Why is allergy increasing? – environmental factors

Data from epidemiological studies have shown that allergic conditions have increased over the last 30–40 years, particularly in developed countries, despite a decrease in the severity of grass pollen seasons. Other epidemiological studies suggest an interaction between allergic diseases and traffic pollution, and laboratory findings indicate that diesel exhaust particles enhance sensitivity to allergens. In an in vitro study, we found evidence to suggest that cigarette smoke may render the airway epithelium more susceptible to adverse effects of allergens. Evidence from other studies indicates that O₃ and NO₂, with or without SO₂, can enhance the airway allergic response in susceptible individuals such as those with asthma and rhinitis. Studies investigating cellular and subcellular mechanisms suggest that pollutants are likely to influence the actions and interactions of a variety of cells, and lead to the synthesis of proinflammatory mediators that modulate the activity and functions of inflammatory cells.     

Effects of air pollutants on development of allergic immune responses in the respiratory tract

The increased incidence of allergic asthma in the human population worldwide has stimulated many explanatory theories. A concomitant decrease in air quality leads to epidemiological and laboratory-based studies to demonstrate a link between air pollutants and asthma. Specifically, ozone, environmental tobacco smoke, and diesel exhaust are associated with enhancement of respiratory allergy to inhaled allergens. This review summarizes the state of the knowledge, both human epidemiology and laboratory animal experiments, linking air pollution to allergy. Critical issues involve development of the lung and the fetal immune response, and the potential for substances like ozone and ETS in the air to modulate early immune responses with lifelong consequences.     

Traffic related pollutants in Europe and their effect on allergic disease

PURPOSE OF REVIEW: The prevalence and incidence of allergic diseases have increased in Europe during the last decades, as in most industrialized countries in other parts of the world. Persistent exposure to traffic related air pollution and especially particulate matter from motor vehicles has often been discussed as one of the factors responsible for this increase. This view seems to be supported by recent human and animal laboratory-based studies, which have shown that particulate pollutants, and in particular diesel exhaust particles, can enhance allergic inflammation and induce the development of allergic immune responses. However, the results from epidemiologic research provide a more complex picture. RECENT FINDINGS: It has been clearly shown in many studies that traffic related air pollution contributes to increased mortality risk; in particular in relation to cardiopulmonary causes. Traffic related air pollution also increases the risk of non-allergic respiratory symptoms and disease. However, for allergic symptoms and illnesses like asthma, allergic rhinitis, atopic dermatitis, wheeze, and allergic sensitization less consistent results have been found. This is the reason why the World Health Organisation concludes cautiously that traffic related air pollution may increase the risk of allergy development and may exacerbate symptoms in particular in susceptible subgroups. This review concentrates on recent epidemiologic studies on the long-term effects of exposure to traffic related air pollution on allergic disease in Europe. SUMMARY: In conclusion, the evidence for an increased risk for asthma and hay fever still is weak but seems to be strengthened a little. However, many questions are left open.     

Environmental risk factors and allergic bronchial asthma

The prevalence of allergic respiratory diseases such as bronchial asthma has increased in recent years, especially in industrialized countries. A change in the genetic predisposition is an unlikely cause of the increase in allergic diseases because genetic changes in a population require several generations. Consequently, this increase may be explained by changes in environmental factors, including indoor and outdoor air pollution. Over the past two decades, there has been increasing interest in studies of air pollution and its effects on human health. Although the role played by outdoor pollutants in allergic sensitization of the airways has yet to be clarified, a body of evidence suggests that urbanization, with its high levels of vehicle emissions, and a westernized lifestyle are linked to the rising frequency of respiratory allergic diseases observed in most industrialized countries, and there is considerable evidence that asthmatic persons are at increased risk of developing asthma exacerbations with exposure to ozone, nitrogen dioxide, sulphur dioxide and inhalable particulate matter. However, it is not easy to evaluate the impact of air pollution on the timing of asthma exacerbations and on the prevalence of asthma in general. As concentrations of airborne allergens and air pollutants are frequently increased contemporaneously, an enhanced IgE-mediated response to aeroallergens and enhanced airway inflammation could account for the increasing frequency of allergic respiratory allergy and bronchial asthma. Pollinosis is frequently used to study the interrelationship between air pollution and respiratory allergy. Climatic factors (temperature, wind speed, humidity, thunderstorms, etc) can affect both components (biological and chemical) of this interaction. By attaching to the surface of pollen grains and of plant-derived particles of paucimicronic size, pollutants could modify not only the morphology of these antigen-carrying agents but also their allergenic potential. In addition, by inducing airway inflammation, which increases airway permeability, pollutants overcome the mucosal barrier and could be able to "prime" allergen-induced responses. There are also observations that a thunderstorm occurring during pollen season can induce severe asthma attacks in pollinosis patients. After rupture by thunderstorm, pollen grains may release part of their cytoplasmic content, including inhalable, allergen-carrying paucimicronic particles.     

Roles of pollution in the prevalence and exacerbations of allergic diseases in Asia

The prevalence of asthma and allergic diseases has been found to be increasingly rapidly, especially in developing countries. Environmental factors have been found to be important contributors to the manifestations of allergic diseases. Air pollution has been extensively studied in different regions of the world. The levels of ambient air pollutants in many Asian countries are very high when compared with those in developed Western countries. However, the prevalence of asthma was relatively low across many Asian countries. Many studies have clearly documented that environmental air pollution is an important factor resulting in exacerbations of asthma. In particular, levels of traffic-related pollutants are increasing rapidly across many Asian countries in parallel with the level of urbanization and economic development. The loss of protective factors associated with a rural environment will further contribute to the adverse effect on patients with allergic diseases such as asthma. In this review the roles of air pollution were examined in relation to the inception and exacerbations of allergic diseases in Asia.     

Additive effect of diesel exhaust particulates and ozone on airway hyperresponsiveness and inflammation in a mouse model of asthma

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (P(enh)) was measured. Levels of IL-4 and IFN-gamma were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher P(enh) than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-gamma were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-gamma suggesting that DEP amplify Th2 immune response.     

Air pollution in autoimmune rheumatic diseases: A review

Air pollution consists of a heterogeneous mixture of gasses and particles that include carbon monoxide, nitrates, sulfur dioxide, ozone, lead, toxic by-product of tobacco smoke and particulate matter. Oxidative stress and inflammation induced by inhaled pollutants may result in acute and chronic disorders in the respiratory system, as well as contribute to a state of systemic inflammation and autoimmunity. This paper reviews the mechanisms of air contaminants influencing the immune response and autoimmunity, and it focuses on studies of inhaled pollutants triggering and/or exacerbating rheumatic diseases in cities around the world. Remarkably, environmental factors contribute to the onset of autoimmune diseases, especially smoking and occupational exposure to silica in rheumatoid arthritis and systemic lupus erythematosus. Other diseases such as scleroderma may be triggered by the inhalation of chemical solvents, herbicides and silica. Likewise, primary vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) may be triggered by silica exposure. Only few studies showed that air pollutants could trigger or exacerbate juvenile idiopathic arthritis and systemic lupus erythematosus. In contrast, no studies of tropospheric pollution triggering inflammatory myopathies and spondyloarthropathies were carried out. In conclusion, air pollution is one of the environmental factors involved in systemic inflammation and autoimmunity. Further studies are needed in order to evaluate air pollutants and their potentially serious effects on autoimmune rheumatic diseases and the mechanisms involved in the onset and the exacerbation of these diseases.     

Biology of diesel exhaust effects on respiratory function

In recent decades, clinicians and scientists have witnessed a significant increase in the prevalence of allergic rhinitis and asthma. The factors underlying this phenomenon are clearly complex; however, this rapid increase in the burden of atopic disease has undeniably occurred in parallel with rapid industrialization and urbanization in many parts of the world. Consequently, more people are exposed to air pollutants than at any point in human history. Worldwide, increases in allergic respiratory disease have mainly been observed in urban communities. Epidemiologic and clinical investigations have suggested a strong link between particulate air pollution and detrimental health effects, including cardiopulmonary morbidity and mortality. The purpose of this review is to provide an evidence-based summary of the health effects of air pollutants on asthma, focusing on diesel exhaust particles (DEPs) as a model particulate air pollutant. An overview of observational and experimental studies linking DEPs and asthma will be provided, followed by consideration of the mechanisms underlying DEP-induced inflammation and a brief discussion of future research and clinical directions.     

Limonene and its ozone-initiated reaction products attenuate allergic lung inflammation in mice

Inhalation of indoor air pollutants may cause airway irritation and inflammation and is suspected to worsen allergic reactions. Inflammation may be due to mucosal damage, upper (sensory) and lower (pulmonary) airway irritation due to activation of the trigeminal and vagal nerves, respectively, and to neurogenic inflammation. The terpene, d-limonene, is used as a fragrance in numerous consumer products. When limonene reacts with the pulmonary irritant ozone, a complex mixture of gas and particle phase products is formed, which causes sensory irritation. This study investigated whether limonene, ozone or the reaction mixture can exacerbate allergic lung inflammation and whether airway irritation is enhanced in allergic BALB/cJ mice. Naïve and allergic (ovalbumin sensitized) mice were exposed via inhalation for three consecutive days to clean air, ozone, limonene or an ozone–limonene reaction mixture. Sensory and pulmonary irritation was investigated in addition to ovalbumin-specific antibodies, inflammatory cells, total protein and surfactant protein D in bronchoalveolar lavage fluid and hemeoxygenase-1 and cytokines in lung tissue. Overall, airway allergy was not exacerbated by any of the exposures. In contrast, it was found that limonene and the ozone–limonene reaction mixture reduced allergic inflammation possibly due to antioxidant properties. Ozone induced sensory irritation in both naïve and allergic mice. However, allergic but not naïve mice were protected from pulmonary irritation induced by ozone. This study showed that irritation responses might be modulated by airway allergy. However, aggravation of allergic symptoms was observed by neither exposure to ozone nor exposure to ozone-initiated limonene reaction products. In contrast, anti-inflammatory properties of the tested limonene-containing pollutants might attenuate airway allergy.     

Neuroimmune interactions in allergic skin diseases

PURPOSE OF REVIEW: Recent studies have advanced our understanding that allergic inflammation triggers neuronal dysfunction, thereby modulating inflammation-related changes in affected tissues including the skin. Vice versa, evidence has emerged that inflammatory responses are controlled by neurons. Moreover, structural cells and invading immune cells express neuronal receptors and release mediators which directly communicate with nerve endings in the skin. RECENT FINDINGS: During the allergic response, skin cells do not only represent a significant source of neuromediators but also represent targets for neuropeptides or neurotrophins as well as neurotransmitters in the inflamed tissue. During the last decade, it has become obvious that a large variety of molecules influence the adaptive as well as the innate immune response. Beside neuropeptide receptors, proteinase-activated receptors, novel histamine receptors, different cytokine or chemokine receptors play a role in the pathophysiology of atopic and allergic diseases. SUMMARY: Peripheral sensory and autonomic nerves are critically involved in many pathways of the innate and adoptive immune system during allergic and atopic skin diseases. Further dissection of receptor-mediated and intracellular signal pathways will help to develop more effective therapeutic approaches for allergic and inflammatory skin diseases.     

Respiratory health effects of air pollution: update on biomass smoke and traffic pollution

Mounting evidence suggests that air pollution contributes to the large global burden of respiratory and allergic diseases, including asthma, chronic obstructive pulmonary disease, pneumonia, and possibly tuberculosis. Although associations between air pollution and respiratory disease are complex, recent epidemiologic studies have led to an increased recognition of the emerging importance of traffic-related air pollution in both developed and less-developed countries, as well as the continued importance of emissions from domestic fires burning biomass fuels, primarily in the less-developed world. Emissions from these sources lead to personal exposures to complex mixtures of air pollutants that change rapidly in space and time because of varying emission rates, distances from source, ventilation rates, and other factors. Although the high degree of variability in personal exposure to pollutants from these sources remains a challenge, newer methods for measuring and modeling these exposures are beginning to unravel complex associations with asthma and other respiratory tract diseases. These studies indicate that air pollution from these sources is a major preventable cause of increased incidence and exacerbation of respiratory disease. Physicians can help to reduce the risk of adverse respiratory effects of exposure to biomass and traffic air pollutants by promoting awareness and supporting individual and community-level interventions.     

Maternal diesel inhalation increases airway hyperreactivity in ozone-exposed offspring

Air pollutant exposure is linked with childhood asthma incidence and exacerbations, and maternal exposure to airborne pollutants during pregnancy increases airway hyperreactivity (AHR) in offspring. To determine if exposure to diesel exhaust (DE) during pregnancy worsened postnatal ozone-induced AHR, timed pregnant C57BL/6 mice were exposed to DE (0.5 or 2.0 mg/m(3)) 4 hours daily from Gestation Day 9-17, or received twice-weekly oropharyngeal aspirations of the collected DE particles (DEPs). Placentas and fetal lungs were harvested on Gestation Day 18 for cytokine analysis. In other litters, pups born to dams exposed to air or DE, or to dams treated with aspirated diesel particles, were exposed to filtered air or 1 ppm ozone beginning the day after birth, for 3 hours per day, 3 days per week for 4 weeks. Additional pups were monitored after a 4-week recovery period. Diesel inhalation or aspiration during pregnancy increased levels of placental and fetal lung cytokines. There were no significant effects on airway leukocytes, but prenatal diesel augmented ozone-induced elevations of bronchoalveolar lavage cytokines at 4 weeks. Mice born to the high-concentration diesel-exposed dams had worse ozone-induced AHR, which persisted in the 4-week recovery animals. Prenatal diesel exposure combined with postnatal ozone exposure also worsened secondary alveolar crest development. We conclude that maternal inhalation of DE in pregnancy provokes a fetal inflammatory response that, combined with postnatal ozone exposure, impairs alveolar development, and causes a more severe and long-lasting AHR to ozone exposure.     

Obesity and eosinophilic inflammation: does leptin play a role

It has been pointed out that obesity is a risk factor for, and is involved in the exacerbation of asthma. Mounting evidence about adipose tissue-derived proteins (adipokines) gave rise to the current understanding of obesity as a systemic inflammatory disorder. In this review, we summarized the involvement of leptin, focusing on eosinophil functions. Several studies have indicated that leptin can restrain eosinophil apoptosis, enhance migration, increase adhesion molecules and induce cytokine production. Since leptin also acts on a variety of immune cells related to allergic response, increased leptin in obese individuals potentially explains the mechanism by which obesity leads to an exacerbation of asthma. Further studies targeting adipokines will delineate the association between obesity and eosinophil-associated diseases.     

Airway hyperresponsiveness

Bronchial hyperresponsiveness (BHR) is an essential part of the definition of asthma. Although our understanding of the allergic inflammatory and immunologic mechanisms of asthma have markedly increased, the mechanism of BHR remains to be elucidated. Increased BHR is associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain occupational chemicals. An important research use of determining the degree of BHR to direct and indirect challenge is to determine the efficacy of pharmacologic and immunodulatory agents. Beta-adrenergic agents inhibit BHR and certain genetic polymorphisms of the beta-adrenergic receptor are associated with increased BHR. When β-adrenergic receptors are blocked, sensitivity to allergens is markedly increased in patients with asthma and animal models of asthma. Allergen challenge and clinical asthma are associated with synthesis and release of pro-inflammatory cytokines such as IL-1 and TNF-α which have been shown to decrease the response to β-agonists and increased the reactivity to methacholine and the airways neutrophils and alveolar macrophages. The Th2 cytokine IL-13 is increased in the airways of asthmatics and increases BHR in normal unsensitized animals. The mechanisms of this effect of IL-13 are being intensively investigated. Our group has shown that IL-13 induced BHR persisted for at least 7 days and the soluble receptor IL-13R2α protected against their BHR. Other investigators have demonstrated that IL-13 is necessary and sufficient for the induction of BHR and that eosinophilic airway inflammation in the absence of IL-13 fails to induce BHR. These studies indicate that treatment of human asthma with antagonists of IL-13 may be very effective.     

Airway hyperresponsiveness: a story of mice and men and cytokines

Bronchial hyperresponsiveness (BHR) is an essential part of the definition of asthma. Although our understanding of the allergic inflammatory and immunologic mechanisms of asthma have markedly increased, the mechanism of BHR remains to be elucidated. Increased BHR is associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain occupational chemicals. An important research use of determining the degree of BHR to direct and indirect challenge is to determine the efficacy of pharmacologic and immunodulatory agents. Beta-adrenergic agents inhibit BHR and certain genetic polymorphisms of the beta-adrenergic receptor are associated with increased BHR. When beta-adrenergic receptors are blocked, sensitivity to allergens is markedly increased in patients with asthma and animal models of asthma. Allergen challenge and clinical asthma are associated with synthesis and release of pro-inflammatory cytokines such as IL-1 and TNF-alpha which have been shown to decrease the response to beta-agonists and increased the reactivity to methacholine and the airways neutrophils and alveolar macrophages. The Th2 cytokine IL-13 is increased in the airways of asthmatics and increases BHR in normal unsensitized animals. The mechanisms of this effect of IL-13 are being intensively investigated. Our group has shown that IL-13 induced BHR persisted for at least 7 days and the soluble receptor IL-13R2alpha protected against their BHR. Other investigators have demonstrated that IL-13 is necessary and sufficient for the induction of BHR and that eosinophilic airway inflammation in the absence of IL-13 fails to induce BHR. These studies indicate that treatment of human asthma with antagonists of IL-13 may be very effective.     

Nerve growth factor: an important molecule in allergic inflammation and tissue remodelling

BACKGROUND: Several studies provide evidence that nerve growth factor (NGF) has an expanding role in neuroimmune interactions. METHODS: We review our data on circulation levels of NGF in allergic diseases as well as on the relationships between this neurotrophin and primary and secondary effector cells of allergic inflammation. RESULTS: In vernal keratoconjunctivitis, a close relationship exists between the increased NGF plasma values and the number of mast cells infiltrating the conjunctiva. NGF serum values are also increased in other allergic diseases and asthma, and are related to the severity of the inflammatory process and disease. Human CD4+ T cell clones (preferentially of activated Th2 type) produce and release NGF, and express high-affinity NGF receptors. NGF is preformed in and can act on human peripheral blood eosinophils to preferentially release inflammatory mediators. Immunoreactivity for high affinity NGF receptors is present both in basal epithelial cells and in the inflamed stroma of the allergic conjunctiva. Topical administration of NGF results in a complete healing of neurotophic corneal ulcers in man, thus suggesting a profound effect of NGF on human fibroblasts and extracellular matrix. CONCLUSION: Data presented suggest that NGF is an important molecule in allergic inflammation and tissue remodelling occurring in allergic diseases.     

Neuroimmunological findings in allergic skin diseases

PURPOSE OF REVIEW: Recent studies have gained widespread information about the complex regulation of genetic, environmental, immunologic, and pharmacologic factors that contribute to the development of allergic inflammatory skin diseases such as atopic dermatitis. Neuroimmune mechanisms, however, still remain to be elucidated. This review will focus on the interaction between the cutaneous immune and peripheral nervous system in allergic inflammatory skin such as atopic dermatitis. RECENT FINDINGS: Neuropeptides and neuropeptide-positive nerve fibres are prominently increased in lesions of atopic dermatitis. The density of nerve fibres is increased while peripheral nerve endings are in an active state of excitation. In this regard, neurotrophins particularly described for their functional role on nerve cells are also expressed in atopic dermatitis skin. In addition, neurotrophins modulate the functional role of eosinophils as main target effector cells in atopic dermatitis, as described recently. Interestingly, eosinophils are capable of neurotrophin as well as neuropeptide production itself, pointing to a bidirectional communication between neuronal cell populations and main target effector cells. SUMMARY: Neurotrophins and neuropeptides modulate both the functional activity of sensory neurons and immune cells. We have therefore developed the concept of a neuroimmune network between target effector cells and sensory nerves that links pathogenic events to dysfunctions of the cutaneous immune and peripheral nervous system in allergic inflammatory skin diseases.     

Diesel exhaust exposure favors TH2 cell recruitment in nonatopic subjects by differentially regulating chemokine production

BACKGROUND: The prevalence of allergic diseases has increased in the last 20 years, and a number of studies have shown that diesel exhaust particle-associated polyaromatic hydrocarbons can exacerbate the allergic reaction. Much less is known about their potential capacity to generate a T(H)2-type allergic reaction in nonatopic subjects. OBJECTIVE: The aim of this study was to test the hypothesis that diesel exhaust exposure might favor, in nonatopic donors, T(H)2-type cell recruitment, either through increased production of T(H)2-attracting chemokines or decreased production of T(H)1-attracting chemokines. METHODS: PBMCs from nonatopic donors were incubated with diesel exhaust particle-polyaromatic hydrocarbons, and the supernatants were evaluated for the presence of pro-T(H)1 chemokines (IFN-gamma-induced protein 10 and monokine Induced by IFN-gamma) and pro-T(H)2 chemokines (macrophage-derived chemokine, I-309, and pulmonary and activation-regulated chemokine) by means of ELISA. The functional effect was evaluated by using chemotaxis assays with polarized T(H)1 and T(H)2 cells. RESULTS: Diesel exhaust exposure of PBMCs from nonatopic donors induced a late increase after 48 hours in pulmonary and activation-regulated chemokine mediated by IL-13 and a decrease in IFN-gamma-induced protein 10 levels selectively at both the protein and mRNA levels. The functional effect of these chemokine variations resulted in an enhanced chemotaxis of T(H)2, but not T(H)1, cells. CONCLUSION: These findings show that diesel exhaust exposure might be involved in the genesis of allergic diseases by differentially regulating chemokines favoring the recruitment of T(H)2 cells in nonatopic subjects. CLINICAL IMPLICATIONS: Environmental factors, especially air pollution, might favor the genesis of allergic diseases.