Respiratory Viruses, Eosinophilia and Their Roles in Childhood Asthma.

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Respiratory Viruses, Eosinophilia and Their Roles in Childhood Asthma.

Int Arch Allergy Immunol. 2010 Nov 25;155(1):1-11

Authors: Callaway Z, Kim CK

With the advent of highly sensitive and specific screening of respiratory specimens for viruses, new viruses are discovered, adding to the growing list of those associated with wheezing illness and asthma exacerbations. It is not known whether early childhood infections with these viruses cause asthma, and, if so, what exactly are the pathophysiologic mechanisms behind its development. The current consensus is that respiratory viral infection works together with allergy to produce the immune and physiologic conditions necessary for asthma diasthesis. One link between viruses and asthma may be the eosinophil, a cell that plays a prominent role in asthma and allergy, but can also be found in the body in response to viral infection. In turn, the eosinophil and its associated products may be novel therapeutic targets, or at the very least, used to elucidate the complex pathophysiologic pathways of asthma and other respiratory illnesses. Together or separately, they can be used for diagnosis, treatment and monitoring. Not only symptoms, but also the underlying disease mechanisms must be taken into consideration for the optimal care of a patient.

PMID: 21109743 [PubMed – as supplied by publisher]

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Allergen-Induced Coexpression of bFGF and TGF-?1 by Macrophages in a Mouse Model of Airway Remodeling: bFGF Induces Macrophage TGF-?1 Expression in vitro.

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Allergen-Induced Coexpression of bFGF and TGF-?1 by Macrophages in a Mouse Model of Airway Remodeling: bFGF Induces Macrophage TGF-?1 Expression in vitro.

Int Arch Allergy Immunol. 2010 Nov 25;155(1):12-22

Authors: Yum HY, Cho JY, Miller M, Broide DH

Background: Basic fibroblast growth factor (bFGF) is a cytokine that is mitogenic for fibroblasts and smooth muscle and may play a role in airway remodeling in asthma. We have used a mouse model of chronic ovalbumin (OVA) allergen-induced airway remodeling to determine whether bFGF and fibroblast growth factor receptor-1 are expressed and regulated by corticosteroids in the airway, as well as to determine whether bFGF mediates expression of another proremodeling cytokine, transforming growth factor (TGF)-?1. Methods: The airway levels and localization of bFGF, FGF receptor-1 and TGF-?1 were determined by ELISA, immunohistology and image analysis in the remodeled airways of chronic OVA-challenged mice treated with either corticosteroids or diluent. In vitro cultures of bone narrow-derived macrophages were used to determine whether bFGF induced TGF-?1 expression. Results: Mice chronically challenged with OVA developed significant airway remodeling that was associated with significantly increased levels of bFGF and TGF-?1. Immunohistochemistry demonstrated significantly increased bFGF and FGF receptor-1 expression by peri- bronchial F4/80+ cells. Double-label immunofluorescence microscopy studies demonstrated that peribronchial macrophages coexpressed bFGF and TGF-?1. In vitro studies demonstrated that incubation of bone marrow-derived macrophages with bFGF induced expression of TGF-?1. Mice treated with corticosteroids and subjected to chronic OVA challenge had significantly reduced levels of bFGF, FGF receptor-1, peribronchial TGF-?1+ cells and airway remodeling. Conclusions: Overall, this study demonstrates that allergen challenge stimulates peribronchial macrophages to coexpress bFGF and TGF-?1 and that bFGF may potentiate macrophage release of TGF-?1 through autocrine and/or paracrine pathways.

PMID: 21109744 [PubMed – as supplied by publisher]

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Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5.

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Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5.

Int Arch Allergy Immunol. 2010 Nov 25;155(1):31-37

Authors: Le TA, Takai T, Vu AT, Kinoshita H, Chen X, Ikeda S, Ogawa H, Okumura K

Background: Thymic stromal lymphopoietin (TSLP), highly expressed by keratinocytes in skin lesions of atopic dermatitis patients and bronchial epithelial cells in asthma, plays a key role in allergic diseases. Information on triggers for the release of TSLP in keratinocytes is still limited. Keratinocytes express Toll-like receptor (TLR) 5, the ligand for which is flagellin, the major structural protein of the flagella of Gram-negative bacteria. IL-4, IL-13 and TNF-? (Th2/TNF) are associated with allergic diseases. TGF-?, one of the ligands for the epidermal growth factor receptor, is overexpressed in keratinocytes in atopic dermatitis. We investigated the induction of TSLP expression in keratinocytes stimulated with flagellin and its modulation by the Th2/TNF cytokines and TGF-?. Methods: Primary human keratinocytes were stimulated with flagellin with or without cytokines. The TSLP released was measured by ELISA. Gene expression was analyzed by quantitative real-time PCR. Results: Stimulation of keratinocytes with flagellin induced the release of TSLP protein and upregulation of the gene expression of TSLP and other pro-inflammatory molecules. The flagellin-induced release of TSLP was enhanced by the Th2/TNF cytokines or TGF-?. Small interfering RNA-mediated knockdown of TLR5 expression suppressed the flagellin-induced TSLP gene expression. Conclusions: Flagellin induces TSLP expression in keratinocytes via TLR5 and the expression can be upregulated by a cytokine milieu with Th2/TNF or TGF-?, suggesting that exposure of barrier-defective skin to Gram-negative bacteria or environmental flagellin contributes to the initiation and/or amplification of Th2-type skin inflammation including atopic dermatitis through the induction of TSLP expression in keratinocytes.

PMID: 21109746 [PubMed – as supplied by publisher]

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In this issue.

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In this issue.

Eur J Immunol. 2010 Dec;40(12):3299-3300

Authors:

COVER IMAGE: The cover image of this issue consists of a confocal image of a mediastinal draining lymph node (MdLN) section, taken 5 days post-infection of C57BL/6 mice with DsRed-expressing Brucella (red). Md1N sections were also stained for lysozyme (green) and MHCII (blue). This image was taken from Archambaud et al. (pp. 3458-3471). In this article the authors investigate the initial innate immune response that follows intranasal inoculation of Brucella abortus in the mouse. The authors demonstrate that alveolar macrophages are critical regulators of the initial innate immune response against Brucella within the lungs, and that pulmonary DC and alveolar macrophages play distinct roles in controlling initial pulmonary Brucella infection. NOD1 CONTRIBUTES TO INTRACELLULAR PATHOGEN CLEARANCE IN THE LUNG: The host immune response to Legionella pneumophila, an important cause of bacterial pneumonia, is regulated by several classes of innate immune receptors. With the exception of NAIP5 and IPAF, the contributions of cytosolic receptors to host response against Legionella are poorly understood. In this issue, Berrington et al. use an animal model of aerosolized infection to investigate the role of the intracellular pathogen receptors NOD1 and NOD2 in the detection of, and host immune response to, L. pneumophila. The authors report that both NOD1 and NOD2 are able to detect Legionella in vitro, but that only NOD1 contributes to the host immune response and the control of bacterial clearance in vivo. Specifically, the authors demonstrate that NOD1 is important for the early increase in proinflammatory cytokine production, as well as the early recruitment of phagocytic cells to the alveolar space. Furthermore, NOD1 enhances bacterial clearance from the lung at later timepoints. These findings suggest a non-redundant role for NOD1 in the host innate immune response against Legionella in the lung.pp. 3519-3527 TLR CIRCUMVENT DAP12-MEDIATED REGULATION IN MAST CELLS: In mast cells, TLR agonists both induce cytokine production and enhance the antigen-mediated response. However, unlike antigen, TLR agonists do not induce degranulation. Recent reports have indicated that, by recruiting the tyrosine kinase Syk, DAP12, a small transmembrane protein that possesses a single ITAM motif, affects TLR-induced responses in certain cells of the hematopoietic lineage, including dendritic cells and macrophages. In this issue, SmrŽ et al. investigate whether DAP12 similarly influences TLR-mediated responses in mast cells. Surprisingly, the authors report that, although DAP12 is expressed in mast cells and can recruit Syk upon phosphorylation, the TLR- and antigen-mediated cytokine production in mast cells neither require, nor are modulated by, DAP12. These results suggest that the role of DAP12 in TLR-mediated cellular responses is cell type-dependent. The authors hypothesize that the inability of TLR to utilize DAP12 to recruit Syk in mast cells may provide an explanation as to why TLR do not induce mast cell degranulation.pp. 3557-3569 SIRP-?+ DC: NEW THERAPEUTIC TARGETS IN ASTHMA?: DC subsets with opposite functions have been identified in the airways. On one side, CD103(+) SIRP-?(-)DC and plasmacytoid DC have been described as the “good guys”, promoting viral clearance and tolerance to inhaled antigens, respectively. On the other side, SIRP-?(+) DC are immunogenic and are described, in a pathologic situation, as the “bad guys”, that induce airway inflammation and Th2 response. In this issue, Raymond et al. show that targeting SIRP-?/CD47 interaction with a CD47-Fc fusion molecule directly inhibits SIRP-?(+) DC trafficking to the draining lymph nodes, without affecting the migration of the other airway DC subpopulations. The authors demonstrate that, as an indirect consequence, CD47-Fc-treated mice do not develop allergic airway inflammation and Th2 response. Moreover, the authors show that SIRP-? ligation by CD47-Fc does not impair DC Ag uptake, Ag presentation, Th2 priming and effector function in vitro. Based on these findings, the authors propose that targeting the CD47/SIRP-? axis may offer previously unknown novel therapeutic perspectives for allergic asthma.pp. 3510-3518 IMPAIRED TREG MIGRATION IN MULTIPLE SCLEROSIS: Naturally occurring Treg (CD4(+) FoxP3(+)) are key regulators of the immune response, dampening autoimmunity and inflammation. By close interaction with the antigen-presenting cells, Treg are able to suppress the activation and expansion of effector T cells within the secondary lymphoid tissues, as well as at the sites of inflammation. As Treg represent only 5% of the CD4(+) T-cell population, Schneider-Hohendorf et al. set out to investigate whether Treg present features that compensate for their lower numbers. In this issue, the authors describe an enhanced migratory capacity of murine and human Treg, when compared to their effector counterparts. However, the authors demonstrate that, in the context of multiple sclerosis, Treg lose this feature and cannot surpass effector cells in migratory rates under steady state conditions. This impairment in Treg-migratory capacity adds another dimension to the known Treg defects found in multiple sclerosis, further underlining the important role of Treg in autoimmunity.pp. 3581-3590 NOVEL FUNCTION FOR THE IMMUNOPROTEASOME IN T-CELL SURVIVAL: 20S proteasomes are protein-degrading machineries with 14 different subunits. The three active site-bearing subunits are replaced by cytokine-inducible homologues, when the cells are stimulated with IFN-? or TNF-?, to form the so-called “immunoproteasomes.” Since the discovery of the immunoproteasomes 20 years ago, it has been assumed that the sole function of these subunit exchanges is to alter protein cleavage, in order to generate more peptide ligands for presentation on MHC class I. Recently, it has been proposed that the immunoproteasomes are also involved in Th17-differentiation and in cytokine regulation. In this issue, Moebius et al. use T-cell transfer experiments into virus-infected mice to show that T cells lacking either of the three immunosubunits fail to persist in the recipient mice. Immunoproteasome-deficient CD8(+) and CD4(+) T cells die in the virus-infected host mice, whereas B cells largely persist. The authors provide evidence that this loss of immunoproteasome-deficient T cells after transfer is not due to the rejection of donor T cells by the host, but rather reflects an essential role of the immunoproteasomes in the survival of T cells in virus-infected mice.pp. 3439-3449.

PMID: 21110311 [PubMed – as supplied by publisher]

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Protective Effects of Mentha haplocalyx Ethanol Extract (MH) in a Mouse Model of Allergic Asthma.

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Protective Effects of Mentha haplocalyx Ethanol Extract (MH) in a Mouse Model of Allergic Asthma.

Phytother Res. 2010 Nov 24;

Authors: Lee MY, Lee JA, Seo CS, Ha H, Lee NH, Shin HK

Mentha haplocalyx Briq., a commonly used herb in traditional Oriental medicine, has a variety of known pharmacological properties. However, neither the protective effects of Mentha haplocalyx ethanol extract (MH) against inflammation of the airway in an asthmatic model nor the mechanisms involved, have previously been reported. In the present study, an ovalbumin (OVA)-induced mouse model of allergic asthma was used to investigate whether MH was effective against the disease through regulation of airway inflammation. The MH treatment significantly inhibited increases in immunoglobulin (Ig) E and T-helper 2 (Th2)-type cytokines such as IL-4 and IL-5 in bronchoalveolar lavage fluid (BALF) and lung tissue. Inflammatory cell infiltration of the airway in mice treated with MH was effectively alleviated when compared with infiltration seen in the OVA-induced group. These data indicated that decreased cytokine levels are the result of the decreased number of invaded leukocytes. Also, the generation of reactive oxygen species (ROS) in BALF was diminished by MH treatment. Taken together, these findings indicate that the administration of MH may have potential therapeutic value in the treatment of inflammatory disease. Copyright © 2010 John Wiley & Sons, Ltd.

PMID: 21108485 [PubMed – as supplied by publisher]

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