Alteration of Immune Responses by N-acetylglucosaminyltransferase V during Allergic Airway Inflammation

Backgroundp-1,6-N-acetylglucosaminyltransferase V (Mgat5 or GlcNac-TV), which is involved in the glyco- sylation of proteins, is known to be important for down-regulation of TCR-mediated T-cell activation and negatively regulates induction of contact dermatitis and experimental autoimmune encephalomyelitis. However, the role of Mgat5 in the induction of allergic airway inflammation remains unclear.MethodsTo elucidate the role of Mgat5 in the pathogenesis of allergic airway inflammation, ovalbumin (OVA)-induced airway inflammation was induced in Mgat5-deficient mice. The OVA-specific lymphocyte proliferation and cytokine production levels, OVA-specific IgG1, IgG2a and IgE levels in the serum, and the number of leukocytes and cytokine levels in the bronchoalveolar lavage (BAL) fluid were compared between wild-type and Mgat5-deficient mice.ResultsOVA-specific lymphocyte proliferation and production of IFN-y and IL-10, but not IL-4, were increased in Mgat5-deficient mice, suggesting that Th2-type immune responses are seemed to be suppressed by increased IFN-y and IL-10 production in these mice. However, Th2-type responses such as OVA-specific IgG1, but not IgE, and IL-5 levels in BAL fluids were increased in Mgat5-deficient mice. Meanwhile, the number of eosinophils was normal, but the numbers of neutrophils, macrophages and lymphocytes were reduced, in these mutant mice during OVA-induced airway inflammation.ConclusionsMgat5-dependent glycosylation of proteins can modulate acquired immune responses, but it is not essential for the development of OVA-induced eosinophilic airway inflammation.     

Immunological Changes After Hyposensitization in House-Dust-Sensitive Asthmatic Children: A Review

Patients with allergic diseases are characterized by the presence of elevated total serum IgE and specific IgE antibodies against a variety of environmental allergens. To explore the causes for augmented IgE antibody production and the working mechanisms of hyposensitization (HS), a series of studies has been conducted on house-dust-sensitive, newly diagnosed, and hyposensitized asthmatic children and normals.

The specific IgE and IgG antibodies were measured by radioallergosorbent test; the lymphoproliferative capability was measured by ³H-thymidine incorporation; the allergen-specific suppressor activity was determined by the extent of house-dust-activated, interleukin-2 (IL-2)-expanded lymphocytes to suppress the allergen-induced proliferation of autologous mononuclear cells (MNC); and IL-2 was produced by stimulating MNC with allergen or phytohemagglutinin (PHA) and quantitated by its capability to support the proliferation of mouse IL-2-dependent cytotoxic T-cell line.

The results showed: 1) HS was effective in 90% of patients in terms of decreased attacks and medication taken; 2) the patients were defective in suppressor T-cell function for IgE production; 3) HS was able to restore the regulatory T-cell function and increase the production of IgG-blocking antibody; and 4) IL-2 production may be used as an indicator for initiation and discontinuation of HS.

Therefore, hyposensitization is an effective and specific treatment for allergic bronchial asthma and can partially correct an immunoregulatory aberration in atopic individuals.     

Allergen-induced bronchial hyperreactivity and eosinophilic inflammation occur in the absence of IgE in a mouse model of asthma

In patients with asthma, elevations of IgE correlate both with allergic inflammation of the airways and with bronchial hyperreactivity (BHR). Several investigations, using mouse models of this disease, have indicated a central role for IgE in the pathogenesis of the eosinophilic inflammation as well as in the obstructive airway physiology of BHR. Some diagnostic studies and therapeutic strategies for asthma are based on the putative role of IgE in asthma pathogenesis. Here, we use mice with a null mutation of the C locus to show that bronchial inflammation and BHR in response to allergen inhalation both can occur in the absence of IgE. We demonstrate that the eosinophilic bronchial inflammation elicited in an established mouse model of hypersensitivity to Aspergillus fumigatus (Af) is accompanied by the asthmatic physiology of BHR. Wild-type and IgE-deficient mice were sensitized intranasally with Af extract. Both groups of animals developed bronchoalveolar lavage eosinophilia and pulmonary parenchymal eosinophilia. This was accompanied by increased serum levels of total and Af-specific IgE in the wild-type animals only. This Af-sensitization protocol resulted in significant BHR in both wild-type mice and IgE-deficient mice. Interestingly, unsensitized IgE-deficient mice had increased bronchial responsiveness compared with unsensitized wild-type controls. We conclude that BHR and airways inflammation can be fully expressed via IgE-independent mechanisms. These may involve the activation of mast cells by factors other than IgE as well as a mucosal lymphocyte-mediated immune response to allergen.     

House dust mite facilitates ovalbumin-specific allergic sensitization and airway inflammation

RATIONALE: Mouse models of allergic airway disease have greatly contributed to our understanding of disease induction and pathogenesis. Although these models typically investigate responses to a single antigen or allergen, humans are frequently exposed to a myriad of allergens, each with distinct antigenic potential. OBJECTIVES: Given that airway exposure to ovalbumin (OVA), a prototypic innocuous antigen, induces inhalation tolerance, we wished to investigate how this response would be altered if OVA were encountered concurrently with a house dust mite extract (HDM), which we have recently shown is capable of eliciting a robust allergic airway inflammatory response that is mediated, at least in part, by granulocyte-macrophage colony-stimulating factor. METHODS: Balb/c mice were exposed daily to HDM (intranasally) followed immediately by exposure to aerosolized OVA for 5 weeks. To allow the inflammatory response elicited by HDM to subside fully, mice were then allowed to rest, unexposed, for 8 weeks, at which time they were rechallenged with aerosolized OVA for 3 consecutive days. MEASUREMENTS AND MAIN RESULTS: At this time, we observed a robust eosinophilic inflammatory response in the lung that was associated with an increase in bronchial hyperreactivity. Moreover, we documented significantly elevated serum levels of OVA-specific IgE and IgG(1) and increased production of the Th2 cytokines interleukin 4 (IL-4), IL-5, and IL-13 by splenocytes stimulated in vitro with OVA. CONCLUSION: Our data demonstrate the potential of a potent allergen such as HDM to establish a lung microenvironment that fosters the development of allergic sensitization to otherwise weak or innocuous antigens, such as OVA.     

Importance of myeloid dendritic cells in persistent airway disease after repeated allergen exposure

RATIONALE: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice. METHODS: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors. RESULTS: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia. CONCLUSIONS: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.     

Inhibition of complement activation decreases airway inflammation and hyperresponsiveness

Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but before allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness. To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor complement receptor-related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classic and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (Days 1 and 14) and challenged (Days 24-26) with ovalbumin. Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization before allergen challenge. Crry-Ig significantly prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia as well as the numbers of lung lymphocytes, decreased levels of interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and decreased serum ovalbumin-specific IgE and IgG1. These results suggest that prevention of complement activation may have a therapeutic role in the treatment of allergic airway inflammation and asthma in sensitized individuals.     

Helminth-derived products inhibit the development of allergic responses in mice

RATIONALE: Epidemiological studies suggest that infections with helminths protect from the development of asthma. Supporting this view is our published finding that infection with Nippostrongylus brasiliensis decreased ovalbumin-induced Th2 responses in the lung of mice. OBJECTIVES: To evaluate if N. brasiliensis excretory-secretory products also prevent the development of asthma. METHODS: Mice were immunized with ovalbumin/alum intraperitoneally in the absence or presence of helminthic products and then challenged intranasally with ovalbumin. Six days later, we analyzed if the mice developed Th2 responses in the lung. MAIN RESULTS: The application of the helminthic products together with ovalbumin/alum during the sensitization period totally inhibited the development of eosinophilia and goblet cell metaplasia in the airways and also strongly reduced the development of airway hyperreactivity. Allergen-specific IgG1 and IgE serum levels were also strongly reduced. These findings correlated with decreased levels of IL-4 and IL-5 in the airways in product-treated animals. The suppressive effects on the development of allergic responses were independent of the presence of Toll-like receptors 2 and 4, IFN-gamma, and most important, IL-10. Interestingly, suppression was still observed when the helminthic products were heated or treated with proteinase K. Paradoxically, we found that strong helminth product-specific Th2 responses were induced in parallel with the inhibition of ovalbumin-specific responses. CONCLUSION: Our results suggest that helminths suppress the development of asthma by secreting substances that modulate allergic responses without affecting the generation of helminth-specific Th2 immunity. The identification of these products may lead to the design of novel therapeutic intervention strategies for the treatment of asthma.     

Allergic bronchopulmonary mycosis complicating cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused by bronchial colonization with Aspergillus fumigatus that affects approximately 10% of patients with cystic fibrosis (CF). The diagnosis in CF patients is difficult because the cardinal symptoms of ABPA occur frequently in CF, ie, pulmonary infiltrates and wheezing, as well as the frequent colonization with A fumigatus that leads to humoral reactivity. If left untreated, ABPA leads to bronchiectasis and pulmonary fibrosis. The pathogenesis of ABPA seems to be a prolonged asthmatic late-phase reaction orchestrated by CD4+ Th2-like T cells in response to persistent pulmonary A fumigatus allergen exposure. Thus, polyclonal and A fumigatus-specific IgE antibodies (and IgA and IgG) and blood pulmonary eosinophilia are stimulated by Th2-derived cytokines such as IL-4 and IL-5. In addition, IL-4 would also promote pulmonary transendothelial migration of eosinophils, basophils, and lymphocytes via induction of cell adhesion molecules and their ligands. IgE mast cell interactions would also contribute to the bronchial reactivity and inflammation. Recent advances have begun to identify immunodominant A fumigatus allergens. Evaluation of the quantity of IgE antibodies (and IgA and IgG) and T-cell cytokine responses to specific A fumigatus allergens should aid in the diagnosis and immunopathogenesis of ABPA, especially in CF patients.     

Protective effect of Bifidobacterium infantis CGMCC313-2 on ovalbumin-induced airway asthma and b-lactoglobulininduced intestinal food allergy mouse models

AIM To determine whether oral administration of Bifidobacterium infantis CGMCC313-2(B. infantis CGMCC313-2) inhibits allergen-induced airway inflammation and food allergies in a mouse model.METHODS Ovalbumin(OVA)-induced allergic asthma and b-lactoglobulin-induced food allergy mouse models were used in this study. Following oral administration of B. infantis CGMCC313-2 during or after allergen sensitization, histopathologic changes in the lung and intestine were evaluated by hematoxylin and eosin(HE) staining. In the allergic asthma mouse model, we evaluated the proportion of lung-infiltrating inflammatory cells. OVAspecific IgE and IgG1 levels in serum and cytokine levels in bronchoalveolar lavage fluid(BALF) were also assessed. In the food allergy mouse model, the levels of total Ig E and cytokines in serum were measured.RESULTS Oral administration of B. infantis CGMCC313-2 during or after allergen sensitization suppressed allergic inflammation in lung and intestinal tissues, while the proportion of infiltrating inflammatory cells was significantly decreased in the BALF of allergic asthma mice. Moreover, B. infantis CGMCC313-2 decreased the serum levels of total Ig E in food allergy mice, and reductions in IgE and IgG1 were also observed in OVA-induced allergic asthma mice. The expression of interleukin-4(IL-4) and IL-13 in both serum and BALF was suppressed following the administration of B. infantis CGMCC313-2, while an effect on serum IL-10 levels was not observed.CONCLUSION B. infantis CGMCC313-2 inhibits the secretion of allergen-induced IgE, IL-4 and IL-13, and attenuates allergic inflammation.     

Multispecies probiotics combination prevents ovalbumin-induced airway hyperreactivity in mice

Background

Probiotics could be beneficial to health and some of them have shown to modulate immune responses.

Helminth infection inhibits airway allergic reaction and dendritic cells are involved in the modulation process

Several previous studies have demonstrated that some helminth infections can inhibit allergic reactions, but the examination on the effect of live Schistosoma japonicum ( SJ ) infection on allergic inflammation remains limited. The aim of this study was to examine the effect and mechanism of chronic SJ infection on airway allergic inflammation in a murine model. The data showed that chronic SJ infection suppressed airway eosinophilia, mucus production and antigen-specific IgE responses induced by ovalbumin (OVA) sensitization and challenge. Cytokine production analysis showed that chronic SJ infection reduced allergen-driven interleukin (IL)-4 and IL-5 production, but had no significant effect on IFN-γ production. More importantly, we found that the adoptive transfer of dendritic cells (DCs) from SJ -infected mice dramatically decreased airway allergic inflammation in the recipients, which was associated with significant decrease of IL-4/IL-5 production and increase of IL-10 production. The results suggest that SJ infection may inhibit the development of allergy and that DCs may be involved in the process of helminth infection-mediated modulation of allergic inflammation.     

Mechanisms of IgE Inflammation

The prevalence of diseases such as allergic asthma and rhinitis continues to increase in the United States, affecting millions of people. It is well-established that allergy contributes to the pathogenesis of most asthma, especially in children and young adults. Despite current therapy (eg, inhaled corticosteroids, anti-leukotrienes, and bronchodilators), patients with moderate to severe asthma remain symptomatic and experience frequent exacerbations of disease requiring oral corticosteroids, emergency department treatments, and hospitalizations. Allergic diseases are traditionally referred to as immediate or type 1 hypersensitivity reactions, with IgE as a critical factor. IgE is involved in allergic inflammation, especially in early-phase response, but it may also be involved in the late-phase allergic response. A direct correlation between serum IgE levels and asthma exists. As logarithm IgE values increase, asthma prevalence increases linearly, even in patients who are categorized as having nonallergic asthma. In addition, there is a significant, although low association in allergic rhinitis with IgE levels and positive skin test reactivity to pollens. Recent advances in our understanding of the role of IgE in allergic inflammation have led to the development of a monoclonal antibody to IgE that reduces IgE levels, thereby reducing allergic inflammation. This review aims to provide an overview of the basic science of the IgE molecule and the clinical efficacy of anti-IgE therapy in allergic and asthmatic diseases.     

Levamisole: Might It Be used in Treatment and Prevention of Atopic Diseases?

As an antihelmintic and Th₁‐biased immunostimulant, levamisole has been used to restore impaired cell mediated immunity. We sought to explore whether the Th₁ driving effect of levamisole may also have an influence on the course of allergic diseases, by shifting the Th₂ dominant immunity more toward Th₁‐mediated response. BALB/c mice were sensitized intraperitoneally on days 0, 7, and 15 with ovalbumin (OVA). After the sensitization, they were challenged intranasally with OVA once a day for 6 consecutive days. Levamisole (2.5 mg/kg) was administered orally three times a week during sensitization and challenge. After the last challenge, differential cell counts were performed, and IL‐4 and IFNγ levels were measured in the bronchoalveolar lavage fluids (BALF). Serum total IgE level was determined, and lungs were examined histologically. The present study establishes that mice administered with oral levamisole gave significantly lower IL‐4 levels on sensitization with OVA; however, IFNγ production, eosinophil infiltration, and serum IgE levels remained unaffected. In conclusion, use of levamisole may have important implications in the management of the allergic inflammation.     

Immediate systemic hypersensitivity reaction associated with topical application of Australian tea tree oil.

Australian tea tree oil has been used as a veterinary antiseptic for many years and, more recently, has been extended into human use. There have been many reports of allergic contact dermatitis and toxicity reactions, but it has never been implicated in immediate systemic hypersensitivity reactions. A 38-year-old man experienced immediate flushing, pruritus, throat constriction, and lightheadedness after topical application of tea tree oil. Our purpose was to determine whether this represented an immunoglobulin E (IgE)--mediated reaction. Skin-prick and intradermal testing was performed, as well as enzyme-linked immunosorbent assays for specific IgG and IgE against tea tree oil. The patient had a positive wheal and flare reaction on intradermal testing with tea tree oil. All five patient controls were negative on skin testing. No specific IgG or IgE was detected. We present the first reported case of an immediate systemic hypersensitivity reaction occurring after topical application of Australian tea tree oil, confirmed by positive wheal and flare reaction on skin testing.     

Immunomodulation of allergic response in children and adolescents: What we can learn from lymphatic filarial infection

Background

Although it is well known that allergic diseases involve a strong Th2 immune response, with production of high levels of specific IgE allergen, knowledge on the association between filarial infection and allergies, among paediatric patients is scarce.

A new paradigm for Immunoglobulin E in allergic diseases

Recent observations at the level of the antigen presenting cell, as well as the T cell, point toward a pivotal role for interleukin (IL)-10 in the control of immunoglobulin E (IgE)-mediated allergic diseases, such as asthma and rhinitis. This has led to restructuring of the Th1/Th2 paradigm with IL-10 acting to modulate Th2-driven IgE antibody (Ab) responses. The modified Th2 response to cat allergen is associated with high-dose allergen exposure and the presence of high titer IgG and IgG4 Ab; however, IgE Ab and allergic symptoms are absent. Characteristics of this immune response indicate that it is a variant of the allergic response, which develops in an IL-10-dependent manner, but it is distinct from other types of nonallergic or tolerant responses. These observations point toward a new paradigm for the development of IgE-mediated responses. This may be important for advancing our understanding of the response to immunotherapy and anti-IgE, and for defining immune mechanisms that drive allergic responses.     

Polyclonal IgE Induces Mast Cell Survival and Cytokine Production

BackgroundAg-dependent activation of IgE-bearing mast cells is a critical first step in immediate hypersensitivity and other allergic responses. Recent studies have revealed Ag-independent effects of monoclonal mouse IgE molecules on mast cell survival and activation. However, no studies have been performed on the effects of polyclonal IgE molecules. Here, we tested whether polyclonal mouse and human IgE molecules affect survival and cytokine production in mast cells.MethodsMast cells were cultured in the presence of polyclonal mouse and human IgE molecules, and cell survival and cytokine production were analyzed.ResultsPolyclonal mouse IgE molecules in sera from mice with atopic dermatitis-like allergic skin inflammation, enhanced survival and cytokine production in mast cell cultures. Similar to the effects of monoclonal IgE, the polyclonal IgE effects were mediated by the high-affinity IgE receptor, FcεRI. Human polyclonal IgE molecules present in sera from atopic dermatitis patients were also capable of activating mast cells, and inducing IL- 8 production in human cord blood-derived mast cells.ConclusionsThese results imply that polyclonal IgE in atopic dermatitis and other atopic conditions might modulate mast cell number and function, thus amplifying the allergic response.     

Beneficial effects of Galectin-9 on allergen-specific sublingual immunotherapy in a Dermatophagoides farinae-induced mouse model of chronic asthma

Background

Allergen-specific sublingual immunotherapy is a potential disease-modifying treatment for allergic asthma. Galectin-9 (Gal-9), a β-galactoside-binding protein with various biologic effects, acts as an immunomodulator in excessive immunologic reactions by expanding regulatory T cells (Treg) and enhancing transforming growth factor (TGF)-β signaling. We investigated the efficacy of sublingually administered Gal-9 as an adjuvant to a specific allergen in a Dermatophagoides farinae (Df)-induced mouse model of chronic asthma.

Aging Exacerbates Restraint Stress-Induced Inhibition of Antigen-Specific Antibody Production in Mice

BackgroundWe have recently found that exposure to acute restraint stress suppresses antigen-specific antibody production, including IgE, in a murine model of allergic rhinitis. Although age-related alterations in immune responses are known, it remains unclear whether aging modulates the antibody production under stressful conditions. In this study, we set out to determine the effects of aging on antibody production under acute restraint stress in mice.MethodsBoth young and aged CBA/J mice were repeatedly sensitized intranasally with phospholipase A2 (PLA2) without adjuvants. Restraint stress was applied using uniform cylinders once a week for a continuous 8 h period, on 5 occasions in total. Blood samples were taken at 0, 20 and 30 days after primary sensitization, and production of PLA2-specific antibodies and levels of IL-4, IFN-γ, IL-10 and IL-1β in sera were determined by ELISA.ResultsRepeated intranasal sensitization with PLA2 induced PLA2-specific IgE, IgG1 and IgG2a production in aged mice. We found that exposure to restraint stress significantly inhibited production of PLA2-specific IgE, IgG1 and IgG2a in aged mice. In addition, antibody production under restraint stress decreased significantly in aged mice when compared with young mice. No IL-4, IFN-γ, IL-10 or IL-1β were detected in sera from non-stressed or stressed aged mice.ConclusionsAging exacerbates the immunosuppressive role of acute restraint stress in antigen-specific antibody production in mice.     

Levamisole: Might It Be used in Treatment and Prevention of Atopic Diseases?

As an antihelmintic and Th₁-biased immunostimulant, levamisole has been used to restore impaired cell mediated immunity. We sought to explore whether the Th₁ driving effect of levamisole may also have an influence on the course of allergic diseases, by shifting the Th₂ dominant immunity more toward Th₁-mediated response. BALB/c mice were sensitized intraperitoneally on days 0, 7, and 15 with ovalbumin (OVA). After the sensitization, they were challenged intranasally with OVA once a day for 6 consecutive days. Levamisole (2.5 mg/kg) was administered orally three times a week during sensitization and challenge. After the last challenge, differential cell counts were performed, and IL-4 and IFNγ levels were measured in the bronchoalveolar lavage fluids (BALF). Serum total IgE level was determined, and lungs were examined histologically. The present study establishes that mice administered with oral levamisole gave significantly lower IL-4 levels on sensitization with OVA; however, IFNγ production, eosinophil infiltration, and serum IgE levels remained unaffected. In conclusion, use of levamisole may have important implications in the management of the allergic inflammation.