Environmental exposures drive the development of allergic diseases
Authors: Luo Zhang, Cezmi A. Akdis
Journal: Allergy (2024)

The global prevalence of allergic diseases, such as allergic rhinitis (AR) and asthma, has gradually increased since 1960s. AR prevalence has surged by 5%–25% across various regions in the past few decades.1 Similarly, the prevalence of asthma has progressively increased over the last 65 years in industrialized countries and 30–40 years in urbanized areas of low- and middle-level income countries, correlating with the ongoing processes of urbanization and industrialization.2 After the industrial revolution and particularly after 1950s when common usage of fossil fuels had started, increased energy consumption and increased waste discharge have led to global warming and climate change, causing air pollution, and chemical hazards—significant contributors to the escalating prevalence of allergic diseases.3, 4 Allergic diseases are triggered by environmental allergens and influenced by climate changes. Studies on the relationship between outpatient visits for AR, airborne pollen concentration, and meteorological factors indicate a robust connection between outpatient visits and seasonal airborne pollen concentration.5 In northern China, springtime temperatures are low and dry, causing allergic symptoms and increasing the number of patients with AR, whereas increased humidity reduces outpatient visits. Meanwhile, climate changes, such as thunderstorms, increased temperature and humidity, impact environmental allergen exposure. Global warming contributes to changes in local vegetation patterns, prolonging vegetation periods for allergenic plants. This increases airborne pollen concentrations and prolongs the allergy season. Studies indicate that global warming has caused pollen belts to expand in size and migrate northward over the past 30 years.6 In the current issue, Yin et al. investigated the changes in sensitization profiles to aeroallergens among Chinese patients with AR from 2009 to 2021.7 Their findings provide comprehensive insights into prevalent aeroallergens crucial for AR diagnosis in China. They identify the most common aeroallergens, and reveal rapidly increasing sensitization rates to cat, dog, and humulus pollen over the last decade. Nonetheless, there still exist undefined allergens that are different from what is already known. Song et al. identified fructose-bisphosphate aldolase as new pollen allergens in two Artemisia species, and report their molecular characterization which is necessary to prompt the clinical application.8 Air pollutants serve as irritants and toxins, amplifying the allergenicity of allergens. The "epithelial barrier theory" posits that increased environmental exposure to toxic and inflammatory substances linked to industrialization and modernization disrupts the epithelial barriers, causes microbial dysbiosis and impairs immune homeostasis. This facilitates the presentation of allergens, initiating allergic responses.9 Tight junction (TJ) proteins serve as a pivotal constituent of the epithelial barrier, acting as the primary defense against external stimuli. Abnormal expression of TJs plays an essential role in the development and progression of inflammatory airway diseases. In the current issue, Huang et al. give a detailed review and discussion on potential factors contributing to impair and repair of TJs in the nasal epithelium based on their structure, function, and formation process.10 Substantial evidence demonstrate the association between exposure to air pollutants and an increased risk of allergic disorders.11 Notably, children and adolescents exhibit higher sensitivity to air pollution compared to adults.12 Additionally, a synergistic effect between air pollutants and pollens may heighten allergenicity and sensitisation, exacerbating symptoms of AR and even nonallergic rhinitis.13 Air pollutants can directly influence the characteristics of aeroallergens. Oak pollen exposed to elevated levels of SO2 or NO2 significantly increased fragility and disruption of the pollen, subsequently leading to increased release of pollen cytoplasmic granules.14 Reducing risk exposure, such as air pollution is crucial for prevention and treatment of allergic diseases. In the current issue, Chen et al. highlight that improved ambient air quality is associated with a decreased prevalence of childhood asthma.15 Preschool children in Shanghai exhibited a significantly lower prevalence of doctor-diagnosed asthma and wheezing in 2019 than in 2011, independently associated with exposure to particulate matter (PM)2.5, PM2.5–10, and PM10. Moreover, establishing monitoring and early warning systems for weather-related events can mitigate the impact of air pollution and aeroallergens on atopic diseases. Collaborating with the Beijing Tongren Hospital, Weather China has established a pollen monitoring system containing numerous observation stations that forecast daily airborne pollen concentrations. Utilising these daily pollen deposition values, Yin et al. constructed a prediction grading model of Artemisia pollen allergy based on a 5-grade optimized pollen deposition-level scale in the Beijing area. This model offers early warnings for patient protection and treatment, providing a scientific basis for allergen-specific immunotherapy in the clinical setting.16 Chinese scholars have consistently advanced findings on the connections and mechanisms linking allergic diseases to environmental exposure. Sun et al. demonstrate the impact of air pollutants and meteorological factors on AR outpatient visits in Shanghai, China. Elevated levels of NO2 and O3 were strongly associated with increased hospital visits of AR patients.17 In addition, He et al. detail an association between daily 1-km resolution levels of ambient air pollution and hospital visits for allergic diseases.18 By utilizing a 1 × 1 km grid-based level of ambient pollution as a proxy for individual exposure, they revealed significant adverse impacts of individual exposure to PM2.5 and O3, resulting in immediate and next-day outpatient visits for allergic diseases. Moreover, the population-average exposure to ambient SO2 and PM10 was linked to an increased risk of allergic diseases. Climate changes, particularly temperature fluctuations may play a pivotal role in asthma development. Lu et al. reported that extreme temperatures promote the development of allergic asthma in mice.19 Exposure to extreme temperatures, particularly high temperatures, enhances the expression of inflammatory cytokines, induces oxidative stress in tissues, worsens airway hyperresponsiveness, and exacerbates allergic asthma. Advancing research on asthma pathogenesis could be accelerated by reconstructing humanized mice equipped with the human immune system. Zhang et al. established a humanized asthma mouse model through intranasal administration of human IL-33 to huHSC-NOG-EXL mouse that possess the human immune system.20 These humanized asthmatic mice exhibited significant eosinophilic inflammation, collagen deposition, and mucous secretion in lung tissue, offering a potential merit in clinical strategies for asthma studies. Neutrophils are recognized as key drivers of severe asthma; however, the regulation of neutrophil lung trafficking, a crucial step in neutrophilic asthma, remains unclear. Jia et al. combined data from human clinical samples with in vitro and in vivo models of neutrophilic asthma and neutrophil migration, and revealed potential roles of reduced developmental endothelial locus-1 (DEL-1) in mediating severe neutrophilic asthma. The downregulation of DEL-1 and subsequent increase in neutrophil migration into the airways of patients with severe asthma suggest that targeting this pathway may be beneficial for treating those patients.21 Allergen immunotherapy (AIT) is one of the most important therapies for AR. Tang et al. evaluated the safety and efficacy of Artemisia annua Allergens Sublingual Immunotherapy (SLIT) Drops in Chinese children with seasonal AR. The results indicate that 28-week SLIT treatment was effective and safe for children with Artemisia pollen-induced seasonal AR, with no major safety concerns.22 However, some patients do not response well to AIT. Identifying predictive biomarkers for AIT response is crucial for enhancing clinical efficacy. In the current issue, researchers identified allergen-specific IgE/total IgE ratio, follicular regulatory T/type 2 follicular helper T cell ratio, and CD23+ nonswitched B cell frequency as the key biomarkers discriminating responders from nonresponders in the Tongji cohort comprised 72 AR patients who completed one-year SCIT follow-up.23 The atopic march's progression, starting with AD in infancy, followed by the development of allergic asthma and AR, remains a complex phenomenon. Understanding why some children only develop AD, while others proceed with the atopic march is not well-established. In a comprehensive long-term prospective cohort study involving primarily urban, low-income, minority populations at high risk, Wang et al. revealed shared and differential risk factors for AD-only and the progression from AD to atopic march. These findings hold promise for early risk assessment and the identification of children at high risk of atopic march.24 Considering the involvement of skin microbiome in AD pathogenesis, Xu et al. investigated the effects of the skin microbial metabolite propionate on acute and chronic pruritus. Their research demonstrated that propionate treatment significantly alleviated various itches and allokinesis while improving skin inflammation in an AD mouse model. The protective effect of propionate against persistent itch is mediated by direct modulation of sensory TRP channels and neuropeptide production in neurons.25 Exploring itch regulation through the skin microbiome presents a novel strategy for the treatment of AD. Type 2 inflammation is a characteristic of allergic diseases and various other inflammatory disorders, including chronic rhinosinusitis with nasal polyps (CRSwNP). In their recent study, Wang et al. identified a likely significant role of tenascin C in the formation of type 2 inflammation-related edema, ultimately exacerbating disease severity in CRSwNP. Tenascin C induces the production of matrix metalloproteinase, enhancing collagen degradation, advancing our comprehension of the mechanisms underlying edema in CRSwNP.26 T helper 2 (Th2) cell activation and T regulatory cell (Treg) deficiency are key features of allergic disease. Li et al. comment on the important findings published in Immunity, which identified an isoform of retinoic acid receptor alpha (RARα) that plays decisive roles in the control of T cell activation.27, 28 In contrast to RA-dependent transcriptional activation of nuclear RARs, RA negatively influences RARα at the plasma membrane, which results in suboptimal activation and enhanced Treg differentiation. Advances in the underlying mechanisms have driven the discovery of biologics targeting key molecules in the pathogenesis of type 2 inflammation. Dupilumab, as a humanized IgG4 monoclonal antibody targeting IL-4Rα, has shown positive feedback in treating AD patients with different ethnic backgrounds. However, there still lack real-world data for Chinese patients with big sample size. Yang et al. conducted a retrospective, single-center, noncomparative study of all patients diagnosed with moderate-to-severe AD treated with dupilumab, and report similar effectiveness of dupilumab in both quick response and steady control in Chinese AD patients of all ages.29 Furthermore, an upregulation of type 2 related genes has also been observed in skin samples from patients with palmoplantar pustulosis (PPP). In a targeted treatment approach, Zheng et al. administered dupilumab to patients with PPP. Those patients exhibited a robust positive response to dupilumab, offering new insights into the treatment and pathogenesis of PPP.30 In retrospect, Allergy and Chinese researchers has established greater international cooperation and communication, extending their focus beyond allergic diseases to address global health challenges. Notably, Allergy published its initial COVID-19 article by Chinese scholars on 19 February 2020, preceding the first COVID-19 case in Europe.31 This ground-breaking study, suggesting that asthma and allergy are not susceptibility factors for SARS-CoV-2 infection,32 marked a significant contribution. In addition, they demonstrated that human to human contact is essential for the spread of the disease and described detailed clinical, laboratory and radiology characteristics of 140 hospitalized COVID-19 patients in Wuhan, China. High levels of D-dimer, C-reactive protein, and procalcitonin were associated with severe patients as biomarkers for prediction and follow up. Eosinopenia, together with lymphopenia, were proposed as an important biomarker for severe COVID-19 and worse outcomes. In the past 4 years, these studies published in Allergy during the early stages of the COVID-19 pandemic comprehensively addressed a spectrum of relevant questions within the context of allergy and asthma.31 Amid the swift evolution of artificial intelligence and natural language processing, Shu et al. proposed the implementation of the "human-in-the-loop" strategy, asserting its profound potential to enhance the capabilities of large language models in medical enquiry, as highlighted in this issue.33 The findings presented by Chinese scholars in this publication aim to further advance our understanding of the environmental influences and immune mechanisms underlying allergic diseases. The editors of Allergy acknowledge the continuous efforts of Chinese scholars in the field of allergies, and look forward to increased international cooperation and contributions. Not available. This work was supported by grants from the National Key R&D Program of China (2022YFC2504100), the Program for Changjiang Scholars and Innovative Research Team (IRT13082), and Beijing municipal public welfare development and reform pilot project for medical research institutes (JYY2023-1). C. A. Akdis has received research grants from the Swiss National Science Foundation, European Union (EU CURE, EU Syn-Air-G), Novartis Research Institutes (Basel, Switzerland), Stanford University (Redwood City, Calif), Seed Health (Boston, USA), and SciBase (Stockholm, Sweden); is the Co-Chair for EAACI Guidelines on Environmental Science in Allergic diseases and Asthma, Chair of the EAACI Epithelial Cell Biology Working Group; and is on the Advisory Boards of Sanofi/Regeneron (Bern, Switzerland, New York, USA), Stanford University Sean Parker Asthma Allergy Center (CA, USA), Novartis (Basel, Switzerland), Glaxo Smith Kline (Zurich, Switzerland), Bristol-Myers Squibb (New York, USA), Seed Health (Boston, USA), and SciBase (Stockholm, Sweden); and is the Editor-in-Chief of Allergy. The data that support the findings of this study are available from the corresponding author upon reasonable request.