Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production
17 Nov 1997-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 186, Iss: 10, pp 1737-1747
TL;DR: It is suggested that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
Abstract: Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased mucus secretion is an important clinical symptom and contributes to airway obstruction in asthma. Activated CD4 Th1 and Th2 cells have both been identified in airway biopsies of asthmatics but their role in mucus production is not clear. Using CD4 T cells from mice transgenic for the OVA-specific TCR, we studied the role of Th1 and Th2 cells in airway inflammation and mucus production. Airway inflammation induced by Th2 cells was comprised of eosinophils and lymphocytes; features found in asthmatic patients. Additionally, there was a marked increase in mucus production in mice that received Th2 cells and inhaled OVA, but not in mice that received Th1 cells. However, OVA-specific Th2 cells from IL-4–deficient mice were not recruited to the lung and did not induce mucus production. When this defect in homing was overcome by administration of TNF-α, IL-4 −/− Th2 cells induced mucus as effectively as IL-4 +/+ Th2 cells. These studies establish a role for Th2 cells in mucus production and dissect the effector functions of IL-4 in these processes. These data suggest that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
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TL;DR: In this paper, the type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma.
Abstract: The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4 + T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.
2,532 citations
Journal Article•
TL;DR: In this article, the type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma.
Abstract: The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4 + T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.
2,429 citations
TL;DR: This article showed that IL-4 receptor α chain-dependent pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL4 receptor and showed that selective neutralization of IL-13, a cytokine related to interleukin-4 that also binds to the α chain of the IL 4 receptor, ameliorated asthma phenotype.
Abstract: The pathogenesis of asthma reflects, in part, the activity of T cell cytokines. Murine models support participation of interleukin-4 (IL-4) and the IL-4 receptor in asthma. Selective neutralization of IL-13, a cytokine related to IL-4 that also binds to the α chain of the IL-4 receptor, ameliorated the asthma phenotype, including airway hyperresponsiveness, eosinophil recruitment, and mucus overproduction. Administration of either IL-13 or IL-4 conferred an asthma-like phenotype to nonimmunized T cell–deficient mice by an IL-4 receptor α chain–dependent pathway. This pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL-4 receptor.
1,904 citations
TL;DR: The targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR in transgene-positive animals.
Abstract: Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4+ Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden‐like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden‐like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses. J. Clin. Invest. 103:779-788 (1999).
1,695 citations
Cites background from "Induction of Airway Mucus Productio..."
...Multiple lines of evidence suggest that allergen-specific CD4+ Th2 cells play an essential role in initiating and generating these abnormalities (8, 17, 27)....
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...For example, in experiments using passively transferred in vitro polarized and activated Th2 cells, IL-4 plays an important role in T-cell recruitment from the vascular space and the migration of eosinophils from the lung into the airway, but it cannot account for the ability of Th2 cells to stimulate mucus elaboration or induce AHR to methacholine (17, 18)....
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TL;DR: Results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans are discussed and the extraordinary heterogeneity of asthma is described.
Abstract: Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (T(H)2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the T(H)17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
1,268 citations
References
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Journal Article•
TL;DR: A knowledge of the chain specificities of anti-Ia monoclonal antibodies should prove useful for a variety of studies aimed at dissecting Ia structure-function relationships.
Abstract: The chain specificities of 18 Ak and 26 Ab-reactive anti-Ia monoclonal antibodies have been determined. L cells were transfected with haplotype-matched (A alpha k:A beta k, A alpha b:A beta k) or haplotype-mismatched (A alpha k:A beta b, A alpha b:A beta k) cDNA pairs, lines expressing high levels of surface A complex were selected, and antibody reactivity with a panel of reagents was assessed by cytofluorimetric analysis. Most of the antibodies recognized a determinant specified by one chain, either alpha or (more commonly) beta. A few examples of more complex determinants were also observed. A knowledge of the chain specificities of anti-Ia monoclonal antibodies should prove useful for a variety of studies aimed at dissecting Ia structure-function relationships.
76 citations
Additional excerpts
...A1 [33]) and anti–Ig-coated magnetic beads (Advanced Magnetics, Inc....
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TL;DR: Possible roles of eosinophil products in modulating the release of mucus from airway explants were investigated and three proteins derived from EO granules, EO-derived neurotoxin, Eo cationic protein (ECP), and major basic protein (MBP) were separated.
Abstract: Possible roles of eosinophil (EO) products in modulating the release of mucus from airway explants were investigated. Cell- and membrane-free lysates from purified human EOs (1 to 20 x 10(5)) caused a dose-dependent release of respiratory glycoconjugates (RGC) from cultured feline tracheal explants. Crude extracts from isolated EO granules also stimulated RGC release, suggesting that a granular protein might be responsible. Three proteins derived from EO granules, EO-derived neurotoxin, EO cationic protein (ECP), and major basic protein (MBP) were separated by sequential sizing and affinity chromatography. ECP (0.025 to 25 micrograms/ml) caused a dose-dependent increase in RGC release from both feline and human airway explants and also stimulated the release of the serous cell-marker, lactoferrin, from human bronchial explants. EO-derived neurotoxin (0.025 to 50 micrograms/ml) failed to affect RGC release, whereas MBP (50 micrograms/ml) significantly inhibited RGC release from feline explants. Thus, ECP stimulates RGC and lactoferrin release from airway explants, whereas MBP inhibits RGC release.
72 citations
TL;DR: Transgenic mice have been generated that express B7-1 on the β-cells of the pancreatic islets of Langerhans and this illustrates that B 7-1 is a very potent co-stimulatory molecule in vivo and that its presence on the surface of tissue cells can potentiate the autoimmune process.
Abstract: B7-1 is a co-stimulatory molecule that signals T-cells that recognize antigen to proliferate and differentiate into effector T-cells. The same cell must present antigen and express co-stimulatory molecules, such as B7-1, to activate naive T-cells. Thus, tissues that do not express co-stimulatory molecules would not be expected to induce immune responses, while expression of a co-stimulator on tissue cells may convert them into effective antigen-presenting cells and induce autoimmunity. To test this, transgenic mice have been generated that express B7-1 on the beta-cells of the pancreatic islets of Langerhans. On a B6 genetic background, B7-1 expression on beta-cells does not predispose to diabetes. B6 mice are resistant to diabetes. However, when B7-1 is expressed on the beta-cells of B6 mice backcrossed once to the genetically susceptible NOD strain, the onset of diabetes is accelerated and the autoimmune attack intensified. This illustrates that B7-1 is a very potent co-stimulatory molecule in vivo and that its presence on the surface of tissue cells can potentiate the autoimmune process.
69 citations
Journal Article•
TL;DR: Results show for the first time that a chronic T-cell-mediated immune response is present in the bronchial tissue of asymptomatic asthmatics, and that the HLA-DR expression promoted correlates with the hyperresponsive status.
Abstract: Physiological and Immunopathological parameters were investigated in 15 patients with diagnosed asthma, and 6 non-asthmatics presenting with other chest symptoms. The 15 symptom-free asthmatics expressed bronchohyperresponsiveness with a mean provocative dose producing a 20% fall in forced expiratory volume in one second (PD20FEV1) of 1 mg histamine. None of the non-asthmatics responded to 16 mg histamine. Twenty four hours later bronchoscopy was performed and endobronchial biopsies were obtained. Histological staining of frozen biopsy sections revealed a mononuclear cell infiltrate in all 15 asthmatics, while only 1 of the 6 non-asthmatics showed mild inflammation. Monoclonal antibodies were used to identify subsets of lymphocytes, activation markers, macrophages, and HLA-DR expression within the peribronchial infiltrates. In all samples, activated T-cells and macrophages were identified and HLA-DR expression was found to be raised, but the CD4: CD8 ratio was highly variable. No clear relationship was found between cellular distribution and measured lung function parameters. A highly significant correlation was found between the level of HLA-DR expression on the infiltrating cells (quantified microdensitometrically) and bronchial hyperresponsiveness. These results show for the first time that a chronic T-cell-mediated immune response is present in the bronchial tissue of asymptomatic asthmatics, and that the HLA-DR expression promoted correlates with the hyperresponsive status. These data promote the hypothesis that a T-cell-mediated response contributes to a predisposition to bronchial hyperresponsiveness in asthmatics.
58 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...The presence of activated Th2 cells and eosinophils in the airways of asthmatics have been associated with more severe airway hyperresponsiveness (24, 25)....
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TL;DR: The coordinated genetic control of the surface levels of the Thy‐1 determinant and the mitogenic determinant suggests that both determinants are situated on the same molecule in the T cell membrane.
Abstract: Rabbit anti-mouse brain (RaMBr) antiserum can induce Lyt-1+, Lyt-2-, T cells to proliferate and stimulates the same T cell subset to induce B cell proliferation. The aim of this report is to demonstrate that the mitogenic determinant recognized on the T cell surface by RaMBr antiserum is located on the Thy-1 molecule expressing the products of the Thy-1a and Thy-1b alleles. Evidence is drawn from serological and genetic experiments. The brain T cell cross-reactive, mitogenic determinant is not expressed on Thy-1- mutants of the BW5147 T cell lymphoma that fail to express the Thy-1 molecule but do express other T cell surface proteins such as T-200 and gp 69, 71. Monoclonal anti-Thy-1.1 and anti-Thy-1.2 antibodies block the binding to the appropriate T cells of the majority of the serum antibody from RaMBr antiserum. The absorption of mitogenic antibody was blocked in a similar fashion, thus demonstrating the close association of the determinant and the Thy-1 antigen defined by monoclonal alloantibodies. The mitogenic and Thy-1.1 determinants are probably located on the same molecule because of the data obtained with the BW5147 Thy-1- mutants and the observation that Thy-1a T cells, which express a lower level of surface Thy-1 than Thy-1b T cells, also express lower levels of the determinant recognized by RaMBr antiserum. Furthermore, in (AKR x DBA/2)F1 mice (Thy-1a/b) which express less Thy-1.1 antigen than Thy-1.2 at the surface, the mitogenic determinant was found to be preferentially associated with Thy-1.2. The coordinated genetic control of the surface levels of the Thy-1 determinant and the mitogenic determinant suggests that both determinants are situated on the same molecule in the T cell membrane.
43 citations