Thymic stromal lymphopoietin rather than IL-33 drives food allergy after epicutaneous sensitization to food allergen.

BACKGROUND: A major route of sensitization to food allergen is through an impaired skin barrier. IL-33 and thymic stromal lymphopoietin (TSLP) have both been implicated in epicutaneous sensitization and food allergy, albeit in different murine models. OBJECTIVE: We assessed the respective contributions of TSLP and IL-33 to the development of atopic dermatitis (AD) and subsequent food allergy in TSLP and IL-33 receptor (ST2)-deficient mice using an AD model that does not require tape stripping. METHOD: TSLP receptor (TSLPR)-/-, ST2-/-, and BALB/cJ control mice were exposed to 3 weekly epicutaneous skin patches of one of saline, ovalbumin (OVA), or a combination of OVA and Aspergillus fumigatus (ASP), followed by repeated intragastric OVA challenges and development of food allergy. RESULTS: ASP and/or OVA patched, but not OVA-alone patched, BALB/cJ mice developed an AD-like skin phenotype. However, epicutaneous OVA sensitization occurred in OVA patched mice and was decreased in ST2-/- mice, resulting in lower intestinal mast cell degranulation and accumulation, as well as OVA-induced diarrhea occurrences on intragastric OVA challenges. In TSLPR-/- mice, intestinal mast cell accumulation was abrogated, and no diarrhea was observed. AD was significantly milder in OVA + ASP patched TSLPR-/- mice compared to wild type and ST2-/- mice. Accordingly, intestinal mast cell accumulation and degranulation were impaired in OVA + ASP patched TSLPR-/- mice compared to wild type and ST2-/- mice, protecting TSLPR-/- mice from developing allergic diarrhea. CONCLUSION: Epicutaneous sensitization to food allergen and development of food allergy can occur without skin inflammation and is partly mediated by TSLP, suggesting that prophylactic targeting of TSLP may be useful in mitigating the development of AD and food allergy early in life in at-risk infants.

Environmental Determinants of Coronavirus Disease 2019 (COVID-19).

PURPOSE FOR REVIEW: Since the coronavirus SARS-CoV-2 outbreak in China in late 2019 turned into a global pandemic, numerous studies have reported associations between environmental factors, such as weather conditions and a range of air pollutants (particulate matter, nitrogen dioxide, ozone, etc.) and the first wave of COVID-19 cases. This review aims to offer a critical assessment of the role of environmental exposure risk factors on SARS-CoV-2 infections and COVID-19 disease severity. RECENT FINDINGS: In this review, we provide a critical assessment of COVID-19 risk factors, identify gaps in our knowledge (e.g., indoor air pollution), and discuss methodological challenges of association and causation and the impact lockdowns had on air quality. In addition, we will draw attention to ethnic and socioeconomic factors driving viral transmission related to COVID-19. The complex role angiotensin-converting enzyme 2 (ACE2) plays in COVID-19 and future promising avenues of research are discussed. To demonstrate causality, we stress the need for future epidemiologic studies integrating personal air pollution exposures, detailed clinical COVID-19 data, and a range of socioeconomic factors, as well as in vitro and in vivo mechanistic studies.

IL33 contributes to diesel pollution-mediated increase in experimental asthma severity.

BACKGROUND: Exposure to traffic pollution, notably diesel exhaust particles (DEP), increases risk for asthma and asthma exacerbations. The contribution of cytokines generated by stressed lung epithelial cells (IL25, IL33, TSLP) to DEP-induced asthma severity remains poorly understood. METHODS: BALB/c mice were exposed intratracheally once to DEP or 9 times over 3-weeks to either saline, DEP, and/or house dust mite extract (HDM). Airway hyper-responsiveness (AHR), pulmonary inflammation, and T-cell subsets were assessed 24 hours after the last exposure in mice sufficient and deficient for the IL33 receptor ST2. RESULTS: DEP exposure induces oxidative stress, IL6, neutrophils and pulmonary accumulation of IL33, but not IL25 or TSLP or other features of allergic disease. When mice are co-exposed to DEP and low doses of HDM, DEP increases IL33 lung levels and Th2 responses. ST2 deficiency partially protected mice from HDM + DEP induced AHR in association with decreased type 2 inflammation and lung levels of IL5+ IL17A+ co-producing T-cells. Upon in vitro HDM challenge of lung cells from HDM ± DEP exposed ST2-/- mice, secretion of IL5, IL13, IL6 and IL17A was abrogated by a mechanism involving IL33 signaling in both dendritic cells and T-cells. HDM + DEP exposed bone marrow derived dendritic cells and IL33 pulsed BMDC promote a mixed Th2/Th17 response that was dependent on ST2 expression by CD4+ T-cells. CONCLUSION: IL33 contributes to DEP mediated increase in allergen-induced Th2 inflammation and AHR in a mouse model of severe steroid resistant asthma, potentially through the accumulation of pathogenic IL5+ IL17A+ CD4+ effector T-cells.

Assessing exposure to outdoor air pollution for epidemiological studies: Model-based and personal sampling strategies.

Epidemiologic studies have found air pollution to be causally linked to respiratory health including the exacerbation and development of childhood asthma. Accurately characterizing exposure is paramount in these studies to ensure valid estimates of health effects. Here, we provide a brief overview of the evolution of air pollution exposure assessment ranging from the use of ground-based, single-site air monitoring stations for population-level estimates to recent advances in spatiotemporal models, which use advanced machine learning algorithms and satellite-based data to accurately estimate individual-level daily exposures at high spatial resolutions. In addition, we review recent advances in sensor technology that enable the use of personal monitoring in epidemiologic studies, long-considered the "holy grail" of air pollution exposure assessment. Finally, we highlight key advantages and uses of each approach including the generalizability and public health relevance of air pollution models and the accuracy of personal monitors that are useful to guide personalized prevention strategies. Investigators and clinicians interested in the effects of air pollution on allergic disease and asthma should carefully consider the pros and cons of each approach to guide their application in research and practice.

Vitamin D supplementation attenuates asthma development following traffic-related particulate matter exposure.

BACKGROUND: Recent literature suggests that children who are vitamin D deficient are uniquely susceptible to the effects of traffic-related air pollution (TRAP) exposure. This is highly significant because large segments of the population reside in zones of high TRAP exposure. OBJECTIVE: We sought to determine whether vitamin D supplementation mitigates the effect of TRAP exposure on asthma development, asthma exacerbation, and/or airway inflammation and to determine the timing of vitamin D supplementation that confers maximal health benefit. METHODS: Using established mouse models of asthma, we examined the effect of prenatal and postnatal vitamin D supplementation on asthma development, as well as the utility of vitamin D as a treatment for established asthma in the context of diesel exhaust particle (DEP) exposure. RESULTS: DEP and allergen coexposure resulted in increased airway hyperresponsiveness (AHR) and accumulation of pathogenic TH2/TH17 cells in the lungs of vitamin D-deficient mice compared with control mice. Prenatal and postnatal vitamin D supplementation significantly attenuated the development of AHR and decreased pulmonary accumulation of TH2/TH17 cells after coexposure to TRAP and allergen but not to allergen alone. Restoration of normal vitamin D status had no effect on AHR once asthma was already established. CONCLUSIONS: Our data establish that vitamin D confers protection against asthma development specifically in the context of TRAP exposure. Although vitamin D replacement did not reverse established asthma, restoration of normal vitamin D status in early life significantly attenuated the development of AHR in the setting of DEP-exacerbated allergic asthma and reduced numbers of lung TH2/TH17 cells, which portend the development of severe asthma.

Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens.

KIF3A, the gene encoding kinesin family member 3A, is a susceptibility gene locus associated with asthma; however, mechanisms by which KIF3A might influence the pathogenesis of the disorder are unknown. In this study, we deleted the mouse Kif3a gene in airway epithelial cells. Both homozygous and heterozygous Kif3a gene-deleted mice were highly susceptible to aeroallergens from Aspergillus fumigatus and the house dust mite, resulting in an asthma-like pathology characterized by increased goblet cell metaplasia, airway hyperresponsiveness, and Th2-mediated inflammation. Deletion of the Kif3a gene increased the severity of pulmonary eosinophilic inflammation and expression of cytokines (Il-4, Il-13, and Il-17a) and chemokine (Ccl11) RNAs following pulmonary exposure to Aspergillus extract. Inhibition of Kif3a disrupted the structure of motile cilia and impaired mucociliary clearance, barrier function, and epithelial repair, demonstrating additional mechanisms by which deficiency of KIF3A in respiratory epithelial cells contributes to pulmonary pathology. Airway epithelial KIF3A suppresses Th2 pulmonary inflammation and airway hyperresponsiveness following aeroallergen exposure, implicating epithelial microtubular functions in the pathogenesis of Th2-mediated lung pathology.

ß-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses.

BACKGROUND: Allergic sensitization to fungi has been associated with asthma severity. As a result, it has been largely assumed that the contribution of fungi to allergic disease is mediated through their potent antigenicity. OBJECTIVE: We sought to determine the mechanism by which fungi affect asthma development and severity. METHODS: We integrated epidemiologic and experimental asthma models to explore the effect of fungal exposure on asthma development and severity. RESULTS: We report that fungal exposure enhances allergen-driven TH2 responses, promoting severe allergic asthma. This effect is independent of fungal sensitization and can be reconstituted with ß-glucan and abrogated by neutralization of IL-17A. Furthermore, this severe asthma is resistant to steroids and characterized by mixed TH2 and TH17 responses, including IL-13+IL-17+CD4+ double-producing effector T cells. Steroid resistance is dependent on fungus-induced TH17 responses because steroid sensitivity was restored in IL-17rc-/- mice. Similarly, in children with asthma, fungal exposure was associated with increased serum IL-17A levels and asthma severity. CONCLUSION: Our data demonstrate that fungi are potent immunomodulators and have powerful effects on asthma independent of their potential to act as antigens. Furthermore, our results provide a strong rationale for combination treatment strategies targeting IL-17A for this subgroup of fungus-exposed patients with difficult-to-treat asthma.

Exposure to allergen and diesel exhaust particles potentiates secondary allergen-specific memory responses, promoting asthma susceptibility.

BACKGROUND: Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood. OBJECTIVE: We sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children. METHODS: The effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes. RESULTS: DEP coexposure with HDM resulted in persistent TH2/TH17 CD127(+) effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased TH2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children. CONCLUSION: These findings suggest that DEP exposure results in accumulation of allergen-specific TH2/TH17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.

Air pollution and allergic diseases.

PURPOSE OF REVIEW: Exposure to traffic-related air pollutants (TRAPs) has been implicated in asthma development, persistence, and exacerbation. This exposure is highly significant because increasingly large segments of the population worldwide reside in zones that have high levels of TRAP, including children, as schools are often located in high traffic pollution exposure areas. RECENT FINDINGS: Recent findings include epidemiologic and mechanistic studies that shed new light on the impact of traffic pollution on allergic diseases and the biology underlying this impact. In addition, new innovative methods to assess and quantify traffic pollution have been developed to assess exposure and identify vulnerable populations and individuals. SUMMARY: This review will summarize the most recent findings in each of these areas. These findings will have a substantial impact on clinical practice and research by the development of novel methods to quantify exposure and identify at-risk individuals, as well as mechanistic studies that identify new targets for intervention for individuals most adversely affected by TRAP exposure.

Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice.

Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly understood. This is highly significant because the skin biome is rich with potential TLR4 agonists. We aimed to establish the contribution of TLR4 to atopic dermatitis and determine the mechanism by which TLR4 acts in an experimental model of atopic dermatitis. MyD88, TLR4, or Toll-IL-1R domain-containing adapter-inducing IFN-ß (TRIF)-deficient and wild-type mice were epicutaneously exposed to Aspergillus fumigatus allergen over 3 wk. Impaired skin barrier function was assessed by measuring transepidermal water loss (TEWL). Skin levels of innate and adaptive genes were quantified. In an experimental model of atopic dermatitis, TEWL, allergic sensitization, and epidermal thickness were increased following cutaneous allergen exposure, and these were further enhanced in the absence of TLR4. Increased allergen-induced skin levels of innate (S100A8/A9, IL-1ß, TNF-α, and CXCL2) and Th17 genes (IL-17A and IL-17F) were observed in TLR4-deficient mice compared with wild-type mice. The absence of MyD88 alleviated disease (decreased TEWL, skin thickness, proinflammatory cytokines), whereas TRIF deficiency exacerbated disease. In conclusion, signaling through the TLR4 and TRIF pathways limits skin barrier dysfunction, cutaneous allergic sensitization, and proinflammatory cytokine production.

Surface availability of beta-glucans is critical determinant of host immune response to Cladosporium cladosporioides.

BACKGROUND: It is well accepted that mold exposure is a major contributor to the development of asthma, and beta-glucans are often used as a surrogate for mold exposure in the environment. Beta-glucans are an important component of mold spores and are recognized by the immune system by their receptor, Dectin-1. Cladosporium cladosporioides spores have a high beta-glucan content, but the beta-glucans are not available on the surface of live spores. OBJECTIVE: We sought to determine whether altering the exposure of beta-glucans in C cladosporioides through heat killing could alter the immune response through binding to Dectin-1. METHODS: In a murine model of mold-induced asthma, mice were repeatedly exposed to either live or heat-killed C cladosporioides and the phenotype was determined by the measurement of airway hyperresponsiveness, airway inflammation, and cytokine production. Pro-inflammatory cytokines from dendritic cells were measured by using quantitative PCR and ELISA. RESULTS: Live C cladosporioides induced robust airway hyperresponsiveness, eosinophilia, and a predominately TH2 response, while heat-killed C cladosporioides induced a strong TH17 response and neutrophilic inflammation, but very mild airway hyperresponsiveness. Heat killing of C cladosporioides spores effectively exposed beta-glucans on the surface of the spores and increased binding to Dectin-1. In the absence of Dectin-1, heat-killed spores induced a predominantly TH2 response analogous to live spores. Furthermore, the production of TH17-skewing IL-6, IL-23, and TNF-α by dendritic cells in response to heat-killed C cladosporioides was dependent on Dectin-1. CONCLUSIONS: The host immune response to C cladosporioides is dependent on the surface availability of beta-glucans rather than the total beta-glucan content.

Diesel exhaust particle induction of IL-17A contributes to severe asthma.

BACKGROUND: IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEPs) are a major component of traffic-related air pollution and are implicated in asthma pathogenesis and exacerbation. OBJECTIVE: We sought to determine the mechanism by which DEP exposure affects asthma severity using human and mouse studies. METHODS: BALB/c mice were challenged with DEPs with or without house dust mite (HDM) extract. Airway inflammation and function, bronchoalveolar lavage fluid cytokine levels, and flow cytometry of lung T cells were assessed. The effect of DEP exposure on the frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma. RESULTS: In mice exposure to DEPs alone did not induce asthma. DEP and HDM coexposure markedly enhanced airway hyperresponsiveness compared with HDM exposure alone and generated a mixed T(H)2 and T(H)17 response, including IL-13(+)IL-17A(+) double-producing T cells. IL-17A neutralization prevented DEP-induced exacerbation of airway hyperresponsiveness. Among 235 high DEP-exposed children with allergic asthma, 32.2% had more frequent asthma symptoms over a 12-month period compared with only 14.2% in the low DEP-exposed group (P = .002). Additionally, high DEP-exposed children with allergic asthma had nearly 6 times higher serum IL-17A levels compared with low DEP-exposed children. CONCLUSIONS: Expansion of T(H)17 cells contributes to DEP-mediated exacerbation of allergic asthma. Neutralization of IL-17A might be a useful potential therapeutic strategy to counteract the asthma-promoting effects of traffic-related air pollution, especially in highly exposed patients with severe allergic asthma.

Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma.

The mammalian target of rapamycin (mTOR) signaling pathway integrates environmental cues, promotes cell growth/differentiation, and regulates immune responses. Although inhibition of mTOR with rapamycin has potent immunosuppressive activity, mixed effects have been reported in OVA-induced models of allergic asthma. We investigated the impact of two rapamycin treatment protocols on the major characteristics of allergic asthma induced by the clinically relevant allergen, house dust mite (HDM). In protocol 1, BALB/c mice were exposed to 10 intranasal HDM doses over a period of 24 d and treated with rapamycin simultaneously during the sensitization/exposure period. In protocol 2, rapamycin was administered after the mice had been sensitized to HDM (i.p. injection) and prior to initiation of two intranasal HDM challenges over 4 d. Airway hyperreactivity (AHR), IgE, inflammatory cells, cytokines, leukotrienes, goblet cells, and activated T cells were assessed. In protocol 1, rapamycin blocked HDM-induced increases in AHR, inflammatory cell counts, and IgE, as well as attenuated goblet cell metaplasia. In protocol 2, rapamycin blocked increases in AHR, IgE, and T cell activation and reduced goblet cell metaplasia, but it had no effect on inflammatory cell counts. Increases in IL-13 and leukotrienes were also blocked by rapamycin, although increases in IL-4 were unaffected. These data demonstrated that rapamycin can inhibit cardinal features of allergic asthma, including increases in AHR, IgE, and goblet cells, most likely as a result of its ability to reduce the production of two key mediators of asthma: IL-13 and leukotrienes. These findings highlight the importance of the mTOR pathway in allergic airway disease.

A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma.

BACKGROUND: Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and SERPINB4 are induced in patients with asthma; however, their mechanistic role in asthma has yet to be determined. OBJECTIVE: To evaluate the role of Serpin3a, the murine homolog of SERPINB3 and SERPINB4, in asthma. METHODS: We studied wild-type Balb/c and Serpinb3a-null mice in house dust mite or IL-13-induced asthma models and evaluated airway hyperresponsiveness, inflammation, and goblet cell hyperplasia. RESULTS: Airway hyperresponsiveness and goblet cell hyperplasia were markedly attenuated in the Serpinb3a-null mice compared with the wild-type mice after allergen challenge, with minimal effects on inflammation. Expression of sterile alpha motif pointed domain containing v-ets avian erythroblastosis virus E26 oncogene homolog transcription factor (SPDEF), a transcription factor that mediates goblet cell hyperplasia, was decreased in the absence of Serpinb3a. IL-13-treated Serpinb3a-null mice showed attenuated airway hyperresponsiveness, inflammation, and mucus production. CONCLUSION: Excessive mucus production and mucus plugging are key pathologic features of asthma, yet the mechanisms responsible for mucus production are not well understood. Our data reveal a novel nonredundant role for Serpinb3a in mediating mucus production through regulation of SPDEF expression. This pathway may be used to target mucus hypersecretion effectively.