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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01 Jan 2002
TL;DR: The 5q31-33 region contains a number of genes, including IL-13, that could be involved in the aetiology of allergic asthma and are very likely candidates to beinvolved in the inheritance of asthma.
Abstract: The 5q31-33 region contains a number of genes, including IL-13, that could be involved in the aetiology of allergic asthma. Other genes of interest in this region are the Th2 cytokines IL-4 and IL-5; the p40 chain of the Th1 cytokine inducer IL-12; IL-3; IL-9; CD14; the s2-adrenergic receptor; the corticosteroid receptor and the transcription factors interferon regulatory factor 1 (IRF1) and transcription factor 7 (TCF7). Other diseases such as schistosomiasis may also be (at least partly) controlled by this region. In humans, the severity of infection caused bySchistosomamansoniis linked to a marker on chromosome 5g31 [1]. In mice, resistance to this disease is regulated by Th2 cytokines; in particular, neutralisation of IL-13 leads to reduced pulmonary granuloma formation and total serum IgE levels, while Th2 cytokine production (IL-4, IL-5, and IL-13) remains intact [2]. The important role of Th2 cytokines in human asthma is underscored by the fact that T cells, acquired from bronchial biopsies, display an increased capacity to produce IL-4, IL-5, and IL-13 [3-5]. Interestingly, pulmonary expression of IL-13 is observed in both allergic and non-allergic asthma [6], while IL-4 expression may be more restricted to allergic asthma [7]. Because of their biological effects, IL-4 and IL-13, located at close proximity on 5q31, are very likely candidates to be involved in the inheritance of asthma. Firstly, for an antibody isotype switch to IgE, B cells require stimulation by either IL-4 or IL-13 [8, 9], and secondly these cytokines induce VCAM-1 expression on endothelial cells and pulmonary fibroblasts [10, 11], which may cause the accumulation of eosinophils at the site of the allergic reaction [12]. Recently, other effector functions of IL-4 and IL-13 have been described, independent of IgE and eosinophils.
Cites background from "Induction of Airway Mucus Productio..."
...It turned out that Th2 cells from IL-4-deficient mice were induc ing pulmonary mucus production as effectively as IL-4+1+ Th2 cells [ 14 ]....
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Dissertation•
01 Jan 2015
TL;DR: The aim of this Thesis is to demonstrate the importance of knowing the carrier and removal status of canine coronavirus in the development of SMGs in relation to other infectious diseases.
Abstract: ......................................................................................................................... i Acknowledgements .................................................................................................... iii List of Figures .............................................................................................................. ix List of Tables ............................................................................................................... xi 1. Introduction ........................................................................................................... 1 1.1 The Mammalian Respiratory System ............................................................................ 1 1.1.1 Structure of the Mammalian Respiratory System ............................................. 1 1.1.2 Protection of the Mammalian Respiratory System ........................................... 3 1.2 The SMGs of the Respiratory System ............................................................................ 3 1.2.1 Temporal Localisation of the SMGs ........................................................................... 3 1.2.2 Cellular Composition of the SMGs ............................................................................... 4 1.3 The SMGs and Airway Disease ....................................................................................... 5 1.3.1 Cystic Fibrosis ........................................................................................................................ 5 1.3.2 Asthma ........................................................................................................................................ 8 1.3.3 Chronic Obstructive Pulmonary Disease ................................................................ 9 1.4 Signalling in SMG Development .................................................................................. 10 1.4.1 Wnt/β-‐catenin Signalling .............................................................................................. 10 1.4.2 Bone Morphogenetic Protein Signalling ............................................................... 11 1.4.3 Ectodysplasin A Signalling ............................................................................................ 15 1.4.4 Fibroblast Growth Factor (FGF) Signalling .......................................................... 17 1.5 FGF Family of Signalling Factors ................................................................................ 17 1.5.1 FGF Ligands ............................................................................................................................ 17 1.5.2 FGF Receptors ....................................................................................................................... 18 1.5.3 FGF Intracellular Signalling Pathway ..................................................................... 21 1.5.4 The Ras/MAPK Pathway ................................................................................................ 23 1.5.5 Downstream Targets of the MAPK Pathway ....................................................... 23 1.5.6 Modulators of the MAPK Pathway ............................................................................ 24 1.6 Branching Morphogenesis ............................................................................................. 26 1.6.1 Branching of the Drosophila melanogaster Tracheal System .................. 26 1.6.2 Branching of the Mammalian Lung .......................................................................... 27 1.6.3 Branching of the Mammalian Salivary Gland ..................................................... 29 1.7 Aims of this Thesis ........................................................................................................... 33 2. Materials and Methods ....................................................................................... 34 2.1 Animals .............................................................................................................................. 34 2.1.1 Animals .................................................................................................................................... 34 2.1.2 Embryo Collection .............................................................................................................. 34 2.1.3 Postnatal Pup Collection ................................................................................................ 35 2.1.4 Adult Collection ................................................................................................................... 35 2.2 Dissection and Preparation of Tissue .......................................................................... 35
01 Jan 2001
TL;DR: In this article, the authors studied the induction, distribution and modulation of allergen-induced upper airway inflammation in a BALB/c mouse model and found that the selective infiltration of respiratory but not olfactory epithelium by eosinophils was unassociated with a measurable induction of epithelial ICAM-1 or eotaxin expression.
Abstract: Summary Background To further elucidate mechanisms of human allergic rhinosinusitis, we studied the induction, distribution and modulation of allergen-induced upper airway inflammation in a BALB/c mouse model. Methods Allergic inflammation induced with ovalbumin (OVA) by intraperitoneal (IP) injection in alum was compared to repeated intranasal instillation. The type and distribution of inflammatory cells was compared in the respiratory and olfactory epithelial compartments. Eosinophil distribution was assessed using Scarlet Red stain and a polyclonal antibody recognizing eosinophil major basic protein (MBP). The role of interleukin (IL)-5 in upper airway inflammation was tested by administration of polyclonal anti-IL-5 antibody during the sensitization protocol. Results Unsensitized control mice receiving saline failed to develop upper airway eosinophil infiltration. IP OVA-sensitized mice developed marked upper airway mucosal eosinophil infiltration after aerosol OVA challenge, whereas repeated intranasal instillation of OVA produced qualitatively similar, but less intense eosinophil infiltration. Using either sensitization protocol, eosinophil infiltration was seen in areas of the lower portion of the nasal septum, the floor and the lower lateral walls of the mid-caudal region of the nasal cavity. Immunofluorescence staining for MBP confirmed this distribution of eosinophils but also demonstrated some eosinophils in the maxillary sinuses and in circumscribed regions of the ethmoturbinates. All areas of eosinophil infiltration were lined by respiratory epithelium. The selective infiltration of respiratory but not olfactory epithelium by eosinophils was unassociated with a measurable induction of epithelial ICAM-1 or eotaxin expression. OVA-induced upper airway eosinophil infiltration was found to be IL-5 dependent, since administration of a polyclonal anti-IL-5 antibody (TRFK-5) during OVA sensitization resulted in a marked modulation (80% decrease) in eosinophil infiltration in response to subsequent OVA challenge. Conclusion The mouse upper airway, specifically in areas containing respiratory epithelium, is a target for OVA-induced allergic inflammation. This selective infiltration of respiratory, but not olfactory, epithelium is, in part, dependent upon IL-5. This model is useful for further dissection of the inflammatory response with genetic manipulations and targeted immunological approaches.
References
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Journal Article•
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
7,567 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...The lower limit of sensitivity for each of the ELISAs was 0.6 ng/ml (IFNg ), 5 pg/ml (IL-4), 0.010 ng/ml (IL-5), and 200 pg/ml (IL-10)....
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...CD4 Th2 cells make a different panel of cytokines, including IL-4, IL-5, and IL-10 (17, 18)....
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...Assays were standardized with recombinant IFNg , IL-5, IL-10 (Endogen), and IL-4 (Collaborative Research, Inc.)....
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...1 A ), and IL-10 (data not shown)....
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...IL-4 2/2 OVA-specific Th2 cells produced comparable levels of IL-5 and IL-10 when compared to IL-4 1/1 OVA-specific Th2 cells, but IL-4 was produced only by IL-4 1/1 Th2 cells....
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TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...
2,898 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...Th2 cells secreting IL-4 and IL-5 have been shown to be present and activated in the bronchial wall of asthmatic individuals (9, 23)....
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TL;DR: This paper used hybridoma monoclonal antibodies obtained after immunization of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes.
Abstract: Xenogeneic immunizations have the advantage of detecting a wide range of antigenic determinants because many commonly occurring proteins have diverged significantly during the course of evolution and are thus antigenic in other species. The broadness of xenogeneic responses, however, means that the antisera they produce are usually complex and require extensive absorptions to make them specific for a single antigen. This problem has now been overcome by generating hybridomas producing monoclonal antibodies (Kohler & Milstein 1975). These permit dissection ofthe xenogeneic response so that large amounts of individual antibodies can be obtained, each of which recognizes only one of the determinants recognized by a broadly reactive conventional antiserum. Williams et al. (1977) used hybridoma monoclonal antibodies obtained after immunizations of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes, i.e., differentiation antigens. Springer et al. (1978a) and Stern et al. (1978) used a similar approach to study mouse lymphocyte antigens. They prepared monoclonal antibodies by immunizing rats with mouse lymphocytes and showed that these monoclonals recognized previously undetected mouse cell surface determinants including a glycoprotein antigen that appears to be specific for macrophages (Springer et al. 1978b). Trowbridge (1978) also used rat anti-mouse immunizations to generate a monoclonal antibody against the non-polymorphic lymphocyte surface antigen T200.
1,916 citations
"Induction of Airway Mucus Productio..." refers methods in this paper
...To generate Th1 or Th2 cells from DO11.10 mice, CD4 T cells were isolated by negative selection as previously described (31) using mAbs to CD8 (clone 53-6.72, clone 2.43 [ 32 ]), Class II MHC I-A d (212.A1 [33]) and anti‐Ig-coated magnetic beads (Advanced Magnetics, Inc....
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TL;DR: Results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance in mice transgenic for a T cell receptor that reacts to this peptide.
Abstract: In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4+ CD8+ TCRlo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.
1,831 citations
TL;DR: Some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo, but the serum levels of IgG1 and IgE are strongly reduced.
Abstract: Interleukin-4 (IL-4) promotes the growth and differentiation of many hematopoietic cells in vitro; in particular, it directs the immunoglobulin (Ig) class switch to IgG1 and IgE. Mice homozygous for a mutation that inactivates the IL-4 gene were generated to test the requirement for IL-4 in vivo. In the mutant mice T and B cell development was normal, but the serum levels of IgG1 and IgE were strongly reduced. The IgG1 dominance in a T cell-dependent immune response was lost, and IgE was not detectable upon nematode infection. Thus, some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo.
1,262 citations