Development Of Allergic Asthma Research Articles

Immune responses to fungal aeroallergen in Heligmosomoides polygyrus-infected mice vary by age

Parasite infections in the developing world have been considered to promote resistance to immune-mediated diseases such as asthma. Mouse studies have shown that helminths and their products reduce the development of allergic asthma. Since epidemiologic studies that show similar protection are in relation to geohelminth infections that occur in early life, we hypothesized that the parasite-mediated protection against asthma may differ by age. Mice infected with Heligmosomoides polygyrus at 3-weeks of age had similar asthma phenotype compared to mice infected at 28-weeks of age wherein airway eosinophilia was unaltered but tissue inflammation and GC metaplasia were reduced. In contrast, mice infected at 18-weeks of age had elevated macrophagic airway inflammation with accompanying tissue pathology. The presence of γδ T cells and Treg cells in the airways was also regulated by age at worm infection. Our findings demonstrate the importance of age in immune responses that may regulate gut and lung diseases.

Age-Dependent Allergic Asthma Development and Cystathionine Gamma-Lyase Deficiency.

The pathogenic mechanisms for the higher prevalence of allergic asthma in children than in adults have not been settled. The aim of the present study is to examine whether the age-dependent development of allergic asthma is caused by age-dependent expression of cystathionine gamma-lyase (CSE), a key enzyme that catalyzes the production of hydrogen sulfide (H2S). Allergic asthma was induced with ovalbumin in wild-type (WT) and CSE knock-out (KO) mice at young and old ages. CSE expression and H2S production were lower in immune cells of young WT mice than in those of old WT mice. Coincidentally, more severe asthmatic symptoms with a greater type-2 immunoreaction were found in young WT mice than old WT mice. H2S supplementation reversed the asthmatic symptoms. Lower expression levels of CSE proteins were also found in human umbilical cord blood mononuclear cells in comparison with that of peripheral blood mononuclear cells from adult people. The age-dependent asthma propensity vanished in CSE-KO mice, but these mice developed more severe asthma than WT mice. More splenocytes were differentiated to type-2 cytokine-generating cells in young WT mice and in CSE-KO mice at all ages. This differentiation was inhibited by H2S donors. GATA3 translocation to the nucleus and type-2 immunoreaction of splenocytes were inhibited after GATA3 was S-sulfhydrated by H2S. Innovation and Conclusion: For the first time, this study demonstrated that lower abundance of CSE expression and H2S production enhances type-2 immunoreaction and renders a higher incidence of allergic asthma at a young age. As such, H2S level may be a biomarker for asthma development and a H2S-based strategy can be perceived for asthma prevention and treatment. Antioxid. Redox Signal. 27, 931-944.

Dysregulation of metabolic pathways in a mouse model of allergic asthma

Asthma is a complex lung disease resulting from the interplay of genetic and environmental factors. To understand the molecular changes that occur during the development of allergic asthma without genetic and environmental confounders, an experimental model of allergic asthma in mice was used. Our goals were to (1) identify changes at the small molecule level due to allergen exposure, (2) determine perturbed pathways due to disease, and (3) determine whether small molecule changes correlate with lung function. In this experimental model of allergic asthma, matched bronchoalveolar lavage (BAL) fluid and plasma were collected from three groups of C57BL6 mice(control vs sensitized and/or challenged with ovalbumin, n=3-5/group) 6 hour, 24 hour, and 48 hour after the last challenge. Samples were analyzed using liquid chromatography-mass spectrometry-based metabolomics. Airway hyper-responsiveness (AHR) measurements and differential cell counts were performed. In total, 398 and 368 dysregulated metabolites in the BAL fluid and plasma of sensitized and challenged mice were identified, respectively. These belonged to four, interconnected pathways relevant to asthma pathogenesis: sphingolipid metabolism (P=6.6×10-5 ), arginine and proline metabolism (P=1.12×10-7 ), glycerophospholipid metabolism (P=1.3×10-10 ), and the neurotrophin signaling pathway (P=7.0×10-6 ). Furthermore, within the arginine and proline metabolism pathway, a positive correlation between urea-1-carboxylate and AHR was observed in plasma metabolites, while ornithine revealed a reciprocal effect. In addition, agmatine positively correlated with lung eosinophilia. These findings point to potential targets and pathways that may be central to asthma pathogenesis and can serve as novel therapeutic targets.

The Effect of Chinese Herbal Medicine Formula mKG on Allergic Asthma by Regulating Lung and Plasma Metabolic Alternations.

Asthma is a chronic inflammatory disorder of the airway and is characterized by airway remodeling, hyperresponsiveness, and shortness of breath. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicines (TCM), has been demonstrated to have good therapeutic effects on experimental allergic asthma. However, its anti-asthma mechanism remains currently unknown. In the present work, metabolomics studies of biochemical changes in the lung tissue and plasma of ovalbumin (OVA)-induced allergic asthma mice with mKG treatment were performed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Partial least squares–discriminate analysis (PLS−DA) indicated that the metabolic perturbation induced by OVA was reduced after mKG treatment. A total of twenty-four metabolites involved in seven metabolic pathways were identified as potential biomarkers in the development of allergic asthma. Among them, myristic acid (L3 or P2), sphinganine (L6 or P4), and lysoPC(15:0) (L12 or P16) were detected both in lung tissue and plasma. Additionally, l-acetylcarnitine (L1), thromboxane B2 (L2), 10-HDoHE (L10), and 5-HETE (L11) were first reported to be potential biomarkers associated with allergic asthma. The treatment of mKG mediated all of those potential biomarkers except lysoPC(15:0) (P16). The anti-asthma mechanism of mKG can be achieved through the comprehensive regulation of multiple perturbed biomarkers and metabolic pathways.

Expression levels of transcription factor PU.1 and interleukin-9 in atopic dermatitis and their relation to disease severity and eruption types.

The role of immunological factors in atopic dermatitis (AD) pathogenesis is well established. T-helper (TH) cells are central in AD pathogenesis. A relatively new subset of T cells, Th9 cells, was shown to be involved in the development of allergic asthma and allergic rhinitis, while its role in AD is still to be investigated. This study aimed to measure gene expression levels of interleukin-9 (IL-9) and PU.1, and to examine relationships with disease severity, serum IgE, and eruption types in AD patients. The study enrolled 30 AD patients, 30 psoriasis patients, and 30 healthy subjects. The severity of AD was assessed using the SCORAD index. IL-9 and PU.1 expressions were measured by using real-time quantitative polymerase chain reaction (RQ-PCR). Serum IgE was measured by IgE (human) enzyme-linked immunosorbent assay (ELISA) Kit. IL-9 and PU.1 gene expressions were significantly higher in AD patients than in controls (P1 = 0.007, P2 < 0.001, respectively). In the atopic dermatitis patients, expression of IL-9 and PU.1 were significantly positively correlated with SCORAD index (P1 = 0.004, P2 = 0.002) and clinically with erythema and edema scores. IL-9 and PU.1 expressions were positively significantly correlated (P = 0.005) and positively correlated with serum IgE in the AD group (P1 = 0.017, P2 = 0.023). No significant difference was noted between AD patients with or without histories of other atopies regarding expression levels of IL-9 and PU.1 (P1 = 0.677, P2 = 0.135). PU.1 and IL-9 may play a role in AD pathogenesis and relate to disease severity and clinical eruption types.

Bacteria isolated from lung modulate asthma susceptibility in mice

Asthma is a chronic, non-curable, multifactorial disease with increasing incidence in industrial countries. This study evaluates the direct contribution of lung microbial components in allergic asthma in mice. Germ-Free and Specific-Pathogen-Free mice display similar susceptibilities to House Dust Mice-induced allergic asthma, indicating that the absence of bacteria confers no protection or increased risk to aeroallergens. In early life, allergic asthma changes the pattern of lung microbiota, and lung bacteria reciprocally modulate aeroallergen responsiveness. Primo-colonizing cultivable strains were screened for their immunoregulatory properties following their isolation from neonatal lungs. Intranasal inoculation of lung bacteria influenced the outcome of allergic asthma development: the strain CNCM I 4970 exacerbated some asthma features whereas the pro-Th1 strain CNCM I 4969 had protective effects. Thus, we confirm that appropriate bacterial lung stimuli during early life are critical for susceptibility to allergic asthma in young adults.

Recent developments in the role of reactive oxygen species in allergic asthma.

Allergic asthma has a global prevalence, morbidity, and mortality. Many environmental factors, such as pollutants and allergens, are highly relevant to allergic asthma. The most important pathological symptom of allergic asthma is airway inflammation. Accordingly, the unique role of reactive oxygen species (ROS) had been identified as a main reason for this respiratory inflammation. Many studies have shown that inhalation of different allergens can promote ROS generation. Recent studies have demonstrated that several pro-inflammatory mediators are responsible for the development of allergic asthma. Among these mediators, endogenous or exogenous ROS are responsible for the airway inflammation of allergic asthma. Furthermore, several inflammatory cells induce ROS and allergic asthma development. Airway inflammation, airway hyper-responsiveness, tissue injury, and remodeling can be induced by excessive ROS production in animal models. Based on investigations of allergic asthma and ROS formation mechanisms, we have identified several novel anti-inflammatory therapeutic treatments. This review describes the recent data linking ROS to the pathogenesis of allergic asthma.

Airborne exposure to laboratory animal allergens

Exposure to laboratory animal allergens remains a significant cause of IgE-mediated occupational allergy and asthma. Since 2005, we have measured the major mouse and rat allergens (mus m 1 and rat n 1) collected on filters from air sampling in a range of UK and non-UK animal facilities. Supplied core data allowed us to construct an anonymized database of atmospheric results in ng m–3 containing 3080 mouse and 1392 rat analyses. Roughly twice as many static samples compared to personal samples had been sent for analysis. The medians (90th percentiles) for the mouse and rat allergens employing personal atmospheric sampling were 2.6 (60.6) and 0.4 (12.4) ng m–3 respectively; for static samples the equivalent values were 0.2 (3.7) and 0.1 (1.4) ng m–3. Where unequivocal sample descriptors were provided with samples, results were categorised to activities/areas. Medians and 90th percentiles in these categories suggest that staff undertaking cleaning out, dumping of soiled bedding and cleaning cages can still have very substantial potential exposures in some facilities. The move to filtered cages appears to reduce general exposure, but filter changing and/or cleaning can lead to high exposures. In some facilities, animal receipt can cause significant exposures, as well as activities such as bleeding, culling and dosing; all activities involving the handling of animals outside of cages. We believe that the data presented may help those using air measurements in such facilities to improve their control of exposure to such aeroallergens, and thus reduce the risk of both sensitisation and subsequent allergic health problems, including the development of allergic asthma.

Allergic asthma is distinguished by sensitivity of allergen-specific CD4+ T cells and airway structural cells to type 2 inflammation.

Despite systemic sensitization, not all allergic individuals develop asthma symptoms upon airborne allergen exposure. Determination of the factors that lead to the asthma phenotype in allergic individuals could guide treatment and identify novel therapeutic targets. We used segmental allergen challenge of allergic asthmatics (AA) and allergic nonasthmatic controls (AC) to determine whether there are differences in the airway immune response or airway structural cells that could drive the development of asthma. Both groups developed prominent allergic airway inflammation in response to allergen. However, asthmatic subjects had markedly higher levels of innate type 2 receptors on allergen-specific CD4+ T cells recruited into the airway. There were also increased levels of type 2 cytokines, increased total mucin, and increased mucin MUC5AC in response to allergen in the airways of AA subjects. Furthermore, type 2 cytokine levels correlated with the mucin response in AA but not AC subjects, suggesting differences in the airway epithelial response to inflammation. Finally, AA subjects had increased airway smooth muscle mass at baseline measured in vivo using novel orientation-resolved optical coherence tomography. Our data demonstrate that the development of allergic asthma is dependent on the responsiveness of allergen-specific CD4+ T cells to innate type 2 mediators as well as increased sensitivity of airway epithelial cells and smooth muscle to type 2 inflammation.

Experimental food allergy to peanut enhances the immune response to house dust mite in the airways of mice

Food allergy has been associated with an increased risk for the development of allergic asthma. Asthma is a risk factor for the development of an anaphylactic response to food allergens. An immunological interplay between sensitization to different allergens in different compartments of the body might be involved. To evaluate the immunological interplay between intragastrical peanut (PE) sensitization and respiratory sensitization to house dust mite (HDM) allergens. BALB/c mice were intragastrically sensitized to peanut or sham-sensitized and challenged systemically to PE. Between sensitization and challenge, mice were intranasally exposed to HDM extract or PBS, as a control. The response to HDM (eosinophil recruitment, cytokine response, HDM-specific immunoglobulins and airway hyper-reactivity) and to PE (cytokine response, mast cells in gut, mMCP-1 in serum and body temperature) was assessed. A preceding PE sensitization increased HDM-induced production of IL-4, IL-5, IL-13 and IFNγ in lung-draining lymph nodes and total IgE levels in HDM-sensitized mice. However, recruitment of inflammatory cells to the airways or airway hyper-reactivity was not aggravated in PE/HDM double-sensitized mice. Alternatively, HDM-induced airway inflammation did not significantly affect the immune response or the anaphylactic response to a systemic challenge with peanut. Our data show that a preceding peanut sensitization boosted IgE- and HDM-specific Th2 response in the airways in mice. It contributes to the understanding of the underlying immunological mechanism of polysensitization which often occurs in allergic individuals over time.

PDCD1 PD-1.3 polymorphism and allergic bronchial asthma in Russian and Buryat patients

ABSTRACTObjective: The programmed death-1 receptor, PD-1, is a negative regulator of T-cell activation. The PD-1.3 polymorphism of the PD-1 gene (PDCD1) has been previously shown to be associated with several autoimmune and inflammatory disorders including systemic lupus erythematosus and multiple sclerosis. We examined for the first time PD-1.3 association with another inflammatory disease with strong immune component, IgE-mediated bronchial asthma, its severity and its biochemical markers (total serum IgE and IL-4). Methods: PD-1.3 G/A was genotyped by PCR-RFLP analysis using two different populations: Caucasian (492 Russian individuals) and Asian (276 Buryat individuals). Results: We found a significant association of the PD-1.3 polymorphism with IgE-mediated bronchial asthma and total serum IgE level in the Russian population. Combined genotype AA+AG was correlated with risk of developing allergic bronchial asthma (OR = 1.78, 95% CI 1.13–2.78, p = 0.011) and lower concentrations of total serum IgE (p = 0.001) compared with the wild-type genotype GG. However, PD-1.3 was not polymorphic in the Buryat population. Conclusions: PD-1.3 polymorphism of the PD-1 gene (PDCD1) may contribute to the development of allergic asthma in the Russians but not in the Buryats. Our results could be helpful for a better understanding of the effect of this polymorphism on the development of diseases with strong immune components.

Clinical efficacy of immunotherapy in allergic rhinitis.

Aeroallergen immunotherapy (AIT) should be considered for patients who exhibit symptoms of allergic rhinitis (AR), rhinoconjunctivitis, and/or asthma after natural exposure to allergens and who also demonstrate specific immunoglobulin E antibodies against relevant allergens. In this paper, clinical efficacy of immunotherapy in allergic rhinitis is reviewed. Subcutaneous allergen immunotherapy (SCIT) is effective for seasonal and perennial AR. Sustained effectiveness requires several years of treatment. SCIT may prevent the development of allergic asthma in children with AR. Sublingual allergen immunotherapy (SLIT) is currently considered an alternative treatment to the subcutaneous route. The use of SLIT has been included in international guidelines for the treatment of AR with or without conjunctivitis. Patients treated with SCIT are at risk of both local and systemic adverse reactions; however, in most cases, symptoms are readily reversible if they are recognized early and treated promptly. The safety profile of SLIT is good; therefore, SLIT can be self-administered by patients in their homes. In this article, we reviewed the efficacy and safety of allergen immunotherapy.

Occupational sensitization to lactase in the dietary supplement industry

ABSTRACTAerogen lactase exposure carries a risk for the development of allergic asthma and rhinitis; only a few occupationally affected patients have been reported. The authors report the results of allergy testing with employees of a lactase tablets manufacturing plant. The survey involved 13 workers, including a questionnaire, spirometry, basophil activation test (BAT), and skin prick tests (SPTs) with lactase and a panel of common aeroallergens. Furthermore, lactase-specific immunoglobulin E (IgE) antibodies were analyzed. Sensitization to lactase could be proven for 9 workers by SPT and BAT; specific IgE antibodies could be detected in serum samples of all sensitized. However, IgE levels ≥0.35 kU/L were only found in 4 sera. These data confirm that occupational exposure to lactase can induce IgE-mediated respiratory sensitization resulting in allergic diseases. Protective measures should thus be obligatory when working with lactase.

Blockade of IL-23 ameliorates allergic lung inflammation via decreasing the infiltration of Tc17 cells.

IntroductionTc17 cells are interleukin (IL)-17-producing CD8+ T cells and have been found to participate in the development of allergic asthma. Interleukin-23 is a cytokine that may be involved in modulating the IL-17 response via Th17 cells. This study aimed to investigate whether IL-23 also has immunomodulatory effects on Tc17 cells.Material and methodsAn allergic asthmatic mouse model was induced by sensitizing and challenging with ovalbumin (OVA). Anti-IL-23 antibody was administered intratracheally before challenge to the OVA-induced asthmatic mouse model. Airway hyperresponsiveness, lung inflammation, Tc17 cell percentages and IL-17 level in the lung tissue homogenate were measured.ResultsAnti-IL-23 treatment reduced airway hyperresponsiveness (Rn 2.471 ±0.5077 vs. 4.051 ±0.2334, p < 0.05), inflammatory cell infiltration in bronchoalveolar lavage fluid (eosinophils 140.0 ±9.869 vs. 222.4 ±31.55, p < 0.05, neutrophils 75.93 ±6.745 vs. 127.4 ±19.73, p < 0.05), airway inflammation and mucus secretion. Treatment with anti-IL-23 antibody also markedly reduced IL-17 level (398.1 ±28.74 vs. 590.6 ±36.13, p < 0.01) and percentage of Th17 and Tc17 cells in lung tissue homogenate (4.200 ±0.1581 vs. 9.314 ±1.027, p < 0.01 and 2.852 ±0.2566 vs. 5.588 ±0.3631, p < 0.01, Th17 and Tc17 cells respectively).ConclusionsOur data suggest that the IL-23/Tc17 cell axis may be involved in the pathogenesis of asthma as the complement of IL-23/Th17 cells.

Indoor Pollutant Hexabromocyclododecane Has a Modest Immunomodulatory Effect on House Dust Mite Induced Allergic Asthma in Mice.

Hexabromocyclododecane (HBCD) has been recognized as an indoor pollutant. HBCD is added as a flame retardant to many consumer products and leaches from the products into house dust. HBCD might be potentially hazardous to the airways because of inhalation of house dust. Sensitization to house dust mite (HDM) is a risk factor for the development of allergic asthma. In this study, we examined whether HBCD can affect the immune response to HDM allergens. Bone-marrow-derived dendritic cells (BMDCs) were exposed simultaneously to HBCD and HDM in vitro. HBCD enhanced oxidative stress in HDM-pulsed BMDCs, which was accompanied by a higher production of Interleukin (IL)-6 and -10. Adoptive transfer of HDM/HBCD-exposed BMDCs into naı̈ve mice resulted in enhanced levels of IL-17A after inhalational challenge with HDM. Direct mucosal exposure to HBCD during HDM inhalation enhanced IL-4 or IL-17A production, depending on the HDM extract used, but did not aggravate the eosinophilic airway inflammation or airway hyper-reactivity. Our results indicate that exposure to HBCD can have a mild immune-modulating effect by enhancing the inflammatory cytokine production in response to inhaled HDM in mice.

Inhaled house dust programs pulmonary dendritic cells to promote type 2 T-cell responses by an indirect mechanism.

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.

House dust mite allergens mediate the activation of c‑kit in dendritic cells via Toll‑like receptor 2.

Several studies have demonstrated that the c‑kit proto‑oncogene and its ligand, stem cell factor, are important in the development of asthma. House dust mite (HDM; Dermatophagoides pteronyssinus) allergens are a major trigger in the development and exacerbation of asthma. HDM allergens can induce the activation of c‑kit in dendritic cells (DCs), leading to the development of allergic asthma. Previous studies have demonstrated that activation of Toll‑like receptor 2 (TLR2) evokes a T helper (Th)2 immune response and promotes experimental asthma. The aim of the present study was to assess whether HDM mediates the activation of c‑kit in DCs via TLR2. Monocyte‑derived DCs were generated from C57BL/6 mice, and cultured with interleukin (IL)‑4 and granulocyte‑macrophage colony‑stimulating factor. The DCs were then sensitized with HDM (10 µg/ml) for 72 h. TLR2‑specific small interfering (si)RNA was used to silence and inhibit the expression of TLR2 in the DCs. The expression levels of c‑kit and B7 (CD80/CD86) were measured, by analyzing the DC culture supernatant for the presence of IL‑6 and IL‑12. Inhibition of TLR2 using specific siRNA downregulated the expression of c‑kit in the HDM‑activated DCs. In addition, silencing of TLR2 inhibited the expression of CD80/CD86, decreased the production of IL‑6, and increased the production of IL‑12. These results indicated that TRL2 are important in the activation of c‑kit by HDM in DCs.

Gpr97 Is Dispensable for Inflammation in OVA-Induced Asthmatic Mice.

BackgroundAsthma is a complex inflammatory disorder involving the activation and invasion of various immune cells. GPR97 is highly expressed in some immunocytes, including mast cells and eosinophils, which play critical roles in asthma development. However, the role of Gpr97 in regulating airway inflammation in asthma has rarely been reported. In this study, we investigated the potential role of Gpr97 in the development of allergic asthma in mice.MethodsRelevant airway asthmatic mouse models were constructed with both wild-type and Gpr97-/- mice sensitized to 250 μg ovalbumin (OVA). The levels of interleukin IL-4, IL-6 and IFN-γ, which are involved in OVA-induced asthma, in the bronchoalveolar lavage fluid (BALF) and the IgE level in the serum were examined by enzyme-linked immunosorbent assay (ELISA). The invasion of mast cells and eosinophils into lung tissues was assessed by immunohistochemical and eosinophil peroxidase activity assays, respectively. Goblet cell hyperplasia and mucus production were morphologically evaluated with periodic acid-Schiff (PAS) staining.ResultsIn our study, no obvious alteration in the inflammatory response or airway remodeling was found in the Gpr97-deficient mice with OVA-induced asthma. Neither the secretion of cytokines, including IL-4, IL-6 and IFN-γ, nor inflammatory cell recruitment was altered in the Gpr97-deficient mice. Moreover, Gpr97 deficiency did not affect airway remodeling or mucus production in the asthma mouse model.ConclusionOur findings imply that Gpr97 might not be required for the development of airway inflammation in OVA-induced allergic asthma in mice.

The microbiome regulates the eosinophil requirement for development of allergic lung inflammation (HYP2P.337)

Abstract The diversity of gastrointestinal and respiratory microflora is essential in the shaping the host immune responses. In particularly, the propensity for Th2 allergic responses and asthma has recently been linked to the dysbiosis of the gut microbiome. Thus, the early establishment of particular microflora may potentially explain why some individuals are more predisposed to develop asthma and some do not. Eosinophils may also make differential contributions to allergic asthma in different individuals, and we have previously shown that development of allergic asthma is dependent on eosinophils. Here we report that C57Bl/6 ΔdblGATA eosinophil deficient mice housed under “less-restricted specific-pathogen-free” (LR-SPF) conditions are protected against allergic asthma compared to mice house under “restricted specific-pathogen-free” (R-SPF) conditions. 16s rRNA analysis of gut and lung microbiome reveal differences in lung microbiota diversity, suggesting a potential explanation for this phenomenon. Furthermore, consistent with the “microbiota hypothesis”, reducing the microbiota in ΔdblGATA mice by antibiotic treatment resulted in enhanced susceptibility to developing allergic airway inflammation comparable to WT mice. Thus, we conclude that shifts in microbiota can affect the requirement for eosinophil-mediated Th2 responses.

A role for Hox5 genes in T cell function during chronic allergic inflammation (HYP7P.268)

Abstract Allergic asthma is a significant health burden in western countries, and continues to increase in prevalence. T helper 2 (Th2) cells contribute to the development of disease through release of the cytokines interleukin (IL)-4, IL-5 and IL-13, resulting in increased airway eosinophils and mucus hypersecretion. While many factors are involved in the development of allergic asthma, the molecular mechanisms behind the disease remain largely unknown. As the three members of the Hox5 gene family (Hoxa5, Hoxb5 and Hoxc5) have been shown to play a role in lung development, we asked whether these genes also play a role in the adult lung in response to disease. We found that Hox5-deficient mice show exacerbated pathology compared to wild-type controls in a chronic allergen model, with an increased Th2 response as well as changes in lung tissue pathology. Examination of T cells from naïve wild-type or Hox5-deficient mice in Th2 polarizing conditions showed increased proliferation, enhanced Gata3 expression and production of IL-4, IL-5 and IL-13 in Hox5-deficient mice compared to wild-type controls. Overexpression of FLAG-tagged HOX5 proteins in Jurkat cells demonstrated HOX5 binding to the Gata3 locus, supporting a role for HOX5 proteins in direct transcriptional control of Th2 development. These results reveal a novel role for Hox5 genes as developmental regulators of immune cell function and Th2-induced pathology during allergic disease in the lung.