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Allergic respiratory diseases (ARDs) have been one of the major global health problems of the 21st century with an increasing prevalence. A significant proportion of aerobiological particles in the environment is constituted by fungal structures, including those from Alternaria, Cladosporium, Penicillium, and Aspergillus species which are regarded as the four most common fungal genera associated with allergic fungal airway diseases (AFADs). Allergen specific immunotherapy (AIT) has capacity to promote protection as well as long-term tolerance to the allergen, however there have not been adequate number of studies evaluating the efficacy of against AFADs, up till today. Our review would like to draw more attention to the field by summarizing the current literature regarding the clinical use of the immunotherapy, with special focus on Alternaria, and Cladosporium AITs. The area is considered to be vital to public health due to the potential increase in global AFAD cases because of ongoing air pollution and climate impacts. The review also aims to sum up immunological findings associated with mould-AIT which would help further studies to be performed in order to develop an objective method to identify non-responders early in the course of therapy., Competing Interests: Declaration of competing interest Authors have no conflicts of interest to declare., (Copyright © 2024 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

Understanding the functional potential of the gut microbiome is of primary importance for the design of innovative strategies for allergy treatment and prevention. Here we report the gut microbiome features of 90 children affected by food (FA) or respiratory (RA) allergies and 30 age-matched, healthy controls (CT). We identify specific microbial signatures in the gut microbiome of allergic children, such as higher abundance of Ruminococcus gnavus and Faecalibacterium prausnitzii, and a depletion of Bifidobacterium longum, Bacteroides dorei, B. vulgatus and fiber-degrading taxa. The metagenome of allergic children shows a pro-inflammatory potential, with an enrichment of genes involved in the production of bacterial lipo-polysaccharides and urease. We demonstrate that specific gut microbiome signatures at baseline can be predictable of immune tolerance acquisition. Finally, a strain-level selection occurring in the gut microbiome of allergic subjects is identified. R. gnavus strains enriched in FA and RA showed lower ability to degrade fiber, and genes involved in the production of a pro-inflammatory polysaccharide. We demonstrate that a gut microbiome dysbiosis occurs in allergic children, with R. gnavus emerging as a main player in pediatric allergy. These findings may open new strategies in the development of innovative preventive and therapeutic approaches. Trial: NCT04750980., (© 2021. The Author(s).)

In recent years, several new asthma therapeutics have been developed. Although many of these agents show promise in treating allergic asthma, they are less effective against nonallergic forms of asthma. The gut microbiome has important roles in human health and disease, and a growing body of evidence indicates a link between the gut microbiome and asthma. Here, we review those data focusing on the role of the microbiome in mouse models of nonallergic asthma including obese asthma and asthma triggered by exposure to air pollutants. We describe the impact of antibiotics, diet, and early life events on airway responses to the air pollutant ozone, including in the setting of obesity. We also review potential mechanisms responsible for gut-lung interactions focusing on bacterial-derived metabolites, the immune system, and hormones. Finally, we discuss future prospects for gut microbiome-targeted therapies such as fecal microbiome transplantation, prebiotics, probiotics, and prudent use of antibiotics. Better understanding of the role of the microbiome in airway responses may lead to exploration of new microbiome-targeted therapies to control asthma, especially nonallergic forms of asthma.

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.

In this paper we propose to describe the available evidence from the literature on upper airway microbiome and its association with paediatric asthma and allergy. Recent advances in sequencing the bacterial 16S ribosomal RNA (16S rRNA) gene have enabled research into the complex communities of bacteria, known as the microbiome, that exist outside and inside the human body. Although the upper airways have long been recognised to host a microbiome, the lower airways are now known to contain a rich and diverse microbiome. This review first describes the microbiome of the upper and lower airways and then explores associations between the microbiome in the airways and bowel and asthma in children. The characteristics of the microbiome differ between nose and mouth, and between the mouth and bronchus in terms of burden and diversity of bacteria and in the predominant phyla present. There is a small literature which suggests that there are differences in the airway microbiome in early life between children who later have asthma compared to those who do not develop asthma. CONCLUSION: At the time of writing it is not clear whether the microbiome may cause childhood asthma, whether the conditions in the asthmatic airway encourage a different microbiome or whether a third factor confounds the relationship between airway microbiome and childhood asthma., (Copyright © 2020 by Academy of Sciences and Arts of Bosnia and Herzegovina.)

Sensitivity to allergenic fungi (Alternaria alternata) is associated with acute, severe asthma attacks. Antigen presenting cells (APCs) in the lung sense environmental perturbations that induce cellular stress and metabolic changes and are critical for allergic airway inflammation. However, the mechanisms underlying such environmental sensing by APCs in the lung remains unclear. Here we show that acute Alternaria challenge rapidly induces neutrophil accumulation in airways, and alter expressions of Pyruvate Kinase (PKM2) and hypoxia-inducible factor -1α (Hif-1α) that correlates with proinflammatory mediator release. Blockade of IL33 signaling in vivo led to reduce oxidative stress and glycolysis in lung APCs. Lung-specific ablation of CD11c + cells abrogates Alternaria-induced neutrophil accumulation and inflammation. Furthermore, administration of Alternaria into the airways stimulated APCs and elevate the expression of Glut-1. Mechanistically, we establish that PKM2 is a critical modulator of lung APC activation in Alternaria-induced acute inflammation. Allosteric activation of PKM2 by a small molecule ML265 or siRNA-mediated knock down correlated negatively with glycolysis and activation of APCs. These results collectively demonstrates that PKM2-mediated glycolytic reprogramming by fungal allergen Alternaria influences lung APC activation, thereby promotes acute airway inflammation. Our data support a model in which Alternaria sensitization in airways induce a circuitry of glycolysis and PKM2 regulation that confers an acute activation of APCs in the lung, whose targeting might represent a strategy for asthma treatment., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Air pollution events frequently occur in China during the winter. Most investigations of pollution studies have focused on the physical and chemical properties of PM2.5. Many of these studies have indicated that PM2.5 exacerbates asthma or eosinophil inflammation. However, few studies have evaluated the relationship between bacterial loads in PM2.5, and especially pathogenic bacteria and childhood asthma. Airborne PM2.5 samples from heavily polluted air were collected in Hangzhou, China between December 2014 and January 2015. PM2.5 and ovalbumin (OVA) were intratracheally administered twice in 4-week intervals to induce the allergic pulmonary inflammation in adolescent C57/BL6 mice. PM2.5 exposure caused neutrophilic alveolitis and bronchitis. In the presence of OVA, the levels of the Th2 cytokines IL-4, IL-12, and IL-17 were significantly increased in bronchoalveolar lavage fluids (BALF) after PM2.5 exposure, while eosinophil infiltration and mucin secretion were also induced. In addition to adjuvant effects on OVA-induced allergic inflammation, PM2.5 exposure also led to the maturation of dendritic cells. These results suggest that PM2.5 exposure may aggravate lung eosinophilia and that PM2.5-bound microbial can exacerbate allergic and inflammatory lung diseases.

A 42-year-old man with asthma presented in 2007 with chest infiltration and productive cough. Pycnoporus sanguineus and Perenniporia tephropora were repeatedly isolated from sputum and bronchial washing fluids. Because we lacked immunologic evidence, we could not diagnose him with allergic bronchopulmonary mycosis (ABPM) due to these basidiomycetous fungi. At that time, serum-specific IgE and IgG against Schizophyllum commune findings were negative. Inhaled beclomethasone/salmeterol improved his condition. Seven years later, mucous plugs obtained via bronchoscopy at a relapse were compatible with allergic mucin. Because S. commune was isolated from mucous plugs and serum-specific IgG against S. commune turned positive, we diagnosed the patient with ABPM due to S. commune.

Obesity is a risk factor for asthma, especially nonatopic asthma, and attenuates the efficacy of standard asthma therapeutics. Obesity also augments pulmonary responses to ozone, a nonatopic asthma trigger. The purpose of this study was to determine whether obesity-related alterations in gut microbiota contribute to these augmented responses to ozone. Ozone-induced increases in airway responsiveness, a canonical feature of asthma, were greater in obese db/db mice than in lean wild-type control mice. Depletion of gut microbiota with a cocktail of antibiotics attenuated obesity-related increases in the response to ozone, indicating a role for microbiota. Moreover, ozone-induced airway hyperresponsiveness was greater in germ-free mice that had been reconstituted with colonic contents of db /db than in wild-type mice. In addition, compared with dietary supplementation with the nonfermentable fiber cellulose, dietary supplementation with the fermentable fiber pectin attenuated obesity-related increases in the pulmonary response to ozone, likely by reducing ozone-induced release of IL-17A. Our data indicate a role for microbiota in obesity-related increases in the response to an asthma trigger and suggest that microbiome-based therapies such as prebiotics may provide an alternative therapeutic strategy for obese patients with asthma.

The particulate and biological components of indoor air have a substantial impact on human health, especially immune respiratory conditions such as asthma. To better explore the relationship between allergens, the microbial community, and the indoor living environment, we sampled the bedrooms of 65 homes in the Chicago area using 23the patient-friendly Inspirotec electrokinetic air sampling device, which collects airborne particles for characterization of both allergens and microbial DNA. The sampling device captured sufficient microbial material to enable 16S rRNA amplicon sequencing data to be generated for every sample in the study. Neither the presence of HEPA filters nor the height at which the air sampling device was placed had any influence on the microbial community profile. A core microbiota of 31 OTUs was present in more than three quarters of the samples, comprising around 45% of the relative sequence counts in each bedroom. The most abundant single organisms were Staphylococcus, with other core taxa both human and outdoor-associated. Bacterial alpha diversity was significantly increased in bedrooms that reported having open windows, those with flowering plants in the vicinity, and those in homes occupied by dogs. Porphyromonas, Moraxella, Sutterella, and Clostridium, along with family Neisseraceae, were significantly enriched in homes with dogs; interestingly, cats did not show a significant impact on microbial diversity or relative abundance. While dog allergen load was significantly correlated with bacterial alpha diversity, the taxa that significantly correlated with allergen burden did not exclusively overlap with those enriched in homes with dogs. Alternaria allergen load was positively correlated with bacterial alpha diversity, while Aspergillus allergen load was negatively correlated. The Alternaria allergen load was also significantly correlated with open windows. Microbial communities were significantly differentiated between rural, suburban, and urban homes and houses that were physically closer to each other maintained significantly more similar microbiota. We have demonstrated that it is possible to determine significant associations between allergen burden and the microbiota in air from the same sample and that these associations relate to the characteristics of the home and neighborhoods.

Background: Transmaternal exposure to tobacco, microbes, nutrients, and other environmental factors shapes the fetal immune system through epigenetic processes. The gastric microbe Helicobacter pylori represents an ancestral constituent of the human microbiota that causes gastric disorders on the one hand and is inversely associated with allergies and chronic inflammatory conditions on the other., Objective: Here we investigate the consequences of transmaternal exposure to H pylori in utero and/or during lactation for susceptibility to viral and bacterial infection, predisposition to allergic airway inflammation, and development of immune cell populations in the lungs and lymphoid organs., Methods: We use experimental models of house dust mite- or ovalbumin-induced airway inflammation and influenza A virus or Citrobacter rodentium infection along with metagenomics analyses, multicolor flow cytometry, and bisulfite pyrosequencing, to study the effects of H pylori on allergy severity and immunologic and microbiome correlates thereof., Results: Perinatal exposure to H pylori extract or its immunomodulator vacuolating cytotoxin confers robust protective effects against allergic airway inflammation not only in first- but also second-generation offspring but does not increase susceptibility to viral or bacterial infection. Immune correlates of allergy protection include skewing of regulatory over effector T cells, expansion of regulatory T-cell subsets expressing CXCR3 or retinoic acid-related orphan receptor γt, and demethylation of the forkhead box P3 (FOXP3) locus. The composition and diversity of the gastrointestinal microbiota is measurably affected by perinatal H pylori exposure., Conclusion: We conclude that exposure to H pylori has consequences not only for the carrier but also for subsequent generations that can be exploited for interventional purposes., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

We have previously reported that the mouse gut microbiome contributes to pulmonary responses to ozone, a common asthma trigger, and that short-chain fatty acids, end products of bacterial fermentation, likely contribute to this role of the microbiome. A growing body of evidence indicates that there are sex-related differences in gut microbiota and these differences can have important functional consequences. The purpose of this study was to determine whether there are sex-related differences in the impact of the gut microbiota on pulmonary responses to ozone. After acute exposure to ozone, male mice developed greater airway hyperresponsiveness than female mice. This difference was abolished after antibiotic ablation of the gut microbiome. Moreover, weanling female pups housed in cages conditioned by adult male mice developed greater ozone-induced airway hyperresponsiveness than weanling female pups raised in cages conditioned by adult females. Finally, ad libitum oral administration via drinking water of the short-chain fatty acid propionate resulted in augmented ozone-induced airway hyperresponsiveness in male, but not female, mice. Overall, these data are consistent with the hypothesis that the microbiome contributes to sex differences in ozone-induced airway hyperresponsiveness, likely as a result of sex differences in the response to short-chain fatty acids.

Our previous study showed that neonatal S. pneumoniae infection aggravated airway inflammation and airway hyperresponsiveness (AHR) in an OVA-induced allergic asthma model. As airway smooth muscle (ASM) plays a pivotal role in AHR development, we aim to investigate the effects of neonatal S. pneumoniae pneumonia on ASM structure and AHR development. Non-lethal neonatal pneumonia was established by intranasally infecting 1-week-old BALB/C mice with the S. pneumoniae strain D39. Five weeks after infection, the lungs were collected to assess the levels of α -SMA and the contractile proteins of ASM. Our results indicate that neonatal S. pneumoniae pneumonia significantly increased adulthood lung α -SMA and SMMHC proteins production and aggravated airway inflammatory cells infiltration and cytokines release. In addition, the neonatal S. pneumoniae pneumonia group had significantly higher Penh values compared to the uninfected controls. These data suggest that neonatal S. pneumoniae pneumonia promoted an aberrant ASM phenotype and AHR development in mice model.

The gastrointestinal microbiota influences immune function throughout the body. The gut-lung axis refers to the concept that alterations of gut commensal microorganisms can have a distant effect on immune function in the lung. Overgrowth of intestinal Candida albicans has been previously observed to exacerbate allergic airways disease in mice, but whether subtler changes in intestinal fungal microbiota can affect allergic airways disease is less clear. In this study we have investigated the effects of the population expansion of commensal fungus Wallemia mellicola without overgrowth of the total fungal community. Wallemia spp. are commonly found as a minor component of the commensal gastrointestinal mycobiota in both humans and mice. Mice with an unaltered gut microbiota community resist population expansion when gavaged with W. mellicola; however, transient antibiotic depletion of gut microbiota creates a window of opportunity for expansion of W. mellicola following delivery of live spores to the gastrointestinal tract. This phenomenon is not universal as other commensal fungi (Aspergillus amstelodami, Epicoccum nigrum) do not expand when delivered to mice with antibiotic-depleted microbiota. Mice with Wallemia-expanded gut mycobiota experienced altered pulmonary immune responses to inhaled aeroallergens. Specifically, after induction of allergic airways disease with intratracheal house dust mite (HDM) antigen, mice demonstrated enhanced eosinophilic airway infiltration, airway hyperresponsiveness (AHR) to methacholine challenge, goblet cell hyperplasia, elevated bronchoalveolar lavage IL-5, and enhanced serum HDM IgG1. This phenomenon occurred with no detectable Wallemia in the lung. Targeted amplicon sequencing analysis of the gastrointestinal mycobiota revealed that expansion of W. mellicola in the gut was associated with additional alterations of bacterial and fungal commensal communities. We therefore colonized fungus-free Altered Schaedler Flora (ASF) mice with W. mellicola. ASF mice colonized with W. mellicola experienced enhanced severity of allergic airways disease compared to fungus-free control ASF mice without changes in bacterial community composition., Competing Interests: The authors have declared that no competing interests exist.

Introduction: It has been demonstrated recently that the respiratory tract, considered for a long time to be sterile in the healthy subject, contains a vast community of bacteria called the respiratory microbiome. This microbiome, like the intestinal microbiome, is in constant interaction with the immune system of the human host. This relationship has allowed us to formulate some new theories on the pathophysiology of asthma., Background: The respiratory microbiome of the asthmatic differs quantitatively and qualitatively from that of the healthy subject. Equally there seem to be differences in the microbiome according to the degree of severity of the asthma and the response to treatment with corticosteroids. It has been shown in murine models of allergic asthma that an early disturbance of the microbiome by different perinatal factors could be responsible for disorders of the development of the immune system, leading to the development of asthma in the long term., Outlook: As a disorder of the microbiome might be implicated in the pathophysiology of asthma, the maintenance or restoration of a healthy microbiome is emerging as a possible new strategy in the management of the disease., Conclusion: The implication of the microbiome in the pathogenesis of human asthma seems to be more and more likely. This could have possible therapeutic implications, notably the restoration of a healthy microbiome., (Copyright © 2017 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Despite improved awareness of work-related diseases and preventive measures, many workers are still at high risk of developing occupational hypersensitivity airway diseases. This stems from a lack of knowledge of bioaerosol composition and their potential effects on human health. Recently, archaea species were identified in bioaerosols, raising the possibility that they play a major role in exposure-related pathology. Specifically, Methanosphaera stadtmanae (MSS) and Methanobrevibacter smithii (MBS) are found in high concentrations in agricultural environments and respiratory exposure to crude extract demonstrates immunomodulatory activity in mice. Nevertheless, our knowledge of the specific impact of methanogens exposure on airway immunity and their potential to induce airway hypersensitivity responses in workers remains scant. Analysis of the lung mucosal response to methanogen crude extracts in mice demonstrated that MSS and MBS predominantly induced T H 17 airway inflammation, typical of a type IV hypersensitivity response. Furthermore, the response to MSS was associated with antigen-specific IgG 1 and IgG 2a production. However, despite the presence of eosinophils after MSS exposure, only a weak T H 2 response and no airway hyperresponsiveness were observed. Finally, using eosinophil and mast cell-deficient mice, we confirmed that these cells are dispensable for the T H 17 response to MSS, although eosinophils likely contribute to the exacerbation of inflammatory processes induced by MSS crude extract exposure. We conclude that, as MSS induces a clear type IV hypersensitivity lung response, it has the potential to be harmful to workers frequently exposed to this methanogen, and that preventive measures should be taken to avoid chronic hypersensitivity disease development in workers., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Chronic rhinosinusitis consists of several disease processes. Eosinophilic mucin is found in the subtypes of allergic fungal sinusitis (AFS) and eosinophilic mucin chronic rhinosinusitis (EMCRS). These entities frequently require surgical intervention and have high recurrence rates., Objective: We aimed to determine factors in patients with AFS and EMCRS that may be associated with a higher rate of revision surgeries. Our hypothesis is that patients who have polyps, high Lund-Mackay score (LMS), and fungus may have higher revision rates., Study Design: Retrospective cohort study., Methods: This is a retrospective analysis of 117 patients identified over a 5-year period (2005-2009) with the diagnosis of AFS or EMCRS. Contingency tables were created to obtain the odds ratios estimates, and 95% confidence intervals were used to access the association between the outcome (having revision surgery or not) and other clinical binary predictors., Results: Twenty-six of 117 (22%) of the study patients underwent revision surgery. Within the 2-year follow-up period, an additional five of 26 (19%) required another revision surgery. Average LMS was slightly higher in those who underwent revision surgery (16 vs. 13) on a scale of 0 to 24, with an overall mean score of 18 and standard deviation of 6.82 for the whole sample (117). Other factors evaluated were the presence of fungus, polyps, eosinophilic mucin, and the eosinophilic count and medical therapy received., Conclusion: The presence of eosinophilic mucin was significantly associated a higher rate of revision surgery., Level of Evidence: 4. Laryngoscope, 127:59-63, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: As part of the etiology of respiratory allergy we have genetics, prenatal factors and sensitivity to various airborne allergens, between these fungi are found. Relationship has been found between sensitization to fungal in skin tests and allergy pathogenesis and aggravation. There is a few literature in Mexico and in the north of the country it is lacking regarding this problem., Objective: Assess the prevalence of sensitization to fungi in patients with respiratory allergy in skin tests to airborne allergens; determine the most prevalent fungus and prevalence of sensitization to each species of fungus per year, to assess the prevalence of sensitization to fungi by years., Material and Method: Cross-sectional, observational and descriptive study conducted from 1 January 2010 to 31 December 2014 in patients treated at the Regional Center of Allergy and Clinical Immunology (Monterrey, Mexico) where we reviewed a database with patients whom performed skin tests, sensitization to 6 species of fungi were evaluated. We performed tables of data capture and statistical analysis., Results: 4880 patients had respiratory allergy, a 17.1% prevalence of sensitization to fungal skin tests was determined. The fungus specie most prevalent was Alternaria alternata with 5.5%. The year range with the highest prevalence of sensitization was 0-10 years with a 6.7., Conclusions: The prevalence of fungi sensitization was higher than the global prevalence found, but lower than the prevalence found in other researches in Mexico.

Neonatal Chlamydia lung infections are associated with serious sequelae such as asthma and airway hyper-reactivity in children and adults. Our previous studies demonstrated the importance of Th-1 type cytokines, IL-12 and IFN-γ in protection against neonatal pulmonary chlamydial challenge; however, the role of the humoral arm of defense has not been elucidated. We hypothesized that B-cells and IgA, the major mucosal antibody, play a protective role in newborns against development of later life respiratory sequelae to Chlamydia infection. Our studies using neonatal mice revealed that all WT and IgA-deficient (IgA(-/-)) animals survived a sublethal pulmonary Chlamydia muridarum challenge at one day after birth with similar reduction in bacterial burdens over time. In contrast, all B-cell-deficient (μMT) mice succumbed to infection at the same challenge dose correlating to failure to control bacterial burdens in the lungs. Although IgA may not be important for bacterial clearance, we observed IgA(-/-) mice displayed greater respiratory dysfunction 5 weeks post challenge. Specifically, comparative respiratory functional analyses revealed a significant shift upward in P-V loops, and higher dynamic resistance in IgA(-/-) animals. This study provides insight(s) into the protective role of IgA in neonates against pulmonary chlamydial infection induced respiratory pathological sequelae observed later in life., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alternaria alternata spores are considered a well-known biological contaminant and a very common potent aeroallergen source that is found in environmental samples. The most intense exposure to A. alternata allergens is likely to occur outdoors; however, Alternaria and other allergenic fungi can colonize in indoor environments and thereby increase the fungal aeroallergen exposure levels. A consequence of human exposure to fungal aeroallergens, sensitization to A. alternata, has been unequivocally associated with increased asthma severity. Among allergenic proteins described in this fungal specie, the major allergen, Alt a 1, has been reported as the main elicitor of airborne allergies in patients affected by a mold allergy and considered a marker of primary sensitization to A. alternata. Moreover, A. alternata sensitization seems to be a triggering factor in the development of poly-sensitization, most likely because of the capability of A. alternata to produce, in addition to Alt a 1, a broad and complex array of cross-reactive allergens that present homologs in several other allergenic sources. The study and understanding of A. alternata allergen information may be the key to explaining why sensitization to A. alternata is a risk factor for asthma and also why the severity of asthma is associated to this mold. Compared to other common environmental allergenic sources, such as pollens and dust mites, fungi are reported to be neglected and underestimated. The rise of the A. alternata allergy has enabled more research into the role of this fungal specie and its allergenic components in the induction of IgE-mediated respiratory diseases. Indeed, recent research on the identification and characterization of A. alternata allergens has allowed for the consideration of new perspectives in the categorization of allergenic molds, assessment of exposure and diagnosis of fungi-induced allergies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Recently, academic studies suggest that global growth of airway allergic disease has a close association with dietary changes including reduced consumption of fiber. Therefore, appropriate dietary fiber supplementation might be potential to prevent airway allergic disease (AAD)., Objective: We investigated whether dietary fiber intake suppressed the induction of AAD and tried to elucidate the possible underlying mechanisms., Methods: The control mice and AAD model mice fed with 4% standard-fiber chow, while low-fiber group of mice fed with a 1.75% low-fiber chow. The two fiber-intervened groups including mice, apart from a standard-fiber diet, were also intragastric (i.g.) administrated daily with poorly fermentable cellulose or readily fermentable pectin (0.4% of daily body weight), respectively. All animals except normal mice were sensitized and challenged with ovalbumin (OVA) to induce airway allergic inflammation. Hallmarks of AAD were examined by histological analysis and ELISA. The variation in intestinal bacterial composition was assessed by qualitative analysis of 16S ribosomal DNA (rDNA) content in fecal samples using real-time PCR., Results: Low-fiber diet aggravated inflammatory response in ovalbumin-induced allergic mice, whereas dietary fiber intake significantly suppressed the allergic responses, attenuated allergic symptoms of nasal rubbing and sneezing, decreased the pathology of eosinophil infiltration and goblet cell metaplasia in the nasal mucosa and lung, inhibited serum OVA-specific IgE levels, and lowered the levels of Th2 cytokines in NALF and BALF, but, increased Th1 (IFN-γ) cytokines. Additionally, dietary fiber intake also increased the proportion of Bacteroidetes and Actinobacteria, and decreased Firmicutes and Proteobacteria. Levels of probiotic bacteria, such as Lactobacillus and Bifidobacterium, were upgraded significantly., Conclusion: Long-term deficiency of dietary fiber intake increases the susceptibility to AAD, whereas proper fiber supplementation promotes effectively the balance of Th1/Th2 immunity and then attenuates allergic inflammatory responses significantly, as well as optimizes the structure of intestinal microbiota, which suggests potential for novel preventive and therapeutic intervention.

Fungi are ubiquitous and form their own kingdom. Up to 80 genera of fungi have been linked to type I allergic disease, and yet, commercial reagents to test for sensitization are available for relatively few species. In terms of asthma, it is important to distinguish between species unable to grow at body temperature and those that can (thermotolerant) and thereby have the potential to colonize the respiratory tract. The former, which include the commonly studied Alternaria and Cladosporium genera, can act as aeroallergens whose clinical effects are predictably related to exposure levels. In contrast, thermotolerant species, which include fungi from the Candida, Aspergillus, and Penicillium genera, can cause a persistent allergenic stimulus independent of their airborne concentrations. Moreover, their ability to germinate in the airways provides a more diverse allergenic stimulus, and may result in noninvasive infection, which enhances inflammation. The close association between IgE sensitization to thermotolerant filamentous fungi and fixed airflow obstruction, bronchiectasis, and lung fibrosis suggests a much more tissue-damaging process than that seen with aeroallergens. This review provides an overview of fungal allergens and the patterns of clinical disease associated with exposure. It clarifies the various terminologies associated with fungal allergy in asthma and makes the case for a new term (allergic fungal airway disease) to include all people with asthma at risk of developing lung damage as a result of their fungal allergy. Lastly, it discusses the management of fungirelated asthma.

Background: An increased prevalence of allergic disorders in developed countries has been associated with decreased exposure to environmental micro-organisms and an alteration of microbiota colonization. An appropriate model is needed to investigate the mechanisms by which hygiene environment-driven changes in microbiota could regulate allergic disorders., Objective: To discover the correlation between the higher incidence and severity of allergies with the relative hygiene environment in a developed country., Methods: Allergic respiratory inflammation was induced in specific pathogen-free and control rats by sensitization and challenge with ovalbumin. The diversity of lower airway bacteria community was analyzed by polymerase chain reaction denaturing gradient gel electrophoresis and sequencing before ovalbumin sensitization. Allergic respiratory inflammation resulting in cellular infiltrate was measured after the last challenge., Results: The diversity of microbiota in the airway of specific pathogen-free rats decreased compared with the control rats; the more frequent microbiota in the control rats were Proteobacteria and Bacteroidetes. In addition, increased nasal rubbing and sneezing combined with exaggerated IgE production and leukocyte number was observed in ovalbumin-treated specific pathogen-free rats., Conclusion: These data indicate that the excessive "hygienic" environment resulted in a decreased bacterial diversity in the airway during infancy, leading to an increased susceptibility to allergic disease., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In this review we discuss the effects of microbial exposure on the B cell repertoire. Neonatal exposure to conserved bacterial carbohydrates and phospholipids permanently reprograms the natural antibody repertoire directed toward these antigens by clonal expansion, alterations in clonal dominance, and increased serum antibody levels. These epitopes are present not only in bacterial cell walls, but also in common environmental allergens. Neonatal immunization with bacterial polysaccharide vaccines results in attenuated allergic airway responses to fungi-, house dust mite-, and cockroach-associated allergens in mouse models. The similarities between mouse and human natural antibody repertoires suggest that reduced microbial exposure in children may have the opposite effect, providing a potential mechanistic explanation for the hygiene hypothesis. We propose that understanding the effects of childhood infections on the natural antibody repertoire and the mechanisms of antibody-mediated immunoregulation observed in allergy models will lead to the development of prevention/interventional strategies for treatment of allergic asthma.

Objectives: To study the associations between exposure to bioaerosols and work-related symptoms, lung function and biomarkers of airway inflammation in compost workers., Materials and Method: Personal full-shift exposure measurements were performed on 47 workers employed at five windrow plants (n=20) and five reactor plants (n=27). Samples were analyzed for endotoxins, bacteria, fungal and actinomycetes spores. Health examinations were performed on workers and 37 controls before and after work on the day exposure was measured. The examinations included symptoms recorded by questionnaire, lung function by spirometry and nasal dimensions by acoustic rhinometry (AR). The pneumoproteins CC16, SP-D and SP-A were measured in a blood sample drawn at the end of the day., Results: The levels of endotoxins (median 3 EU/m(3), range 0-730 EU/m(3)) and actinomycetes spores (median 0.2 × 10(6) spores/m(3), range 0-590 × 10(6) spores/m(3)) were significantly higher in reactor plants compared to windrow plants. However, windrow composting workers reported more symptoms than reactor composting workers, probably due to use of respiratory protection. Exposure-response relationships between actinomycetes spores exposure and respiratory effects, found as cough and nose irritation during a shift, was significantly increased (OR 4.3, 95% CI 1.1-16, OR 6.1, 95% CI 1.5-25, respectively, p<0.05) among workers exposed to 0.02-0.3 × 10(6) actinomycetes spores/m3, and FEV1/FVC% decreased cross shift (b=-3.2, SE=1.5%, p<0.01). Effects were weaker in the highest exposed group, but these workers used respiratory protection, frequently limiting their actual exposure. No relationships were found between exposure and pneumoprotein concentrations., Conclusions: The major agent in the aerosol generated at compost plants was actinomycetes spores which was associated with work related cough symptoms and work-shift lung function decrease.

The lung, while functioning as a gas exchange organ, encounters a large array of environmental factors, including particulate matter, toxins, reactive oxygen species, chemicals, allergens, and infectious microbes. To rapidly respond to and counteract these elements, a number of innate immune mechanisms have evolved that can lead to lung inflammation and asthma, which is the focus of this review. These innate mechanisms include a role for two incompletely understood cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), which together produce a wide range of cytokines, including interleukin-4 (IL-4), IL-5, IL-13, interferon-γ, IL-17, and IL-22, independently of adaptive immunity and conventional antigens. The specific roles of iNKT cells and ILCs in immunity are still being defined, but both cell types appear to play important roles in the lungs, particularly in asthma. As we gain a better understanding of these innate cell types, we will acquire great insight into the mechanisms by which allergic and non-allergic asthma phenotypes develop., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In the last few decades, aerially transmitted human fungal pathogens have been increasingly recognized to impact the clinical course of chronic pulmonary diseases, such as asthma, cystic fibrosis or chronic obstructive pulmonary disease. Thanks to recent development of culture-free high-throughput sequencing methods, the metagenomic approaches are now appropriate to detect, identify and even quantify prokaryotic or eukaryotic microorganism communities inhabiting human respiratory tract and to access the complexity of even low-burden microbe communities that are likely to play a role in chronic pulmonary diseases. In this review, we explore how metagenomics and comparative genomics studies can alleviate fungal culture bottlenecks, improve our knowledge about fungal biology, lift the veil on cross-talks between host lung and fungal microbiota, and gain insights into the pathogenic impact of these aerially transmitted fungi that affect human beings. We reviewed metagenomic studies and comparative genomic analyses of carefully chosen microorganisms, and confirmed the usefulness of such approaches to better delineate biology and pathogenesis of aerially transmitted human fungal pathogens. Efforts to generate and efficiently analyze the enormous amount of data produced by such novel approaches have to be pursued, and will potentially provide the patients suffering from chronic pulmonary diseases with a better management. This manuscript is part of the series of works presented at the "V International Workshop: Molecular genetic approaches to the study of human pathogenic fungi" (Oaxaca, Mexico, 2012)., (Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.)

Rationale: Human rhinovirus species C (HRV-C) is the most common cause of acute wheezing exacerbations in young children presenting to hospital, but its impact on subsequent respiratory illnesses has not been defined., Objectives: To determine whether acute wheezing exacerbations due to HRV-C are associated with increased hospital attendances due to acute respiratory illnesses (ARIs)., Methods: Clinical information and nasal samples were collected prospectively from 197 children less than 5 years of age, presenting to hospital with an acute wheezing episode. Information on hospital attendances with an ARI before and after recruitment was subsequently obtained., Measurements and Main Results: HRV was the most common virus identified at recruitment (n = 135 [68.5%]). From the 120 (88.9%) samples that underwent typing, HRV-C was the most common HRV species identified, present in 81 (67.5%) samples. Children with an HRV-related wheezing illness had an increased risk of readmission with an ARI (relative risk, 3.44; 95% confidence interval, 1.17-10.17; P = 0.03) compared with those infected with any other virus. HRV-C, compared with any other virus, was associated with an increased risk of a respiratory hospital admission before (49.4% vs. 27.3%, respectively; P = 0.004) and within 12 months (34.6% vs. 17.0%; P = 0.01) of recruitment. Risk for subsequent ARI admissions was further increased in atopic subjects (relative risk, 6.82; 95% confidence interval, 2.16-21.55; P = 0.001). Admission risks were not increased for other HRV species., Conclusions: HRV-C-related wheezing illnesses were associated with an increased risk of prior and subsequent hospital respiratory admissions. These associations are consistent with HRV-C causing recurrent severe wheezing illnesses in children who are more susceptible to ARIs.

Background: While fungal exposures are assumed to provoke wheeze through irritant or allergenic mechanisms, little is known about the differential effects of indoor and outdoor fungi on early-life wheeze., Methods: In a Boston prospective birth cohort of 499 at-risk infants, culturable fungi in bedroom air and dust and outdoor air were measured at the age of 2-3 months. Wheeze was determined using bimonthly telephone questionnaires. Odds ratios were estimated for an interquartile increase in fungal natural log-transformed concentrations, adjusting for predictors of wheeze and potential confounders., Results: Increased odds of 'any wheeze' (≥1 vs 0 episodes) by age one were positively associated with indoor dust Alternaria [odds ratio (OR) = 1.83; 95% confidence interval (CI), 1.07-3.14], Penicillium [OR = 1.18; (0.98-1.43)], and Cladosporium [OR = 1.47; (1.16-1.85)]; indoor air Penicillium [OR = 1.26; (0.92-1.74)]; and outdoor air Cladosporium [OR = 1.68; (1.04-2.72)]. In contrast, indoor dust yeasts were protective [OR = 0.78; (0.66-0.93)]. 'Frequent wheeze' (≥2 vs <2 episodes) by age one was borderline associated with dust yeasts [OR = 0.86; (0.70-1.04)] and indoor air yeasts [OR = 1.53; (0.93-2.53)]. Alternaria concentration was associated with any wheeze for children with maternal mold sensitization [OR = 9.16; (1.37-61.22)], but not for those without maternal mold sensitization [OR = 1.32; (0.79-2.20)]., Conclusions: While wheeze rates were higher with exposures to fungal taxa considered to be irritant or allergenic in sensitive subjects, yeasts in the home had a strong protective association with wheeze in infancy. Molecular microbiologic studies may elucidate specific components of innate microbiologic stimulants that lead to contrasting effects on wheeze development., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Fungi belong to common allergens, which can be found both in occupational and non-occupational environment. The aim of the study was to determine the frequency and factors associated with mould allergy among bakers and farmers reporting work-related respiratory symptoms. The study group comprised 117 bakers and 83 farmers reporting work-related respiratory symptoms. Skin prick tests (SPT) with common, fungal and occupational allergens, estimation of serum total IgE level, spirometry, histamine test and specific inhalative challenge test with occupational allergens were performed in all subjects. The prevalence of hypersensitivity to fungal species was higher among farmers (32.5%) than bakers (16.2%). Positive SPT with mould allergens were found among 10.8% farmers and 6.8% bakers with occupational allergy. The fungi allergens giving positive SPT results most frequently were Candida albicans, Levures mélanges, Aspergillus mix. and Charbons cerealiers in both groups. Among mould allergens, hypersensitivity to Aspergillus genus was the most common in farmers and bakers group, while among Saccharomyces - Candida albicans sensitization was the most frequently detected. Mould hypersensitivity is related to occupational respiratory allergy, especially to asthma and rhinitis in farmers, and occupational asthma in bakers. Although sensitization to Saccharomyces was more frequent, similar correlation was not observed.

Sensitization to fungi, such as the mold Aspergillus fumigatus, is increasingly becoming linked with asthma severity. We have previously shown that lung responses generated via the β-glucan receptor Dectin-1 are required for lung defense during acute, invasive A. fumigatus infection. Unexpectedly, in an allergic model of chronic lung exposure to live A. fumigatus conidia, β-glucan recognition via Dectin-1 led to the induction of multiple proallergic (Muc5ac, Clca3, CCL17, CCL22, and IL-33) and proinflammatory (IL-1β and CXCL1) mediators that compromised lung function. Attenuated proallergic and proinflammatory responses in the absence of Dectin-1 were not associated with changes in Ido (IDO), Il12p35/Ebi3 (IL-35), IL-10, or TGF-β levels. Assessment of Th responses demonstrated that purified lung CD4(+) T cells produced IL-4, IL-13, IFN-γ, and IL-17A, but not IL-22, in a Dectin-1-dependent manner. In contrast, we observed robust, Dectin-1-dependent IL-22 production by unfractionated lung digest cells. Intriguingly, the absence of IL-22 alone mimicked the attenuated proallergic and proinflammatory responses observed in the absence of Dectin-1, suggesting that Dectin-1-mediated IL-22 production potentiated responses that led to decrements in lung function. To this end, neutralization of IL-22 improved lung function in normal mice. Collectively, these results indicate that the β-glucan receptor Dectin-1 contributes to lung inflammation and immunopathology associated with persistent fungal exposure via the production of IL-22.

We sought to determine if sufficient redundancy exists between specific IgE testing for Aspergillus fumigatus and Aspergillus niger to eliminate one of the assays in determining Aspergillus hypersensitivity. We reviewed regional laboratory results comparing A fumigatus-specific IgE with A niger-specific IgE using the Pharmacia UniCAP system (Pharmacia, Kalamazoo, MI). By using the Fisher exact test as an index of concordance among paired results, we showed a significant difference between 109 paired samples for the presence of specific IgE to A fumigatus and A niger (P < .0001). Of these specimens, 94 were negative for IgE to both species, 10 were positive for A fumigatus and negative for A niger; no specimen was positive for A niger and negative for A fumigatus. We conclude that A fumigatus-specific IgE is sufficient to detect Aspergillus hypersensitivity. The assay for A niger-specific IgE is redundant, less sensitive, and unnecessary if the assay for specific IgE for A fumigatus is performed.

Our objective was to conduct an aeromycological and health survey (2002-2007) in a suburban area near Kolkata, India, with the aim of achieving the following goals: (i) to prepare a fungal spore calendar, (ii) to determine the influence of different meteorological parameters, and (iii) to study the respiratory health status of local population in relation to allergy. Airborne fungal spores from more than 50 taxa were found, of which at least 15 were allergenic. The spore-concentration increased during early-winter and rainy season, and diminished during late-winter and mid-summer. Species-specific fluctuations had substantial influences from several meteorological parameters. The suburban area was found to be considerably contaminated with numerous allergenic air-spora, which caused health risk to the local population. Males were more susceptible to respiratory disorders irrespective of their age. In general, respiratory allergic patients in the 20-40 year age-group showed more frequent health problems due to aeroallergens. A positive correlation was found between the respiratory allergy cases and the air-spora concentrations.

Mucosal immune responses to fungal infection range from T helper type 2 (Th2) cell-directed allergic inflammation to Th1-predominant neutrophilic inflammation, but the mechanisms directing these divergent mucosal immune outcomes and the role of T cells in host defense against mucosal fungal infections are not known. Here we examined the mouse mucosal immune responses to 12 filamentous environmental fungal species over a broad range of exposure doses and determined the requirement of T cells for host defense. For all tested fungi, low-grade conidium exposures induced Th2- and eosinophil-predominant allergic lung disease, whereas higher exposures led to rapid conversion to neutrophil- and Th1 cell-predominant inflammation, a phenomenon we term immune phenotype switching. All fungal exposure doses were further linked to the secretion of interleukin-17A (IL-17A). Fungal infections with Curvularia lunata and Aspergillus fumigatus were typically confined to the airway during allergic inflammation but became locally invasive and disseminated to the brain at higher conidium challenge doses, in association with predominant Th1 responses. Fungal dissemination occurred at relatively low challenge doses with the conidia of Aspergillus fumigatus administered to recombinase activating gene 1 (Rag-1)-deficient mice, which lack B and T cells, but B cell-deficient μMT mice and T helper cell-reconstituted Rag-1-deficient mice were comparable to wild-type mice in preventing fungal dissemination. Our findings demonstrate that Th2 cell-predominant allergic responses followed by immune phenotype switching and fungal dissemination are highly predictable outcomes with progressive fungal infectious burdens and that T helper cell responses are protective against lethal fungal dissemination.

Objective: To investigate the relationship between the prevalent species and the seasonal drift law of airborne fungi and respiratory allergic disease in the city of Wuhan., Method: Airborne fungi was investigated by exposed sides from 2007 to 2008, and 1674 patients with respiratory allergic disease that were used to do allergens skin test simultaneously, in order to analyze the simultaneous., Result: Airborne fungi could be detected in air all over the year. In 2007, the exposed films collected 26 734 fungi spores, and 686 other fungi (hypha and not well known fungi), to the sum of 27420. Otherwise, in 2008, the exposed films collected 26 531 fungi spores, and 730 other fungi, to the sum of 27 261. In the survey, 17 types of species of the collected fungi spores were identified, and the predominant species were alternaria sp, ustilaginales, deightoniella sp, uredinales, and the quantity of Fungi alternaria was most of all . And the peak period mainly concentrated from April to June, and from September to October. Otherwise, the positive rate of fungi skin test in patients with respiratory allergic disease was 10.48% in 2007, but 10.07% in 2008. The main period of onset of respiratory allergic disease was from April to June, and from September to October, similar as the seasonal drift law of airborne fungi., Conclusion: The period of onset of respiratory allergic disease was consistent with the seasonal drift law of airborne fungi.

Farming environment and environmental exposure to microbial agents have been suggested to promote favorable development of immune system in children and protect against allergic diseases. However, effects of farm exposure on adult immune responses are less clear. Aim of the present study was to examine associations of farm related factors and measured microbial exposure with stimulated production of interferon-gamma (IFN-γ) and interleukin-4 (IL-4) in peripheral blood samples among farming women. Whole peripheral blood samples were obtained from 112 women living on farms and stimulated with phorbol myristate acetate/ionomycin, lipopolysaccharide and staphylococcal enterotoxin B. Following 24h stimulation, protein levels of IFN-γ and IL-4 in the supernatants were measured by ELISA. From house dust, concentrations of 3-hydroxy fatty acids (C10:0-C14:0, marker for Gram-negative bacteria), muramic acid (Gram-positive bacteria) and ergosterol (fungal biomass) were analyzed with GC-MS/MS and viable microbes by culturing. Information on farm related factors and allergic diseases were collected from self-administered questionnaires. We found that household pets or other current or childhood farm-related factors had only few associations with stimulated cytokine production among studied farming women. Similarly, no strong associations were observed between markers of microbial exposure measured in house dust and cytokine levels. Atopic sensitization, allergic rhinitis and recent respiratory infections were, however, associated with reduced IFN-γ production. Our results suggest that the capacity of the studied environmental factors to modulate immune system is relatively weak in adulthood., (Copyright © 2011 Elsevier GmbH. All rights reserved.)

Actinobacteria are a large group of Gram-positive bacteria common in the environment, especially in the soil. They are morphologically diverse and extremely versatile in their metabolic activities. They produce tens of thousands of secondary metabolites with different biological activities. Exposure to actinobacteria in indoor environments is probably continuous, since they are both common environmental bacteria and human normal flora. However, the occurrence of some species of spore-forming filamentous actinomycetes has been associated with abnormal and health-hazardous situations, such as moisture damage of the building. The measured concentrations of actinobacteria indoors are low. Higher concentrations have been reported during the remediation work of moisture damaged buildings and in agricultural environments. Exposure to high concentrations of actinobacteria can cause allergic alveolitis. Other respiratory disorders have been reported, too and although the measured concentrations are low, the indoor exposure is always a mixture of many different agents, which may have synergistic effects. In vitro and in vivo studies have shown that actinobacteria are very immunoactive and hence, potential causative agents for respiratory and other disorders.

Objectives: Many studies have shown consistent associations between evident indoor dampness or mold and respiratory or allergic health effects, but causal links remain unclear. Findings on measured microbiologic factors have received little review. We conducted an updated, comprehensive review on these topics., Data Sources: We reviewed eligible peer-reviewed epidemiologic studies or quantitative meta-analyses, up to late 2009, on dampness, mold, or other microbiologic agents and respiratory or allergic effects., Data Extraction: We evaluated evidence for causation or association between qualitative/subjective assessments of dampness or mold (considered together) and specific health outcomes. We separately considered evidence for associations between specific quantitative measurements of microbiologic factors and each health outcome., Data Synthesis: Evidence from epidemiologic studies and meta-analyses showed indoor dampness or mold to be associated consistently with increased asthma development and exacerbation, current and ever diagnosis of asthma, dyspnea, wheeze, cough, respiratory infections, bronchitis, allergic rhinitis, eczema, and upper respiratory tract symptoms. Associations were found in allergic and nonallergic individuals. Evidence strongly suggested causation of asthma exacerbation in children. Suggestive evidence was available for only a few specific measured microbiologic factors and was in part equivocal, suggesting both adverse and protective associations with health., Conclusions: Evident dampness or mold had consistent positive associations with multiple allergic and respiratory effects. Measured microbiologic agents in dust had limited suggestive associations, including both positive and negative associations for some agents. Thus, prevention and remediation of indoor dampness and mold are likely to reduce health risks, but current evidence does not support measuring specific indoor microbiologic factors to guide health-protective actions.

Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2-/-, and TLR4-/- mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2-/- mice, but not in TLR4-/- mice, due to differential Treg responses in these genotypes. TLR2-/- mice had reduced numbers of Tregs in the lung during CP infection while TLR4-/- mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.

Neutrophilic asthma is a prevalent, yet recently described phenotype of asthma. It is characterized by neutrophilic rather than eosinophilic airway inflammation and airways hyperresponsiveness (AHR) and may have an infectious origin. Chlamydial respiratory infections are associated with asthma, but how these Th1-inducing bacteria influence Th2-mediated asthma remains unknown. The effects of chlamydial infection on the development of asthma were investigated using a BALB/c mouse model of OVA-induced allergic airways disease (AAD). The effects of current and resolved Chlamydia muridarum infection during OVA sensitization on AAD were assessed and compared with uninfected and nonsensitized controls. Current, but not resolved, infection attenuated hallmark features of AAD: pulmonary eosinophil influx, T cell production of IL-5, mucus-secreting cell hyperplasia, and AHR. Current infection also induced robust OVA-driven neutrophilic inflammation and IFN-gamma release from T cells. The phenotype of suppressed but persistent Th2 responses in association with enhanced neutrophilia is reminiscent of neutrophilic asthma. This phenotype was also characterized by increased pulmonary IL-12 and IL-17 expression and activation of APCs, as well as by reduced thymus- and activation-regulated chemokine. Inhibition of pulmonary neutrophil influx during infection blocked OVA-induced neutrophilic inflammation and T cell IFN-gamma production and reversed the suppressive effects on mucus-secreting cell hyperplasia and AHR during AAD. These changes correlated with decreased IL-12 and IL-17 expression, increased thymus- and activation-regulated chemokine and altered APC activation. Blocking IFN-gamma and IL-17 during OVA challenge had no effect. Thus, active chlamydial respiratory infection during sensitization enhances subsequent neutrophilic inflammation and Th1/Th17 responses during allergen exposure and may have a role in the pathogenesis of neutrophilic asthma.

Purpose of Review: The development of the intestinal microbiota occurs primarily during infancy, and a distortion could potentially contribute to a wide range of diseases. This review summarizes the current understanding of the intestinal microbiota in infants. The potential consequences of different colonization patterns on child health and possible preventive interventions are discussed., Recent Findings: Recent studies and the use of culture-independent techniques have shown that Bifidobacterium is only a minor component of the infant gut microbiota. These techniques have also introduced the concept of a core microbiome in which metabolic function is more important than the presence of a particular bacterial species. A less diverse gut microbiota with high counts of Bacteroides, Clostridium, Enterobacteriaceae and Staphylococcus early in life has been associated with an increased risk for atopic disease. Changes in infant gut colonization were also found in relation to childhood obesity. Probiotics have no proven preventive effect on the development of asthma and an unconfirmed effect on atopic dermatitis. A prebiotic trial could show a preventive effect on the development of both atopic diseases., Summary: Molecular techniques have improved our understanding of the infant gut ecosystem. The available probiotics for prevention of atopic disease are disappointing, and the results with prebiotics need further confirmation. New studies on the relation between gut microbiota and disease should consider asthma and atopic dermatitis separately. Future trials should focus on high-risk groups, determine their long-term effect and also investigate the effect on Bacteroides and Clostridium.

Background: Staphylococcus aureus (SA) in the nose can be a simple colonizer but also may create an intramucosal reservoir causing recurrent infections or can be a specific immune modulator through superantigenic mechanisms. Because the colonization rate of SA is high, but immunologic reactions causing chronic disease are less frequent, the purpose of this study was to identify the presence of intramucosal SA in healthy subjects and in patients with chronic rhinosinusitis (CRS) and to eventually relate those to the specific immunologic changes due to SA enterotoxins., Methods: Nasal tissue was collected in 40 subjects (9 controls, 21 CRS patients with [CRSwNP], and 10 CRS patients without nasal polyps [CRSsNP]). Tissues were homogenized, and mediators and specific IgE-antibodies against SA enterotoxins (SAE-IgE) were measured using the UniCAP system. The tissue was analyzed for the presence of SA by the peptide nucleic acid-fluorescence in situ hybridization (PNA-FISH) technique (AdvanDx), and a semiquantitative scoring system was applied. Mann-Whitney exact test was used for statistical analysis., Results: SA in the mucosal tissue was detected in a higher quantity among CRSwNP subjects with aspirin exacerbated respiratory disease (AERD) versus controls and CRSsNP (p=0.03). Among CRSwNP patients, Th2 markers (eosinophil cationic protein, p=0.006, and total IgE, p=0.004) were increased related to the SAE-IgE status but not related to the presence of SA in the tissue., Conclusion: This study describes the detection of SA within nasal tissue using the PNA-FISH technique. The presence of SA in the submucosa did not correlate with the amplification of the Th2-related inflammation typically found in CRSwNP patients, but this reaction is dependent on the formation of SAE-IgE within mucosal tissue. We also show, for the first time, that submucosal SA is a prevalent finding in CRSwNP patients with AERD.

Background and Objective: Epidemiological evidence indicates a close link between exposure to fungi and deterioration of asthma. However, the role of fungi as an exogenous precipitant for initiation and progression of asthma has been incompletely explored. In this study, the effects of Aspergillus fumigatus exposure on airway inflammation and remodelling in a rat model of chronic asthma were investigated., Methods: The rat model of chronic asthma was established by systemic sensitization and repeated challenge with ovalbumin (OVA). The asthmatic rats were exposed to chronic intranasal inhalation of A. fumigatus spores. Changes in airway inflammation, remodelling and BHR were measured after exposure to the fungus., Results: Chronic inhalation of A. fumigatus spores elevated the production of T helper 2 (Th2) cytokines, increased the concentration of total serum IgE, and resulted in the recruitment of eosinophils and lymphocyte infiltration into the airways of asthmatic rats. Goblet cell hyperplasia, mucus hyperproduction and subepithelial collagen deposition were also induced by inhalation of the fungus. The remodelling changes induced by inhalation of the fungus paralleled the changes in BHR in this rat model of asthma., Conclusions: Chronic exposure to A. fumigatus aggravated Th2 airway inflammation, promoted airway remodelling and increased BHR in OVA-sensitized and -challenged rats.

The hygiene hypothesis suggests that lack of microbial stimulation in early infancy may lead to allergy, but it has been difficult to identify particular protective microbial exposures. We have observed that infants colonised in the first week(s) of life with Staphylococcus aureus have lower risk of developing food allergy. As many S. aureus strains produce superantigens with T-cell stimulating properties, we here investigate whether neonatal mucosal exposure to superantigen could influence the capacity to develop oral tolerance and reduce sensitisation and allergy. BALB/c mice were exposed to staphylococcal enterotoxin A (SEA) as neonates and fed with OVA as adults, prior to sensitisation and i.n. OVA challenge. Our results show that SEA pre-treated mice are more efficiently tolerised by OVA feeding, as shown by lower lung-cell infiltration and antigen-specific IgE response in the SEA pre-treated mice, compared with sham-treated mice. This was not due to deletion or anergy of lymphocytes by SEA treatment, because the SEA pre-treated mice that were fed with PBS showed similar inflammatory response as the sham-treated PBS-fed mice. Our results suggest that strong T-cell activation in infancy conditions the mucosal immune system and promotes development of oral tolerance.

It has been long proposed that exposure to environmental factors early in life may have an educating effect on the development of immune regulatory functions. However, experimental studies on this issue are limited and the related molecular and cellular basis remains unclear. Here we report that neonatal exposure to killed bacteria (Chlamydia muridarum, originally called Chlamydia trachomatis mouse pneumonitis (MoPn)) changed the pattern of the hosts' immune responses to a model allergen (OVA) in adulthood. This was associated with altered phenotype and function of DC. We found that DC from adult mice treated neonatally with UV-killed MoPn exhibited distinct patterns of surface marker and TLR expression and cytokine production from control mice (DC from adult mice neonatally treated with vehicle, (Sham-DC)). More importantly, DC from adult mice treated neonatally with UV-killed MoPn induced significantly lower type-2 antigen-specific T-cell responses than Sham-DC shown in DC:T co-culture experiments in vitro and in adoptive transfer experiments in vivo. In addition, depletion of T cells in vivo largely abolished the phenotypic and functional alterations of DC caused by bacterial exposure, suggesting the involvement of T cell in this process. Our study demonstrates a central role of DC in linking the early-life exposure to microbial products and the balanced development of immune regulatory functions and the involvement of T cells in imprinting of the DC function.