acute gout in humans.

H89 is a potent inhibitor of Protein Kinase A (PKA) and Mitogen- and Stress-Activated protein Kinase 1 (MSK1) with some inhibitory activity on other members of the AGC kinase family. H89 has been extensively used in vitro but its anti-inflammatory potential in vivo has not been reported to date. To assess the anti-inflammatory properties of H89 in mouse models of asthma.Mice were sensitized intraperitoneally (i.p.) to ovalbumin (OVA) with or without alum, and challenged intranasally with OVA. H89 (10 mg/kg) or vehicle was given i.p. two hours before each OVA challenge. Airway hyperresponsiveness (AHR) was assessed by whole-body barometric plethysmography. Inflammation was assessed by the total and differential cell counts and IL-4 and IL-5 levels in bronchoalveolar lavage (BAL) fluid. Lung inflammation, mucus production and mast cell numbers were analyzed after histochemistry. We show that treatment with H89 reduces AHR, lung inflammation, mast cell numbers and mucus production. H89 also inhibits IL-4 and IL-5 production and infiltration of eosinophils, neutrophils and lymphocytes in BAL fluid.Taken together, our findings implicate that blockade of AGC kinases may have therapeutic potential for the treatment of allergic airway inflammation.

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.

Contact hypersensitivity (CHS) is a common T cell-mediated skin disease induced by epicutaneous sensitization to haptens. Mast cells (MCs) are widely deployed in the skin and can be activated during CHS responses to secrete diverse products, including some with pro-inflammatory and anti-inflammatory functions. Conflicting results have been obtained regarding pathogenic versus protective roles of MCs in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products in vivo. Notably, fluorescent avidin-based two-photon imaging approaches enable in vivo selective labeling and simultaneous tracking of MC secretory granules (e.g., during MC degranulation) and MC gene activation by real-time longitudinal intravital microscopy in living mice. The combination of such genetic and imaging tools has shed new light on the controversial role played by MCs in mouse models of CHS. On the one hand, they can amplify CHS responses of mild severity while, on the other hand, can limit the inflammation and tissue injury associated with more severe or chronic models, in part by representing an initial source of the anti-inflammatory cytokine IL-10.

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (Fc[gamma]Rs) in Fc[gamma]R- humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce Fc[gamma]R-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging Fc[gamma]Rs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions., Introduction IgE antibodies (Abs) are key mediators of allergic diseases (1-3). Upon exposure to an allergen in allergic patients, such allergen is recognized by IgE bound to the high-affinity receptor [...]