Wednesday, November 5, 2014
Despite the improvement of air quality in the U.S. since the enhancement of the Clean Air Act in 1990, exposures to outdoor and indoor air pollution remain a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Clinical studies have shown that significant asthma exacerbations were attributable to air pollution exposure, as a result of living in densely populated cities with elevated ambient fine particulate matter (PM2.5) and ozone (O3). In their review, Miller and Peden highlight new data on the effects of pollutant exposure on the innate and adaptive immune responses, genetic and epigenetic modifiers of response to pollutants, and potential interventions to mitigate these effects (J Allergy Clin Immunol 2014; 134(5): 1001-1008).
Several studies have determined that the effects of air pollution are heightened during the prenatal period. This suggests that there is greater vulnerability of the growing lungs and the developing immune system, thus predisposing towards more airway inflammation later in life. Similarly, studies suggest that factors such as chronic low-grade inflammation associated with obesity and stress may predispose towards asthma. Furthermore, the authors describe evidence that the mechanism behind these effects alter the innate and adaptive immunity, inducing a heightened immune response. Another emerging area of investigation is the effects of the environment on oxidative stress genes such as glutathione S-transferase (GST) genes as well as genes associated with Toll-like receptors of the innate immune system. Newer mechanistic lines of investigation focus on epigenetic regulation, and identifying asthma genes whose imprinting may be disrupted by environmental exposures.
Pollutant induced asthma exacerbations are less frequent in patients that use inhaled corticosteroids, suggestive that interventions that target acute inflammatory responses are beneficial, however future studies are required to test the efficacy of interventions in this population. Actively minimizing both indoor and outdoor pollutants and government air care regulations could decrease pollutant impacts on allergic lung disease.
Question for the authors:
How has the improved air quality over recent decades relate to the incidence of pollution related asthma exacerbations?
In studies of both the Atlanta and Beijing Olympic Games, interventions that decreased automotive and point-source combustion were associated with decreased asthma morbidity. Future studies are needed to investigate more thoroughly whether improvements in air quality contribute to fewer asthma exacerbations. This remains a difficult challenge to show as even the best designed epidemiological studies are unable to prove causality.
In the U.S., ethnic minorities and the economically disadvantaged are disproportionately exposed to chronic psychological stressors such as poverty, discrimination and violence. Recent findings support a causal link between exposure to these stressors at the individual or community level and asthma morbidity. Moreover, current evidence suggests that the relation between stress and asthma is complex and partially mediated or modified by environmental exposures, adherence with treatment, co-morbidities and coping mechanisms.
In a review article, Rosenberg et al discuss recent findings suggesting potential biologic mechanisms for stress-related asthma, including changes in the methylation and expression of genes that regulate behavioral, autonomic, neuroendocrine, and immunologic responses to stress (J Allergy Clin Immunol 2014; 134(5): 1009-1015). For example, there may be susceptibility genes that predispose chronically stressed youth to both post-traumatic stress disorder and asthma. Moreover, recent studies show that low socioeconomic status in early life may program sustained resistance to glucocorticoid signaling, which could undermine the efficacy of steroid therapy in subjects who develop asthma.
Wednesday, October 8, 2014
In the October 2014 issue of Journal of Allergy and Clinical Immunology, Brough et al show that early environmental peanut exposure from house dust increases the risk of peanut allergy in children with impaired skin barrier. Children were assessed for peanut allergy and had genetic studies to determine whether they could produce normal filaggrin levels. Dust samples were collected and analyzed for peanut concentration to determine in which groups of children environmental peanut exposure influenced the development of peanut allergy. In normal children environmental peanut exposure did not influence the development of peanut allergy. In contrast, in filaggrin deficient children the risk of peanut allergy increased as peanut concentration in the house dust increased. To read the full article, please click here: http://bit.ly/1qkfHeY
Thursday, October 2, 2014
Atopic eczema (AE, syn. atopic dermatitis) is a major medical condition that causes substantial burden to patients, their families, and society. Various different interventions exist, many of which have been assessed in randomized controlled trials (RCTs). However, there is a lack of core outcome sets for atopic eczema (AE) which is a major obstacle for advancing evidence-based treatment. There are several different instruments identified to assess clinical signs of AE and the global Harmonizing Outcome Measures for Eczema (HOME) initiative has already defined clinical signs, symptoms, quality of life, and long-term control of flares as core outcome domains for AE-trials. To resolve the current lack of standardization of the assessment of clinical signs of AE, the HOME initiative followed a structured process of systematic reviews and international consensus sessions to identify one core outcome measurement instrument to assess clinical signs in all future AE-trials (J Allergy Clin Immunol 2014; 134(4): 800-807).
The authors determined that from 16 different instruments identified to assess clinical signs of AE, only the Eczema Area and Severity Index (EASI) and the objective Scoring Atopic Dermatitis Index (objective SCORAD) were identified as sufficiently tested for inclusion in the core outcome set. The EASI has adequate validity, responsiveness, internal consistency, and intra-observer reliability. The objective SCORAD has adequate validity, responsiveness, and inter-observer reliability, but unclear intra-observer reliability to measure clinical signs of AE. In an international consensus study, patients, physicians, nurses, methodologists, and pharmaceutical industry representatives agreed that EASI is the preferred core instrument to measure clinical signs in all future AE-trials. The EASI was chosen as the core outcome measure for clinical trials because (1) it only includes the 4 essential signs, (2) assesses the severity of AE signs at multiple body sites, rather than at a single representative site for each sign, and (3) gives the extent of AE lesions sufficient weighting.
The HOME initiative recommends that all investigators, pharmaceutical industry, and regulatory authorities observe this consensus and include the EASI in all future atopic eczema trials to enable improved evidence-based decision making and scientific communication in the future. This does not preclude the use of other scales in trials (such as SCORAD) in addition to the core outcome measure. Better training materials for use of EASI are in preparation and will be freely available via the HOME website (). Furthermore, the process of standardization and selection of measurement instruments for the assessment of the other core outcome domains of AE, i.e. symptoms such as pruritus and sleeping problems, quality of life and long-term control of flares, is currently underway.
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and often precedes the development of food allergy and asthma. The defective skin barrier in AD is thought to allow the absorption of allergens through the skin. This promotes systemic allergen sensitization, contributing to the development of food allergy and asthma, as well as skin infections such as Staphylococcus aureus and herpes simplex virus (HSV). This month’s JACI focuses on the importance of both genetic and acquired causes of epithelial skin barrier dysfunction in driving the natural history of AD. In their review, Donald Leung and Emma Guttman-Yassky summarize current insights into AD that may lead to new treatment approaches, including several articles published in this month’s journal (J Allergy Clin Immunol 2014; 134(4): 769-779).
The causes of AD are complex and driven by a combination of genetic, environmental and immunologic factors which likely account for heterogeneity of AD onset, severity and natural history of the disease. While there is currently no cure for AD, recent studies suggest prevention of AD can be achieved by early interventions that protect the skin barrier such as emollients and topical anti-inflammatory treatments. Importantly, the control of lesional AD may improve long term outcomes not only in AD, but in allergic diseases of the gastrointestinal and respiratory tracts as well, due to the reduction of associated allergen sensitization.
Although current treatment options for AD are limited, the authors explain that in addition to Th2 antagonists (i.e. the anti IL-4R drug dupilumab), determining the key role of TSLP-receptor signaling and IL-22 that involve clinical trials with agents that target TSLP, Th22, and TH17/IL-23 will be of interest. Furthermore, the selection of therapeutics for patients with differing degrees of disease severity and /or phenotypes should be guided by defining the extent of activation in the skin and blood. For example, anti IL-23/IL-17 might provide beneficial responses particularly in intrinsic AD patients. The individual contributions of the TH22, Th17, and Th2 immune pathways to the disease phenotype will be clarified through clinical trials coupled with mechanistic studies that are currently in progress. This comprehensive review highlights the importance of translational medicine, from animal models to clinical trials, and how this approach is advancing AD research.
Questions for the authors:
Recently, both basic science and clinical research have provided novel insights into the prevention, identification, and treatment options for AD. Do you anticipate these findings to improve outcomes for not only AD but other allergic diseases as well?
Yes, because the principle underlying causation of allergic diseases likely have in common a defective epithelial barrier and abberant immune response. This is modulated by different resident cells in each organ.
AD is most often a first step in a series of atopic diseases in the Atopic March that often leads to rhinitis, food allergy, and asthma. Could removing the first step in the Atopic March reduce the global burden of atopic disease?
Possibly. The studies in the current issue of JACI support the concept that skin barrier dysfunction enhances sensitization via environmental allergen exposure. A natural progression of this concept would be to correct the skin barrier defect to determine whether elimination of AD could prevent food allergy, asthma and allergic rhinitis.
Thursday, September 4, 2014
Allergic sensitization to inhaled antigens is increasingly common; however, the mechanisms remain poorly understood. Lung epithelial cells, once thought to be merely a passive barrier impeding allergen penetrance, have recently been shown to recognize allergens via expression of pattern recognition receptors (PRRs) and mount an innate immune response driven by the activation of the cytokine NF-кB. In their review, Lambrecht and Hammad discuss recent findings that describe epithelial cells as crucial in allergy inhalation outcomes (J Allergy Clin Immunol 2014; 134(3): 499-507).
Traditionally, allergic asthma has been characterized as a disease of the adaptive immune system, whereby lymphocytes overreact to harmless antigens and mount a type 2 immune response, subsequently causing the activation of effector cells like mast cells, basophils and eosinophils. Recently, research has been changing this view to accommodate the concept that cells of the innate immune system contribute significantly to disease pathogenesis, by recognizing allergens and providing an early warning system of cytokine production and danger signals. The authors discuss the innate immune functions of barrier epithelial cells (AECs) of the airways as they respond to inhaled allergens in mouse models. Specifically, that AECs sense the presence of allergens and relay this information to airway dendritic cells (DCs), which are the most proficient antigen presenting cells of the lung that translate information received by epithelial cells which ultimately signals the T and B lymphocytes of the adaptive immune system. In response to allergen recognition, AECs also orchestrate the early recruitment and activation of type 2 innate lymphocytes (ILC2s), using the same activation signals that also activate DCs. In turn, this activation leads to the production of type 2 cytokines and thus the adaptive immune response.
Although it is now clear how AECs are activated to ultimately recruit and activate DCs leading to Th2 immunity in mouse models in response to allergen, it is unclear if this scheme is reproduced in humans, or if it is true for all allergens. The authors explain that we are only beginning to understand how genetics and environment influence the epithelia-DC crosstalk that leads to allergy and further research will expand how the AEC/DC/ILC2 interaction bridges innate and adaptive immunity at the origin of the allergic sensitization process.
Airway epithelial cells are an important part of the innate immune system in the lung. Not only do they establish mucociliary clearance, epithelial cells produce anti-microbial peptides, chemokines, and cytokines that recruit and activate other cell types and promote pathogen clearance. Recent studies emphasize the importance of epithelial derived cytokines in the promotion of Th2 immune responses, at least in part by conditioning local dendritic cells (DCs). Epithelial cells also from a barrier to the outside world comprised of airway surface liquids, mucus, and apical junctional complexes (AJC) that form between neighboring cells. In their recent review, Georas and Rezaee discuss why defective epithelial barrier function may be linked to Th2 polarization in asthma, and propose a rheostat model of barrier dysfunction that implicates the size of inhaled allergen particles as an important factor influencing adaptive immunity (J Allergy Clin Immunol 2014; 134(3): 509-520).
Increasing evidence indicates that defective epithelial barrier function is a feature of airway inflammation in asthma. A challenge in this area is that barrier function and junctional integrity are difficult to study in the intact lung, but innovative approaches are providing new knowledge in this area. The authors review the structure and function of epithelial apical junctional complexes, emphasizing how regulation of the epithelial barrier impacts innate and adaptive immunity. They propose that epithelial barrier dysfunction is not “all or none”, but rather a graded phenomenon with consequences for allergen uptake and processing that may impact subsequent adaptive immune responses. For example, inducible barrier dysfunction caused by environmental exposures can vary in severity and will affect the penetration of fate of inhaled particles, depending on their size and other physical characteristics. While inhaled allergens alone may be capable of promoting transient barrier disruption, sustained dysfunction is more likely to follow inhalation of toxic air pollutants and respiratory viral infections. In fact, inducible barrier dysfunction is a strategy used by viruses to promote their replication, but likely represents a risk factor for allergen sensitization.
This review goes into great detail about the complexity of the epithelial barrier function and how it relates to the involvement of allergic diseases of the airway. The understanding of the basic structure and function of apical junctional complexes is necessary to determine the mechanisms involved in allergic disease, as is the understanding of epithelial permeability which is a hallmark of mucosal inflammation. Future studies of the mechanisms and consequences of airway epithelial barrier dysfunction in asthma should enhance our understanding of asthma heterogeneity as well as the pathogenesis of allergic diseases.
Questions for the authors: The importance of the epithelial barrier function is relatively new to the study of allergic diseases. What do you think are likely implications of these findings in regards to prevention of allergic diseases? For example, does research suggest that barrier dysfunction could be prevented, thus preventing the cascade of events that causes allergy?
This is a very important question in an area where we need more research. For example, we do not know the relationship between airway epithelial barrier dysfunction and whether this precedes sensitization to aeroallergens. Emerging data indicate that alterations in lung development either in utero or early in life are a risk factor for asthma, and may even precede allergic inflammation. It will be interesting to determine whether altered epithelial barrier integrity is a feature of these alterations in lung development, which will require non-invasive assays that are safe in infants. Although certain therapeutic agents have been shown to have barrier protective / restorative effects on epithelial monolayers in vitro, we have limited understanding of how most commonly used therapies affect airway epithelial integrity and tight junction expression / function in vivo. This is another area that is ripe for future research.