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There is still considerable confusion and debate about the appropriate methods for analyzing prevalence studies, and a number of recent papers have argued that prevalence ratios are the preferred method [...]

The rising prevalence of allergies represents an increasing socioeconomic burden. A detailed understanding of the immunological mechanisms that underlie the development of allergic disease, as well as the processes that drive immune tolerance to allergens, will be instrumental in designing therapeutic strategies to treat and prevent allergic disease. Improved characterization of individual patients through the use of specific biomarkers and improved definitions of disease endotypes are paving the way for the use of targeted therapeutic approaches for personalized treatment. Allergen-specific immunotherapy and biologic therapies that target key molecules driving the Th2 response are already used in the clinic, and a wave of novel drug candidates are under development. In-depth analysis of the cells and tissues of patients treated with such targeted interventions provides a wealth of information on the mechanisms that drive allergies and tolerance to allergens. Here, we aim to deliver an overview of the current state of specific inhibitors used in the treatment of allergy, with a particular focus on asthma and atopic dermatitis, and provide insights into the roles of these molecules in immunological mechanisms of allergic disease., Immunological mechanisms of allergy and tolerance Allergic sensitization and type I and IV hypersensitivity reactions. Allergies develop as a result of an immune response to distinct environmental protein antigens, called [...]

Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD. The keratinocyte differentiation process is under tight regulation. During epidermal differentiation, keratinocytes sequentially switch gene expression programs, resulting in terminal differentiation and the formation of a mature stratum corneum, which is essential for the skin to prevent allergen or microbial invasion. Abnormalities in keratinocyte differentiation in AD skin result in hyperproliferation of the basal layer of epidermis, inhibition of markers of terminal differentiation, and barrier lipid abnormalities, compromising skin barrier and antimicrobial function. There is also compelling evidence for epithelial dysregulation in asthma, food allergy, eosinophilic esophagitis, and allergic rhinosinusitis. This Review examines current epithelial barrier repair strategies as an approach for allergy prevention or intervention., Allergic diseases such as atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis affect more than 30% of the population (1-3). These diseases have in common a dysfunctional epithelial [...]

Allergic disorders include food allergy, allergic rhinitis, and certain forms of asthma resulting from the inappropriate development of immune responses to otherwise innocuous aeroallergens and foods. In this issue of the JCI, Thouvenot and Roitel et al. explore transcription infidelity as a mechanism that underlies the ability of these benign proteins to become allergens. Some foods and bioaerosols that produce allergies have RNA polymerase with a propensity to generate RNA gaps, thereby causing translational frameshifts. These frameshifts often create cationic carboxy-terminus residues that replace hydrophobic amino acids and have enhanced MHC binding, resulting in the tendency to provoke immune responses. IgE antibody responses initiated by these variant transcripts can later lead to IgE against the native molecule and also explain how anaphylaxis may occur in individuals who lacked specific IgE when tested using native protein reagents. This study has the potential to transform the diagnosis and treatment of allergic disorders., Mechanisms by which proteins may become allergens The human organism is targeted by a myriad of foreign proteins each day for which maintenance of health requires immune ignorance. These foreign [...]

Just as in clay moulding or glass blowing, physically sculpting biological structures requires the constituent material to locally flow like a fluid while maintaining overall mechanical integrity like a solid. Disordered soft materials, such as foams, emulsions and colloidal suspensions, switch from fluid-like to solid-like behaviours at a jamming transition.sup.1-4. Similarly, cell collectives have been shown to display glassy dynamics in 2D and 3D.sup.5,6 and jamming in cultured epithelial monolayers.sup.7,8, behaviours recently predicted theoretically.sup.9-11 and proposed to influence asthma pathobiology.sup.8 and tumour progression.sup.12. However, little is known about whether these seemingly universal behaviours occur in vivo.sup.13 and, specifically, whether they play any functional part during embryonic morphogenesis. Here, by combining direct in vivo measurements of tissue mechanics with analysis of cellular dynamics, we show that during vertebrate body axis elongation, posterior tissues undergo a jamming transition from a fluid-like behaviour at the extending end, the mesodermal progenitor zone, to a solid-like behaviour in the presomitic mesoderm. We uncover an anteroposterior, N-cadherin-dependent gradient in yield stress that provides increasing mechanical integrity to the presomitic mesoderm, consistent with the tissue transiting from a wetter to a dryer foam-like architecture. Our results show that cell-scale stresses fluctuate rapidly (within about 1 min), enabling cell rearrangements and effectively 'melting' the tissue at the growing end. Persistent (more than 0.5 h) stresses at supracellular scales, rather than cell-scale stresses, guide morphogenetic flows in fluid-like tissue regions. Unidirectional axis extension is sustained by the reported rigidification of the presomitic mesoderm, which mechanically supports posterior, fluid-like tissues during remodelling before their maturation. The spatiotemporal control of fluid-like and solid-like tissue states may represent a generic physical mechanism of embryonic morphogenesis. Cell collectives in embryonic tissues undergo a fluid-to-solid jamming transition, similar to those that occur in soft materials such as foams, emulsions and colloidal suspensions, to physically sculpt the vertebrate body axis., Author(s): Alessandro Mongera [sup.1] [sup.2] [sup.7] , Payam Rowghanian [sup.1] [sup.2] , Hannah J. Gustafson [sup.1] [sup.2] [sup.3] , Elijah Shelton [sup.1] [sup.2] , David A. Kealhofer [sup.4] , Emmet [...]

Background/objectives EFFORT Asthma study is a randomized controlled trial designed to assess the effects of diet and exercise in non-obese, untrained patients with asthma. We here present results from a subgroup of participants in the diet and control group to assess the feasibility of a high protein and low glycemic index (GI) diet and the effects on body composition. Subjects/methods Of the 149 subjects who were included in the study, 76 subjects (30 males) were randomized into either a diet group (n = 38) or a control group (n = 38) and included in the present analysis. The 8 week intervention consisted of a high protein and low GI diet whilst the control group continued habitual diet. Results Thirty-three patients in the diet and 34 in the control group completed the study. The diet group reduced their energy intake by ~20% and had high dietary compliance. Intake of fatty fish doubled and GI was reduced by 8.4 units. The diet group reduced their weight by 2.3 [plus or minus] 2.2 kg vs. 0.5 [plus or minus] 1.8 (p < 0.001), fat mass by 2.2 [plus or minus] 2.0 kg vs. 0.3 [plus or minus] 1.6 kg (p < 0.001) and preserved lean body mass (-0.02 [plus or minus] 1.1 kg). The control group had no changes in body composition. Conclusions The ad libitum high protein-low GI diet resulted in a greater loss of fat mass among non-obese patients with asthma. The subjects were satisfactory and highly compliant with the dietary regimen., Author(s): Nina Rica Wium Geiker [sup.1] , Louise L. Toennesen [sup.2] , Arne Astrup [sup.1] [sup.3] , Vibeke Backer [sup.2] Author Affiliations: (1) Clinical Nutrition Research Unit, Copenhagen University Hospital [...]

Byline: S. Raghavan, Rajnarayan. Tiwari, Pankaj. Doctor, . RekhaKashyap, Asif. Mahamad, Parveen. Mansuri Background: Flexible foam industry largely uses 2,4 and 2,6 Toluene di-isocyanate as main raw materials and chronic [...]

Background: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. Objectives: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter Methods: We meta-analyzed associations between exposure to [PM.sub.10] (n = 1,949) and [PM.sub.2.5] (n = 1,551) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosinephosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. Results: Six CpGs were significantly associated [false discovery rate (FDR) Conclusions: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes., Introduction Many studies have reported adverse health effects of prenatal air pollution exposure in children, including adverse pregnancy outcomes, reduced lung growth, and increased risks of respiratory morbidity (Lamichhane et [...]

The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS).sup.1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1).sup.3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1--a member of the cadherin superfamily.sup.7,8--to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.New World hantaviruses--which cause a severe human respiratory disease--use surface glycoproteins to bind to the human protocadherin-1 protein and enter endothelial cells in vitro; depleting protocadherin-1 in Syrian golden hamsters largely protects against disease., Author(s): Rohit K. Jangra [sup.1] , Andrew S. Herbert [sup.2] , Rong Li [sup.3] , Lucas T. Jae [sup.4] [sup.12] , Lara M. Kleinfelter [sup.1] , Megan M. Slough [sup.1] [...]

The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1.sup.+ pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that we term 'hillocks'; and disease-relevant subsets of tuft and goblet cells. We developed 'pulse-seq', combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse (Cftr) and human (CFTR). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease.Single-cell RNA sequencing analysis identifies cell types and lineages in airway epithelium, including the pulmonary ionocyte, a new cell type predominantly expressing the cystic fibrosis gene CFTR., Author(s): Daniel T. Montoro [sup.1] [sup.2] [sup.3] [sup.4] , Adam L. Haber [sup.4] , Moshe Biton [sup.4] [sup.5] , Vladimir Vinarsky [sup.1] [sup.2] [sup.3] , Brian Lin [sup.1] [sup.2] [sup.3] [...]

Paracrine signaling from lung epithelium to the surrounding mesenchyme is important for lung SMC development and function and is a contributing factor in an array of pulmonary diseases such as bronchopulmonary dysplasia, pulmonary hypertension, and asthma. Wnt7b, which is exclusively expressed in the lung epithelium, is important for lung vascular smooth muscle integrity, but the underlying mechanism by which Wnt signaling regulates lung SMC development is unclear. In this report, we have demonstrated that Wnt7b regulates a program of mesenchymal differentiation in the mouse lung that is essential for SMC development. Genetic loss-of-function studies showed that Wnt7b and [beta]-catenin were required for expression of Pdgfr[alpha] and Pdgfr[beta] and proliferation in pulmonary SMC precursors. In contrast, gain-of-function studies showed that activation of Wnt signaling increased the expression of both Pdgfr[alpha] and Pdgfr[beta] as well as the proliferation of SMC precursors. We further showed that the effect on Pdgfr expression was, in part, mediated by direct transcriptional regulation of the ECM protein tenascin C (Tnc), which was necessary and sufficient for Pdgfr[alpha]/[beta] expression in lung explants. Moreover, this pathway was highly upregulated in a mouse model of asthma and in lung tissue from patients with pulmonary hypertension. Together, these data define a Wnt/Tnc/Pdgfr signaling axis that is critical for smooth muscle development and disease progression in the lung., Introduction The mammalian king is a highly complex organ that develops from the anterior foregut through interactions between the anterior foregut endoderm and the surrounding mesenchyme. Early in development epithelial-mesenchymal [...]

BACKGROUND: Research has shown associations between pediatric asthma outcomes and airborne particulate matter (PM). The importance of particle components remains to be determined. METHODS: We followed a panel of 45 [...]

OBJECTIVE: The associations between ozone concentrations measured outdoors and both morbidity and mortality may be partially due to indoor exposures to ozone and ozone-initiated oxidation products. In this article I [...]

Asthma is a multifactorial airway disease that arises from a relatively common genetic background interphased with exposures to allergens and airborne irritants. The rapid rise in asthma over the past [...]

New York City Firefighters (FDNY-FFs) were exposed to particulate matter and combustion/ pyrolysis products during and after the World Trade Center (WTC) collapse. Ten months after the collapse, induced sputum [...]

Studies have suggested that children living close to busy roads may have impaired respiratory health. This study was designed to test the hypothesis that exposure to exhaust from heavy traffic [...]

Context.--Surgical and pathologic handling of lung physically affects lung tissue. This leads to artifacts that alter the morphologic appearance of pulmonary parenchyma. Objective.--To describe and illustrate mechanisms of ex vivo artifacts that may lead to diagnostic pitfalls. Design.--In this study 4 mechanisms of ex vivo artifacts and corresponding diagnostic pitfalls are described and illustrated. Results.--The 4 patterns of artifacts are: (1) surgical collapse, due to the removal of air and blood from pulmonary resections; (2) ex vivo contraction of bronchial and bronchiolar smooth muscle; (3) clamping edema of open lung biopsies; and (4) spreading of tissue fragments and individual cells through a knife surface. Morphologic pitfalls include diagnostic patterns of adenocarcinoma, asthma, constrictive bronchiolitis, and lymphedema. Conclusion.--Four patterns of pulmonary ex vivo artifacts are important to recognize in order to avoid morphologic misinterpretations. (Arch Pathol Lab Med. 2016;140:212-220; doi: 10.5858/arpa.2015-0292-OA), Normal lung histology including usual tissue artifacts is well described. (1) Unfortunately, virtually all writings and images are concerned with 'static' morphologic findings. Recently, attention has been focused on dynamic [...]