Early-life exposure to combustion-derived particulate matter causes pulmonary immunosuppression

Elevated levels of combustion-derived particulate matter (CDPM) are a risk factor for the development of lung diseases such as asthma. Studies have shown that CDPM exacerbates asthma, inducing acute lung dysfunction and inflammation; however, the impact of CDPM exposure on early immunological responses to allergens remains unclear. To determine the effects of early-life CDPM exposure on allergic asthma development in infants, we exposed infant mice to CDPM and then induced a mouse model of asthma using house dust mite (HDM) allergen. Mice exposed to CDPM+HDM failed to develop a typical asthma phenotype including airway hyper-responsiveness, T-helper type 2 (Th2) inflammation, Muc5ac expression, eosinophilia, and HDM-specific immunoglobulin (Ig) compared with HDM-exposed mice. Although HDM-specific IgE was attenuated, total IgE was twofold higher in CDPM+HDM mice compared with HDM mice. We further demonstrate that CDPM exposure during early life induced an immunosuppressive environment in the lung, concurrent with increases in tolerogenic dendritic cells and regulatory T cells, resulting in the suppression of Th2 responses. Despite having early immunosuppression, these mice develop severe allergic inflammation when challenged with allergen as adults. These findings demonstrate a mechanism whereby CDPM exposure modulates adaptive immunity, inducing specific antigen tolerance while amplifying total IgE, and leading to a predisposition to develop asthma upon rechallenge later in life.     

Prenatal environmental tobacco smoke exposure increases allergic asthma risk with methylation changes in mice

Allergic asthma remains an inadequately understood disease. In utero exposure to environmental tobacco smoke (ETS) has been identified as an environmental exposure that can increase an individual's asthma risk. To improve our understanding of asthma onset and development, we examined the effect of in utero ETS exposure on allergic disease susceptibility in an asthmatic phenotype using a house dust mite (HDM) allergen‐induced murine model. Pregnant C57BL/6 mice were exposed to either filtered air or ETS during gestation, and their offspring were further exposed to HDM at 6–7 weeks old to induce allergic inflammation. Methylation in the promoter regions of allergic inflammation‐related genes and genomic DNA was quantified. Exposure to HDM resulted in the onset of allergic lung inflammation, with an increased presence of inflammatory cells, Th2 cytokines (IL‐4, IL‐5, and IL‐13), and airway remodeling. These asthmatic phenotypes were significantly enhanced when the mice had been exposed to in utero ETS. Furthermore, prenatal ETS exposure and subsequent HDM (ETS/HDM)‐induced asthmatic phenotypes agree with methylation changes in the selected asthma‐related genes, including IL‐4, IL‐5, IL‐13, INF‐γ, and FOXP3. Global DNA methylation was significantly lower in ETS/HDM‐exposed mice than that of controls, which coincides with the results observed in lung, spleen, and blood DNAs. Prenatal ETS exposure resulted in a severe increase in allergic inflammatory responses after an HDM challenge, with corresponding methylation changes. Prenatal ETS exposure may influence developmental plasticity and result in altered epigenetic programming, leading to an increased susceptibility to asthma. Environ. Mol. Mutagen. 58:423–433, 2017. © 2017 Wiley Periodicals, Inc.     

Validated safety predictions of airway responses to house dust mite in asthma

BACKGROUND: House dust mite (HDM) is the most common aeroallergen causing sensitization in many Western countries and is often used in allergen inhalation challenges. The concentration of inhaled allergen causing an early asthmatic reaction [provocative concentration of inhaled allergen causing a 20% fall of forced expiratory volume in 1 s (FEV(1))(PC(20) allergen)] needs to be predicted for safety reasons to estimate accurately the severity of allergen-induced airway responsiveness. This can be accomplished by using the degree of non-specific airway responsiveness and skin sensitivity to allergen. OBJECTIVE: We derived prediction equations for HDM challenges using PC(20) histamine or PC(20) methacholine and skin sensitivity data obtained from patients with mild to moderate persistent asthma and validated these equations in an independent asthma population. METHODS: PC(20) histamine or PC(20) methacholine, skin sensitivity, and PC(20) allergen were collected retrospectively from 159 asthmatic patients participating in allergen challenge trials. Both the histamine and methacholine groups (n=75 and n=84, respectively), were divided randomly into a reference group to derive new equations to predict PC(20) allergen, and a validation group to test the new equations. RESULTS: Multiple linear regression analysis revealed that PC(20) allergen could be predicted either from PC(20) methacholine only ((10)log PC(20) allergen=-0.902+0.741.(10)log PC(20) methacholine) or from PC(20) histamine and skin sensitivity (SS) ((10)log PC(20) allergen=-0.494+0.231.(10)log SS+0.546.(10)log PC(20) histamine). In the validation study, these new equations accurately predicted PC(20) allergen following inhalation of HDM allergen allowing a safe starting concentration of allergen of three doubling concentrations below predicted PC(20) allergen in all cases. CONCLUSION: The early asthmatic response to inhaled HDM extract is predominantly determined by non-specific airway responsiveness to methacholine or histamine, whereas the influence of the cutaneous sensitivity to HDM appears to be rather limited. Our new equations accurately predict PC(20) allergen and hence are suitable for implementation in HDM inhalation studies.     

Effects of volatile constituents of a rosemary extract on allergic airway inflammation related to house dust mite allergen in mice

Perilla leaf extract is known to have anti-inflammatory properties. Recently, we have demonstrated that rosmarinic acid, a polyphenolic liquid component in perilla, inhibits the allergic airway inflammation induced by house dust mites (HDMs) in vivo. The purpose of this study was to evaluate the effects of intratracheal (i.t.) exposure to volatile constituents of a rosemary extract (VR), gaseous components in perilla, on a murine model of allergic asthma induced by HDM. C3H/HeN mice were treated 7 times weekly with i.t. exposure. The HDM allergen challenge elicited a pulmonary eosinophilic inflammation accompanied by an increase in the lung expression of interleukin (IL)-5, IL-13, and eotaxin. VR inhibited increases in the number of eosinophils, neutrophils, and mononuclear cells around the airways and those in the bronchoalveolar lavage fluid. VR exposure also significantly suppressed the expression of IL-13 enhanced by HDM allergen. These results suggest that i.t. exposure to VR can, at least partially, prevent allergic airway inflammation induced by HDM. The preventive effect is associated with inhibition of the enhanced local expression of IL-13.     

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL‐5 and IL‐13. Here, we used a house dust mite (HDM)‐driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T‐cell activation precedes ILC2 induction. During HDM‐driven allergic airway inflammation the accumulation of ILC2s in BALF is IL‐33 independent, although infiltrating ILC2s produce less cytokines in Il33^?/? mice. Transfer of in vitro polarized OVA‐specific OT‐II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T‐cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM‐mediated allergic airway inflammation in mice critically depends on activation of T cells.     

Severity of Allergic Airway Disease Due to House Dust Mite Allergen Is Not Increased after Clinical Recovery of Lung Infection with Chlamydia pneumoniae in Mice

Chlamydia pneumoniae is associated with chronic inflammatory lung diseases like bronchial asthma and chronic obstructive pulmonary disease. The existence of a causal link between allergic airway disease and C. pneumoniae is controversial. A mouse model was used to address the question of whether preceding C. pneumoniae lung infection and recovery modifies the outcome of experimental allergic asthma after subsequent sensitization with house dust mite (HDM) allergen. After intranasal infection, BALB/c mice suffered from pneumonia characterized by an increased clinical score, reduction of body weight, histopathology, and a bacterial load in the lungs. After 4 weeks, when infection had almost resolved clinically, HDM allergen sensitization was performed for another 4 weeks. Subsequently, mice were subjected to a methacholine hyperresponsiveness test and sacrificed for further analyses. As expected, after 8 weeks, C. pneumoniae-specific antibodies were detectable only in infected mice and the titer was significantly higher in the C. pneumoniae/HDM allergen-treated group than in the C. pneumoniae/NaCl group. Intriguingly, airway hyperresponsiveness and eosinophilia in bronchoalveolar lavage fluid were significantly lower in the C. pneumoniae/HDM allergen-treated group than in the mock/HDM allergen-treated group. We did observe a relationship between experimental asthma and chlamydial infection. Our results demonstrate an influence of sensitization to HDM allergen on the development of a humoral antibacterial response. However, our model demonstrates no increase in the severity of experimental asthma to HDM allergen as a physiological allergen after clinically resolved severe chlamydial lung infection. Our results rather suggest that allergic airway disease and concomitant cellular changes in mice are decreased following C. pneumoniae lung infection in this setting.     

Prior airway exposure to allergen increases virus-induced airway hyperresponsiveness

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis in early life can lead to changes in airway function, but there are likely additional predisposing factors, such as prior allergen exposure, determining which children develop wheezing and asthma. OBJECTIVE: To define the effects of prior airway exposure to sensitizing allergen on the development of airway inflammation and hyperresponsiveness (AHR) to subsequent RSV infection. METHODS: BALB/c mice were exposed to ovalbumin or PBS exclusively through the airways and subsequently infected with RSV or sham-inoculated. AHR, lung inflammation, and the frequency of cytokine-producing T lymphocytes in the lung were determined. RESULTS: In PBS-exposed mice, RSV infection induced AHR and an increased proportion of TH1-type (IFN-gamma and IL-12) cytokine-producing cells in the lungs. However, in mice previously exposed to ovalbumin through the airways and subsequently infected with RSV, the degree of AHR was significantly increased and was associated with an increased proportion of TH2 (IL-4, IL-5) cytokine-producing T lymphocytes. This response was also associated with an increased accumulation of eosinophils, neutrophils, and CD8+ T cells in the lungs. CONCLUSIONS: These data suggest that prior airway exposure to allergen may predispose sensitized hosts to a greater degree of altered airway function upon subsequent respiratory viral infection.     

Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite

BACKGROUND: Although several studies support the efficacy of specific immunotherapy in allergic asthma, its benefit compared with that of standardized pharmacologic intervention remains unknown. OBJECTIVE: A double-blind, placebo-controlled trial in 72 patients with mild-to-moderate asthma and allergy to house dust mite (HDM; Dermatophagoides species) was conducted to assess the effects of specific immunotherapy added to guideline-adjusted pharmacologic treatment and allergen avoidance. METHODS: After 1 observational year of pharmacologic treatment and standard measures of HDM avoidance, 2 groups of asthmatic subjects were randomly assigned to receive specific immunotherapy consisting of subcutaneous injections of either a mixture of Dermatophagoides pteronyssinus and Dermatophagoides farinae vaccine (n=41) or placebo (n=31) for 3 years. Medications were adjusted every 3 months according to the Global Initiative for Asthma guidelines. RESULTS: The adjustment of treatment was associated with a reduction in asthma symptom scores in all subjects. The addition of specific immunotherapy was associated with a decrease in the number of subjects requiring rescue bronchodilators, an increase in morning and evening peak expiratory flow, and a reduced skin sensitivity to HDM extracts. The addition of specific immunotherapy had no significant effects on the cumulative dose of inhaled corticosteroids, asthma symptoms, lung volumes, or bronchial responsiveness to methacholine. CONCLUSION: These results suggest that specific immunotherapy added to pharmacologic treatment and HDM avoidance provides marginal but statistically significant clinical benefits, possibly by reducing the allergic response of asthmatic patients sensitized to HDM.     

Der p 1 and Der p 2 induce less severe late asthmatic responses than native Dermatophagoides pteronyssinus extract after a similar early asthmatic response

Background The models for exposure to house dust in research and clinical practice are selected with respect to their role in IgE‐mediated immediate hypersensitivity. The use of isolated major allergens instead of complex allergen extracts is becoming increasingly popular as it offers some important advantages for quantitative measures in diagnosis and research. Objective To compare house dust mite extract and isolated mite major allergens with respect to their ability to induce early and late asthmatic responses and bronchial hyperreactivity. Methods Bronchial responses to house dust mite (HDM, Dermatophagoides pteronyssinus) extract and isolated major allergens from HDM (Der p 1 and Der p 2) were compared in a double‐blind, randomized, cross‐over study in 20 patients with mild to moderate asthma who were allergic to HDM. Allergen was titrated to a standardized early asthmatic response. Bronchial hyper‐responsiveness to histamine (PC₂₀histamine) was determined before and after allergen inhalation to assess allergen‐induced bronchial hyper‐responsiveness and IL‐5 was measured in serum. In addition, the allergens were applied in intracutaneous skin tests and activation of basophil leucocytes and proliferation of peripheral blood mononuclear cells was tested in vitro. Results After a similar early asthmatic response (mean Δforced expiratory volume in 1 s (FEV₁)_,max?29.4 (SD 7.2) vs. ?33.1 (8.6) %; mean difference 3.6 (95% CI ?0.9 to 8.2) %), the late asthmatic response (mean ΔFEV_1,max?45.9 (21.9) vs. ?32.7 (22.3) %; mean difference 13.2 (3.8–22.3) %), the degree of allergen‐induced bronchial hyper‐responsiveness (mean ΔPC₂₀histamine, 1.8 (1.0) vs. 1.2 (0.9) doubling dose; mean difference 0.6 (0.2–1.1) doubling dose) and serum IL‐5 at 6 h were found to be significantly higher after bronchial challenge with HDM extract than after challenge with an isolated HDM major allergen. Likewise, there was an increased late skin reaction with HDM compared with isolated major allergen after a similar early skin reaction. Conclusion Constituents of HDM extract, other than Der p 1 or Der p 2, with no significant influence on the IgE‐mediated early asthmatic response contribute significantly to the allergen‐induced late asthmatic response and bronchial hyper‐reactivity.     

Maternal respiratory sensitization and gestational allergen exposure does not affect subsequent pup responses to homologous or heterologous allergen

Evidence suggests that the predisposition towards atopy begins early in life. Maternal allergy has been associated with an increased risk of the development of allergic disease in offspring. Some studies suggest that the development of childhood atopy may also be influenced by prenatal allergen exposure. In this study, a respiratory allergen exposure model was used to determine the impact of maternal sensitization (with or without additional exposures during pregnancy) on subsequent pup responses to homologous or heterologous allergen. Female BALB/c mice received two intratracheal aspiration (IA) exposures to Metarhizium anisopliae crude antigen (MACA) or Hank’s buffered salt solution (HBSS) prior to breeding. Some mice also received three additional exposures during pregnancy. Control mothers did not receive treatment. Young adult offspring received three IA exposures to MACA, house dust mite extract (HDM) or HBSS. Offspring sensitized as young adults to either HDM or MACA developed an airway inflammatory response, including increased bronchoalveolar lavage fluid lactate dehydrogenase activity, total protein and total and differential cell counts compared to offspring exposed to HBSS. Increased airway responsiveness to methacholine was observed in pups treated with HDM but not with MACA. Maternal sensitization status (with or without gestational allergen exposure) had no effect on offspring response to either MACA or HDM. In conclusion, this study demonstrates that IA administration of MACA or HDM extract to young adult BALB/c mice induces the development of an inflammatory airway response. In contrast to previous reports, neither maternal sensitization nor gestational allergen exposure could be demonstrated to have a clear effect on offspring sensitization. This discrepancy may be a function of the respiratory sensitization and exposure protocol used in this study, which mimics natural sensitization more closely than do parenteral routes of exposure.     

The neonatal susceptibility window for inhalant allergen sensitization in the atopically predisposed canine asthma model

Allergic asthma often begins in early life and, although many risk factors have been enumerated, the specific factors that initiate disease progression in an individual remain unclear. Using our dog model of early life allergen inhalation, we tested the hypothesis that the atopically biased neonatal immune system would exhibit tolerance to ragweed if allowed to mature normally before exposure or artificially through innate immune stimulation with early life exposure. Dogs were subjected to a series of inhalational ragweed exposures from 1 to 20 weeks old, with or without inhalation of a Toll‐like receptor 4 (TLR4) agonist (CRX‐527), or from 13 to 31 weeks old. Serum allergen‐specific antibody response was assessed at 4, 8 and 20 weeks after the last sensitizing exposure. At 24 or 35 weeks old, airway hyper‐responsiveness to methacholine and ragweed challenges and pulmonary inflammation by bronchoalveolar lavage were tested 1 and 4 days after ragweed challenge at 28 or 39 weeks old. Allergen‐free immune maturation resulted in no airway hyper‐responsiveness and very little ragweed‐specific IgE relative to the control group, but eosinophilia developed upon ragweed challenge. TLR4 agonism yielded no airway hyper‐responsiveness, but a strong airway neutrophilia developed upon ragweed challenge. Our data indicate that an atopic predisposition creates a critical window in which allergen exposure can lead to an asthmatic phenotype. Allergen‐free immune maturation may lead to allergen tolerance. TLR4 agonism before early life allergen exposure may abrogate the development of allergen‐specific bronchonconstriction, but allergen‐specific pulmonary inflammation remains a strong concern.     

Allergic asthma: an overview of metabolomic strategies leading to the identification of biomarkers in the field

Allergic asthma is a prominent disease especially during childhood. Indoor allergens, in general, and particularly house dust mites (HDM) are the most prevalent sensitizers associated with allergic asthma. Available data show that 65–130 million people are mite‐sensitized world‐wide and as many as 50% of these are asthmatic. In fact, sensitization to HDM in the first years of life can produce devastating effects on pulmonary function leading to asthmatic syndromes that can be fatal. To date, there has been considerable research into the pathological pathways and structural changes associated with allergic asthma. However, limitations related to the disease heterogeneity and a lack of knowledge into its pathophysiology have impeded the generation of valuable data needed to appropriately phenotype patients and, subsequently, treat this disease. Here, we report a systematic and integral analysis of the disease, from airway remodelling to the immune response taking place throughout the disease stages. We present an overview of metabolomics, the management of complex multifactorial diseases through the analysis of all possible metabolites in a biological sample, obtaining a global interpretation of biological systems. Special interest is placed on the challenges to obtain biological samples and the methodological aspects to acquire relevant information, focusing on the identification of novel biomarkers associated with specific phenotypes of allergic asthma. We also present an overview of the metabolites cited in the literature, which have been related to inflammation and immune response in asthma and other allergy‐related diseases.     

Effect of fluticasone propionate-salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma.

BACKGROUND: There has been concern that in allergic asthmatic patients there might be an interactive effect on inflammation between regular salmeterol use and exposure to allergens, resulting in increased airway responsiveness. OBJECTIVE: To determine the effects of salmeterol on allergen-induced changes in airway responsiveness and exhaled nitric oxide (ENO) levels in allergic asthmatic patients concomitantly taking inhaled corticosteroids. METHODS: Forty-two asthmatic patients sensitized to pollen allergens were randomly allocated to treatment with fluticasone propionate-salmeterol (n=21) or fluticasone propionate alone (n=21). Spirometry, the methacholine provocation concentration causing a 20% decline in forced expiratory volume in 1 second (PC20), the adenosine 5'-monophosphate (AMP) PC20, and ENO levels were measured before and at the height of the pollen season after 6 weeks of treatment. RESULTS: Changes in the methacholine PC20, the AMP PC20, and ENO levels were not significantly different between treatment groups. No significant changes in the AMP PC20 were observed among the fluticasone propionate-salmeterol and fluticasone propionate groups during natural pollen exposure. However, a significant increase in the methacholine PC20 was observed in the fluticasone propionate-salmeterol group (P = .03) and in the fluticasone propionate group (P = .04); ENO concentrations decreased significantly in both groups during natural allergen exposure (P = .009 and .005). CONCLUSIONS: In patients with pollen-induced asthma, treatment with either fluticasone propionate or fluticasone propionate-salmeterol is associated with significant reductions in methacholine responsiveness and ENO concentrations, even during natural pollen exposure. Furthermore, at least in patients with mild asthma, natural allergen exposure and the regular use of fluticasone propionate-salmeterol are not associated with a greater increase in ENO levels and airway responsiveness than natural allergen exposure and fluticasone propionate use alone.     

T cells and ILC2s are major effector cells in influenza‐induced exacerbation of allergic airway inflammation in mice

Influenza virus infection is an important cause of severe asthma exacerbations, but it remains unclear how a Th1‐mediated antiviral response triggers a prototypical Th2 disease. We investigated CD4⁺ T cells and group 2 innate lymphoid cells (ILC2s) in influenza virus‐infected mice. We found that ILC2s accumulated in the lung rapidly after influenza virus infection, but the induction of IL‐5 and IL‐13 secretion was delayed and concomitant with T cell activation. In an influenza‐induced exacerbation of allergic airway inflammation model we noticed an initial reduction of ILC2 numbers and cytokine production in broncho‐alveolar lavage compared to chronic house dust mite (HDM)‐mediated airway inflammation alone. ILC2s phenotype was characterized by low T1/ST2, ICOS, KLRG1, and CD25 expression, resembling naïve ILC2s. The contribution of ILC2s to type 2 cytokine production in the early stage of the influenza‐induced exacerbation was limited. In contrast, T cells showed increased IL‐4 and IL‐5 production when exposed to both HDM and influenza virus. Upon virus clearance, ILC2s regained an activated T1/ST2^highICOS^highKLRG1^highCD25^high phenotype paired with cytokine production and were major contributors to the type 2 cytokine milieu. Collectively, our data indicate that both T cells and ILC2s contribute to influenza‐induced exacerbation of allergic airway inflammation, but with different kinetics.     

Allergy markers in adults in relation to the timing of pet exposure: the EGEA study

BACKGROUND: Studies suggest that early childhood exposure to pets may protect from the development of atopy, but limited information is available on adults. The association of allergy markers in adulthood with current and childhood exposure to pets was studied considering retrospectively the window of exposure. METHODS: Immunoglobulin E (IgE), skin prick tests (SPT), eosinophils were related to exposure to pets in 187 adult asthmatic cases and 243 controls from the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA) study. Analyses were redone after exclusion of subjects who removed pets or experienced symptoms to animals to take into account selection in that retrospective study. RESULTS: In asthmatic cases, current exposure to pets was unrelated to SPT positivity (+), whereas childhood exposure was significantly related to less SPT+ to any allergen, and to cat in particular, with an association restricted to those exposed before 2 years of age [OR = 0.30 (CI 0.12-0.76)]. Considering the relative timing of exposure in relation to asthma onset showed that the protective effect of exposure to pets occurs for pet exposure starting before asthma onset [OR for SPT+ = 0.19 (CI 0.08-0.48)]. CONCLUSION: Results support the hypothesis that exposure to pets in early life, and in particular before asthma onset, may protect against allergen sensitization in adulthood.     

Food allergy promotes a Th2/Th17 response that drives house dust mite-induced allergic airway inflammation in humanized mice

Food allergy is related to increasing risk of the development of allergic asthma, but the precise interplay between sensitization to different allergens in different compartments of the body is not fully understood. The aim of this study was to develop a novel humanized murine model of mixed food and respiratory allergy that recapitulates the human anaphylactic response and to more clearly understand the impact of food allergies on asthma. Immunodeficient mice transferred with peripheral blood mononuclear cells (PBMCs) from donors with peanut and house dust mite (HDM) allergy were exposed and challenged to peanut. Between peanut exposure and challenge, mice were intranasally treated to HDM. Allergic parameters were analyzed. Allergen-specific immunoglobulin (Ig)E in sera could only be measured in mice treated with peripheral blood mononuclear cells (PBMCs) plus allergen. A preceding peanut exposure increased IgE levels, histamine release, bronchial hyper-responsiveness and lung inflammation. Recruitment of inflammatory cells to the airways was aggravated associated with an enhanced T helper type 2 (Th2)/Th17 cytokine secretion when the two allergies were present. A preceding peanut exposure amplifies allergic asthma in this humanized model, which may contribute to the understanding of underlying immunological mechanism of polysensitization occurring in allergic individuals and evaluation of therapeutic interventions.     

Sex-associated TSLP-induced immune alterations following early-life RSV infection leads to enhanced allergic disease

Many studies have linked severe RSV infection during early-life with an enhanced likelihood of developing childhood asthma, showing a greater susceptibility in boys. Our studies show that early-life RSV infection leads to differential long-term effects based upon the sex of the neonate; leaving male mice prone to exacerbation upon secondary allergen exposure while overall protecting female mice. During initial viral infection, we observed better viral control in the female mice with correlative expression of interferon-β that was not observed in male mice. Additionally, we observed persistent immune alterations in male mice at 4 weeks post infection. These alterations include Th2 and Th17-skewing, innate cytokine expression (Tslp and Il33), and infiltration of innate immune cells (DC and ILC2). Upon exposure to allergen, beginning at 4 weeks following early-life RSV-infection, male mice show severe allergic exacerbation while female mice appear to be protected. Due to persistent expression of TSLP following early-life RSV infection in male mice, genetically modified TSLPR−/− mice were evaluated and demonstrated an abrogation of allergen exacerbation in male mice. These data indicate that TSLP is involved in the altered immune environment following neonatal RSV-infection that leads to more severe responses in males during allergy exposure, later in life. Thus, TSLP may be a clinically relevant therapeutic target early in life.     

General,but not myeloid or type II lung epithelial cell,myeloid differentiation factor 88 deficiency abrogates house dust mite induced allergic lung inflammation

Asthma is a highly prevalent chronic allergic inflammatory disease of the airways affecting people worldwide. House dust mite (HDM) is the most common allergen implicated in human allergic asthma. HDM‐induced allergic responses are thought to depend upon activation of pathways involving Toll‐like receptors and their adaptor protein myeloid differentiation factor 88 (MyD88). We sought here to determine the role of MyD88 in myeloid and type II lung epithelial cells in the development of asthma‐like allergic disease using a mouse model. Repeated exposure to HDM caused allergic responses in control mice characterized by influx of eosinophils into the bronchoalveolar space and lung tissue, lung pathology and mucus production and protein leak into bronchoalveolar lavage fluid. All these responses were abrogated in mice with a general deficiency of MyD88 but unaltered in mice with MyD88 deficiency, specifically in myeloid or type II lung epithelial cells. We conclude that cells other than myeloid or type II lung epithelial cells are responsible for MyD88‐dependent HDM‐induced allergic airway inflammation.     

Airway inflammation and altered alveolar macrophage phenotype pattern after repeated low-dose allergen exposure of atopic asthmatic subjects

BACKGROUND: The alveolar macrophage (AM) constitutes an important link between pulmonary innate and adaptive immunity due to its antigen-presenting capacity and ability to express different immunomodulating mediators. The role of AMs in the pathogenesis of allergic inflammation has yet to be fully determined. OBJECTIVE: To investigate clinical effects and any change in the AM phenotype pattern after inhalation of sub-clinical doses of allergen by asthmatic patients. METHODS: Eight subjects with allergic asthma underwent repeated low-dose allergen provocations equivalent to 10% of PD20. AMs recovered with bronchoalveolar lavage (BAL) were characterized by flow cytometric analysis of adhesion molecules, co-stimulatory molecules and markers for AM population activation and heterogeneity. RESULTS: An allergic airway inflammation, sub-clinical in six out of eight subjects, was obtained after low-dose allergen provocations, as determined by increased airway methacholine reactivity, increased BAL fluid total cell and eosinophil counts and increased serum ECP levels. The AMs showed a post-challenge altered phenotype pattern with a decreased expression of CD11a, CD16, CD71 and HLA class I and an increased expression of CD11b and CD14. The AMs were positive for CD83 and a weak post-challenge increase in the CD83 expression was found. CONCLUSION: Repeated low-dose allergen exposure induces an allergic airway inflammation in asthmatic subjects. The inflammation is associated with an altered AM phenotype pattern, consistent with an influx of monocytes and a hypothetical increased accessory cell function in the airways, possibly contributing to the development and sustenance of airway inflammation in asthma.     

Experimental gastrointestinal allergy enhances pulmonary responses to specific and unrelated allergens

BACKGROUND: Gastrointestinal allergy often precedes or coexists with respiratory allergy. OBJECTIVE: We hypothesized that established experimental gastrointestinal allergy would prime for the development of allergic respiratory responses. METHODS: BALB/c mice were sensitized with ovalbumin (OVA) in the presence of aluminum potassium sulfate and then subjected to intragastric saline or OVA challenges. After the development of allergen-induced gastrointestinal allergy, mice were intranasally exposed to either saline, OVA, or a neoaeroallergen house dust mite (HDM) extract. Airway inflammation (eg, bronchoalveolar lavage fluid cellularity, cytokine levels, and OVA-specific antibody levels) and airway responsiveness to methacholine exposure were assessed after intranasal allergen exposure. RESULTS: A single intranasal exposure to OVA induced significantly more airway inflammation in intragastric OVA-challenged mice compared with that seen in intragastric saline-treated mice. Kinetic analysis revealed that the observed amplification of lung inflammation was sustained for up to 12 days after the last intragastric OVA challenge after resolution of blood eosinophilia. When mice with gastrointestinal allergy were repeatedly challenged with HDM in the respiratory tract, they experienced enhanced airway inflammation, including bronchoalveolar lavage fluid eosinophilia and increased IL-13 levels. CONCLUSION: Taken together, our results demonstrate that OVA-induced gastrointestinal allergy enhances not only allergic airway responses to OVA but also to HDM, an unrelated aeroallergen. CLINICAL IMPLICATIONS: Experimental gastrointestinal allergy primes for responses to allergens in the respiratory tract, enhancing antigen-specific antibody and T(H)2 cytokine production, airway inflammation, and airway hyperresponsiveness.