Immunology of allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease caused predominantly by the ubiquitous fungus Aspergillus fumigatus. ABPA is characterized by eosinophilia, fleeting pulmonary infiltrates, central bronchiectasis, elevated serum IgE and Aspergillus specific IgG and IgE. The pathogenetic mechanism implicated in ABPA is not completely understood. The cytokine response detected in ABPA patients is of a CD4+ Th2 type as evidenced by the production of IL-4, IL-5, and very little or no IFN-g on stimulation of T-lymphocytes with Aspergillus antigens. Animal model studies using wild type and gene knockout mice indicate a more precise mechanism of lung injury in antigen exposed animals. IL-4 knockout mice invariably showed a predominant Th1 response. B-cell deficient and IgE knockout mice exposed to A. fumigatus antigens showed airway response similar to wild type mice indicating a lesser role for IgE and other antibodies in the pathogenesis of murine experimental ABPA. RAG negative mice failed to show airway hyperreactivity response, although airway hyperreactivity was induced in naive RAG negative animals when T-cells from wild type Aspergillus immunized mice were transferred. The results of these studies indicate a multi-factorial immunopathogenesis in ABPA, which include T-cells, IgE, eosinophils, mast cells, and various cytokines and chemokines.     

Anti-interleukin 5 but not anti-IgE prevents airway inflammation and airway hyperresponsiveness.

The role of IL-5 and allergen-specific IgE in the development of eosinophilic airway inflammation and airway hyperresponsiveness (AHR) was investigated in a murine model. BALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injection on Days 1 and 14, followed by airway challenge with OVA on Days 28 and 29. Anti-IL-5 (TRFK-5) or anti-IgE (antibody 1-5) was administered before each airway challenge. Sensitized and challenged mice developed increased OVA-specific IgE serum levels, Th2 cytokine production by peribronchial lymph node (PBLN) cells, increased numbers of eosinophils (predominantly located in the peribronchial regions of the lungs), and increased airway responsiveness to methacholine (MCh). Anti-IgE treatment significantly decreased serum anti-OVA IgE levels and prevented the development of anaphylaxis but failed to affect T cell function, eosinophil airway infiltration, and AHR in sensitized and challenged mice. In contrast, treatment with anti-IL-5 antibody did not affect B cell (Ig serum levels), T cell (cytokine production), or mast cell function (immediate cutaneous reactivity) but completely inhibited development of eosinophilic lung inflammation and AHR. These data identify IL-5-mediated eosinophilia as a major target for development of AHR in this model, with little effect resulting from neutralization of IgE.     

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.     

Interleukin-4 causes susceptibility to invasive pulmonary aspergillosis through suppression of protective type I responses

Aspergillus fumigatus, an opportunistic fungal pathogen, causes multiple allergic and nonallergic airway diseases. Invasive pulmonary aspergillosis (IPA) is a nonallergic, life-threatening disease of immunocompromised patients. In a murine model of IPA, interleukin (IL)-4-deficient (IL-4-/-) BALB/c mice were used to examine the role of IL-4 in lung pathology and immune responses. IL-4-/- mice were more resistant than wild-type mice to infection caused by multiple intranasal injections of viable A. fumigatus conidia. Resistance was associated with decreased lung inflammatory pathology, impaired T helper (Th)-2 responses (including lung eosinophilia), and an IL-12-dependent Th1 response. In contrast, development of host-detrimental antifungal Th2 cells occurred in IL-12-/- and interferon-gamma-/- mice and in IL-4-/- mice when subjected to IL-12 neutralization. These results demonstrate that IL-4 renders mice susceptible to infection with A. fumigatus by inhibition of protective Th1 responses. IL-4 appears to have a distinct role in the pathogenesis of allergic and nonallergic lung diseases caused by the fungus.     

Zinc deficiency and energy restriction modify immune responses in mice during both primary and challenge infection with Heligmosomoides polygyrus (Nematoda)

This study characterized the consequences of zinc-sufficient (Zn+, 60 mg zinc/kg diet, ad libitum ), zinc-deficient (Zn−, 0.75 mg zinc/kg diet, ad libitum ) and energy-restricted (ER, 60 mg zinc/kg diet which was restricted to match food intake of Zn− mice) diets on the in vivo and in vitro immune response of BALB/c mice during both primary and challenge infection with Heligmosomoides polygyrus . In Zn+ mice, both primary and challenge infection with H. polygyrus induced not only a strong Th2 response (IgE, IgG1, eosinophilia, IL-4, IL-5, IL-10), but also elements of a Th1 response (IgG3, IFN-γ). Zinc deficiency significantly depressed Th2-dependent antibody production during both primary and challenge infection, and reduced mitogen and antigen-induced T cell proliferation during the challenge infection. Th2 cytokine production was reduced by zinc deficiency (IL-4), energy restriction (IL-5) and by zinc deficiency possibly in combination with energy restriction (IL-10) during the primary infection whereas Th1 cytokine production (IFN-γ) was depressed during the challenge infection by zinc deficiency, possibly together with energy restriction. Both zinc deficiency and energy restriction reduced eosinophilia with the more profound effect being exerted by zinc deficiency. Thus, both zinc deficiency and its concurrent energy restriction modify immune responses in the mice during primary and challenge infection with H. polygyrus.     

Lipopolysaccharides promote a shift from Th2-derived airway eosinophilic inflammation to Th17-derived neutrophilic inflammation in an ovalbumin-sensitized murine asthma model

Introduction: The currently available treatments for severe asthma are insufficient. Infiltration of neutrophils rather than eosinophils into the airways is an important inflammatory characteristic of severe asthma. However, the mechanism of the phenotypic change from eosinophilic to neutrophilic inflammation has not yet been fully elucidated. Methods: In the current study, we examined the effect of lipopolysaccharides (LPS) on eosinophilic asthmatic mice sensitized with ovalbumin (OVA), as well as the roles of interleukin (IL)-17A/T helper (Th) 17 cells on the change in the airway inflammatory phenotype from eosinophilic to neutrophilic inflammation in asthmatic lungs of IL-17A-deficient mice. Results: Following exposure of OVA-induced asthmatic mice to LPS, neutrophil-predominant airway inflammation rather than eosinophil-predominant inflammation was observed, with increases in airway hyperresponsiveness (AHR), the IL-17A level in bronchoalveolar lavage fluid (BALF) and Th17 cells in the spleen and in the pulmonary hilar lymph nodes. Moreover, the neutrophilic asthmatic mice showed decreased mucus production and Th2 cytokine levels (IL-4 and IL-5). In contrast, IL-17A knockout (KO) mice exhibited eosinophil-predominant lung inflammation, decreased AHR, mucus overproduction and increased Th2 cytokine levels and Th2 cells. Conclusion: These findings suggest that the eosinophilic inflammatory phenotype of asthmatic lungs switches to the neutrophilic phenotype following exposure to LPS. The change in the inflammatory phenotype is strongly correlated with the increases in IL-17A and Th17 cells.     

Surfactant protein D regulates airway function and allergic inflammation through modulation of macrophage function

The lung collectin surfactant protein D (SP-D) is an important component of the innate immune response but is also believed to play a role in other regulatory aspects of immune and inflammatory responses within the lung. The role of SP-D in the development of allergen-induced airway inflammation and hyperresponsiveness (AHR) is not well defined. SP-D levels progressively increased up to 48 hours after allergen challenge of sensitized mice and then subsequently decreased. The levels of SP-D paralleled the development of airway eosinophilia and AHR. To determine if this association was functionally relevant, mice were administered rat SP-D (rSP-D) intratracheally. When given to sensitized mice before challenge, AHR and eosinophilia were reduced by rSP-D in a dose-dependent manner but not by mutant rSP-D. rSP-D administration resulted in increased levels of interleukin (IL)-10, IL-12, and IFN-gamma in bronchoalveolar lavage fluid and reduced goblet cell hyperplasia. Culture of alveolar macrophages together with SP-D and allergen resulted in increased production of IL-10, IL-12, and IFN-gamma. These results indicate that SP-D can (negatively) regulate the development of AHR and airway inflammation after airway challenge of sensitized mice, at least in part, by modulating the function of alveolar macrophages.     

Prophylactic Vaccination with Adjuvant Monophosphoryl Lipid A Prevents Th2-Mediated Murine Asthmatic Responses

Objective. Asthma is a chronic respiratory disorder characterized by airway hyperreactivity, eosinophilic infiltration, high titer of allergen-specific IgE, and overproduction of T helper 2 (Th2) cytokines. Antigen combined with an appropriate adjuvant and administrated through the proper route can elicit suitable immunological responses to protect humans and animals from diseases. Antigen formulated with monophosphoryl lipid A (MPLA) can produce priming of Th1-mediated immune responses. The purpose of this study was to examine the utility of MPLA as an adjuvant to prevent asthma. Methods. BALB/c mice were immunized with ovalbumin (OVA) formulated with or without MPLA by intraperitoneal, footpad, or subcutaneous injection. Vaccinated mice were challenged with OVA aerosol to estimate the protective efficacy of MPLA in comparison to Th2-adjuvant aluminum hydroxide (Alum). Airway hyperresponsiveness to methacholine, eosinophilia in bronchoalveolar lavage fluid (BALF), circulating titers of OVA-specific antibodies, and stimulating levels of IFN-γ and IL-4 cytokines from splenocytes were evaluated. Results. Mice immunized by all injection routes with OVA formulated with MPLA increased the ratio of Th1/Th2 responses compared to mice receiving antigen alone. For prophylactic vaccination purpose, MPLA reduced airway responsiveness and eosinophilic inflammation in the lung, decreased serum OVA-specific IgE level, and increased the serum ratio of OVA-specific IgG2a/IgG1 and the ratio of IFN-γ/IL4 from OVA-activated splenocytes compared with mice vaccinated with Alum. Conclusion. MPLA may be clinically useful in the vaccination of individuals predisposed to 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.     

A protective role for the fifth complement component (c5) in allergic airway disease

RATIONALE: Reports from our laboratory, as well as those from others, have documented the importance of complement activation, the C3a anaphylatoxin, and its receptor, C3aR, in promoting Th2 effector functions in a mouse model of bronchopulmonary allergy. Although deficiency in the fifth complement component (C5) has been linked to enhanced airway hyperresponsiveness in mice, the contribution of C5 to other major biological hallmarks of asthma has not been evaluated. OBJECTIVE: Accordingly, congenic C5-sufficient and C5-deficient mice were subjected to a mouse model of bronchopulmonary allergy to assess the impact of C5 on pulmonary inflammation and Th2 effector functions in experimental asthma. METHODS AND MAIN RESULTS: In contrast to observations reported for C3- and C3aR-deficient animals, C5-deficient mice exhibited significantly increased airway hyperresponsiveness relative to wild-type congenic control mice after antigen challenge. Moreover, challenged C5-deficient mice had a 3.4-fold and 2.7-fold increase in the levels of airway eosinophils and lung interleukin (IL)-4-producing cells, respectively, compared with challenged wild-type mice. Consistent with the numbers of IL-4-producing cells, C5-deficient mice also had increased bronchoalveolar lavage levels of the Th2 cytokines IL-5 and IL-13 and elevated serum levels of total and antigen-specific IgE. CONCLUSIONS: These data indicate that C5 plays an important protective role in allergic lung disease by suppressing inflammatory responses and Th2 effector functions observed in this experimental model. The protection provided by the presence of C5 is likely mediated by C5a, suggesting that C5a may play a significant role in tempering inflammation in Th2-driven diseases such as asthma.     

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.     

The failure of interleukin-10-deficient mice to develop airway hyperresponsiveness is overcome by respiratory syncytial virus infection in allergen-sensitized/challenged mice

Interleukin-10-deficient mice develop a robust pulmonary inflammatory response but no airway hyperresponsiveness (AHR) to inhaled methacholine (MCh) following allergen sensitization and challenge. In the present study, we investigated the effect of respiratory syncytial virus (RSV) infection on AHR and pulmonary inflammation in allergic IL-10-/- mice. Unlike littermate control mice, RSV-infected or ovalbumin (OVA)-sensitized/challenged IL-10-/- mice failed to develop significant AHR. In contrast, sensitized/challenged IL-10-/- mice infected with RSV did develop AHR accompanied by increased eosinophil numbers, both in bronchoalveolar lavage (BAL) and pulmonary tissue, and mucin production in airway epithelium. The cytokine profile in OVA-sensitized/challenged IL-10-/- mice was skewed toward a Th1 response but after RSV infection, this response was more of a Th2 type, with increased IL-5 levels in the BAL. Studies with an RSV mutant that lacks the G and SH genes showed equal enhancement of the AHR response as the parental wild-type strain, indicating that G protein is not essential to this response. These data suggest that RSV infection can overcome the failure of development of AHR in allergic IL-10-/- mice.     

Prevention of IL-6 signaling ameliorates toluene diisocyanate-induced steroid-resistant asthma

BackgroundAccumulating evidence indicated the crucial role for interleukin 6 (IL-6) signaling in the development of allergic asthma. Yet, the role of IL-6 signaling in toluene diisocyanate (TDI)-induced mixed granulocytic airway inflammation still remains unclear. Thus, the aims of this study were to dissect the role of IL-6 signaling and to evaluate the effect of tocilizumab on TDI-induced steroid-resistant asthma.MethodsTDI-induced asthma model was prepared and asthmatic mice were respectively given IL-6 monoclonal antibody, IL-6R monoclonal antibody (tocilizumab, 5 mg/kg, i.p. after each challenge) for therapeutic purposes or isotype IgG as control.ResultsTDI exposure just elevated IL-6R expression in the infiltrated inflammatory cells around the airway, but increased glycoprotein 130 expression in the whole lung, especially in bronchial epithelium. Moreover, TDI inhalation increased airway hyperresponsiveness (AHR) to methacholine, coupled with mixed granulocytic inflammation, exaggerated epithelial denudation, airway smooth muscle thickening, goblet cell metaplasia, extensive submucosal collagen deposition, dysregulated Th2/Th17 responses, as well as innate immune responses and raised serum IgE. And almost all these responses except for raised serum IgE were markedly ameliorated by the administration of IL-6 neutralizing antibody or tocilizumab, but exhibited poor response to systemic steroid treatment. Also, TDI challenge induced nucleocytoplasm translocation of HMGB1 and promoted its release in the BALF, as well as elevated lung level of STAT3 phosphorylation, which were inhibited by anti-IL-6 and anti-IL-6R treatment.ConclusionsOur data suggested that IL-6 monoclonal antibody and tocilizumab might effectively abrogate TDI-induced airway inflammation and remodeling, which could be used as a clinical potential therapy for patients with severe asthma.     

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.     

Indoleamine 2,3-dioxygenase in lung dendritic cells promotes Th2 responses and allergic inflammation

Indoleamine 2,3 dioxygenase (IDO) has emerged as an important mediator of immune tolerance via inhibition of Th1 responses. However, the role of IDO in antigen-induced tolerance or allergic inflammation in the airways that is regulated by Th2 responses has not been elucidated. By using IDO(-/-) mice, we found no impairment of airway tolerance, but, surprisingly, absence of IDO provided significant relief from establishment of allergic airways disease, as evident from attenuated Th2 cytokine production, airway inflammation, mucus secretion, airway hyperresponsiveness, and serum ovalbumin-specific IgE. Myeloid dendritic cells isolated from lung-draining lymph nodes of mice immunized for either Th1 or Th2 response revealed fewer mature dendritic cells in the lymph nodes of IDO(-/-) mice. However, the net functional impact of IDO deficiency on antigen-induced responses was more remarkable in the Th2 model than in the Th1 model. Collectively, these data suggest that IDO is not required for the induction of immune tolerance in the airways but plays a role in promoting Th2-mediated allergic airway inflammation via unique effects on lung dendritic cells.     

IL-10 is necessary for the expression of airway hyperresponsiveness but not pulmonary inflammation after allergic sensitization

Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10-/-) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge.     

Immunomodulation in the treatment and/or prevention of bronchial asthma

The immunologic hallmark of atopic allergy and asthma is an increased production of IgE and T helper (h) type 2 cell cytokines (interleukin (IL)-4, IL-5, IL-9 and IL-13) by Th cells reacting to common environmental allergens. All of us inhale allergens and healthy non-atopics produce allergen-specific IgG1, IgG4 and the Th1 cytokine interferon-α, as well as IL-12 from macrophages. We now have many modalities of immunomodulation to decrease the effect of IL-4 or IL-5 or production and level of IgE or agents to shift the immune response from a Th2 to a Th1 response, thereby decreasing the allergic inflammatory response in the airways. In the present review we focus on conventional immunotherapy, mycobacterial vaccines, DNA vaccines using cytosine guanosine, inhibitors of IL-4 and IL-5 and anti-IgE: Omalizumab.     

Distinct roles for IL-13 and IL-4 via IL-13 receptor alpha1 and the type II IL-4 receptor in asthma pathogenesis

IL-13 and IL-4 are central T helper 2 (Th2) cytokines in the immune system and potent activators of inflammatory responses and fibrosis during Th2 inflammation. Recent studies using Il13ra1(-/-) mice have demonstrated a critical role for IL-13 receptor (IL-13R) alpha1 in allergen-induced airway responses. However, these observations require further attention especially because IL-4 can induce similar lung pathology to IL-13, independent of IL-13, and is still present in the allergic lung. Thus, we hypothesized that IL-13Ralpha1 regulates IL-4-induced responses in the lung. To dissect the role of IL-13Ralpha1 and the type I and II IL-4Rs in experimental asthma, we examined lung pathology induced by allergen, IL-4, and IL-13 challenge in Il13ra1(-/-) mice. We report that IL-13Ralpha1 is essential for baseline IgE production, but Th2 and IgE responses to T cell-dependent antigens are IL-13Ralpha1-independent. Furthermore, we demonstrate that increased airway resistance, mucus, TGF-beta, and eotaxin(s) production, but not cellular infiltration, are critically dependent on IL-13Ralpha1. Surprisingly, our results identify a CCR3- and IL-13Ralpha1-independent pathway for lung eosinophilia. Global expression profiling of lungs from mice stimulated with allergen or IL-4 demonstrated that marker genes of alternatively activated macrophages are differentially regulated by the type I and type II IL-4R. Taken together, our data provide a comprehensive mechanistic analysis of the critical role by which IL-13Ralpha1 mediates allergic lung pathology and highlight unforeseen roles for the type II IL-4R.