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Peter F. Weller - One of the best experts on this subject based on the ideXlab platform.
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Image_1_Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion.TIF
2019Co-Authors: Kelly G. Magalhães, Peter F. Weller, Tatiana Luna-gomes, Fabio Mesquita-santos, Rafael Corrêa, Leonardo Santos Assunção, Georgia Correa Atella, Christianne Bandeira-melo, Patricia T. BozzaAbstract:Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of Eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating Eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human Eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human Eosinophils. Our results showed that stimulation of human Eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human Eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of Eosinophil pre-formed TGFβ. We demonstrated that main Eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human Eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within Eosinophils, indicating that TLR2 mediates LPC-driven human Eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human Eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human Eosinophils acting on distinct Eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human Eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators.
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Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion
Frontiers Media S.A., 2019Co-Authors: Kelly G. Magalhães, Tatiana Luna-gomes, Fabio Mesquita-santos, Rafael Corrêa, Leonardo Santos Assunção, Georgia Correa Atella, Peter F. WellerAbstract:Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of Eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating Eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human Eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human Eosinophils. Our results showed that stimulation of human Eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human Eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of Eosinophil pre-formed TGFβ. We demonstrated that main Eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human Eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within Eosinophils, indicating that TLR2 mediates LPC-driven human Eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human Eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human Eosinophils acting on distinct Eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human Eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators
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vesicle mediated secretion of human Eosinophil granule derived major basic protein
Laboratory Investigation, 2009Co-Authors: Rossana C N Melo, Ann M. Dvorak, Lisa A Spencer, Sandra A C Perez, Josiane S Neves, Staci P Bafford, Ellen S Morgan, Peter F. WellerAbstract:Major basic protein (MBP), the predominant cationic protein of human Eosinophil specific granules, is stored within crystalloid cores of these granules. Secretion of MBP contributes to the immunopathogenesis of varied diseases. Prior electron microscopy (EM) of Eosinophils in sites of inflammation noted losses of granule cores in the absence of granule exocytosis and suggested that Eosinophil granule proteins might be released through piecemeal degranulation (PMD), a secretory process mediated by transport vesicles. Because release of Eosinophil granule-derived MBP through PMD has not been studied, we evaluated secretion of this cationic protein by human Eosinophils. Intracellular localizations of MBP were studied within nonstimulated and eotaxin-stimulated human Eosinophils by both immunofluorescence and a pre-embedding immunonanogold EM method that enables optimal epitope preservation and antigen access to membrane microdomains. In parallel, quantification of transport vesicles was assessed in Eosinophils from a patient with hyperEosinophilic syndrome (HES). Our data demonstrate vesicular trafficking of MBP within eotaxin-stimulated Eosinophils. Vesicular compartments, previously implicated in transport from granules to the plasma membrane, including large vesiculotubular carriers termed Eosinophil sombrero vesicles (EoSVs), were found to contain MBP. These secretory compartments were significantly increased in numbers within HES Eosinophils. Moreover, in addition to granule-stored MBP, even unstimulated Eosinophils contained appreciable amounts of MBP within secretory vesicles, as evidenced by immunonanogold EM and immunofluorescent colocalizations of MBP and CD63. These data suggest that Eosinophil MBP, with its multiple extracellular activities, can be mobilized from granules by PMD into secretory vesicles and both granule- and secretory vesicle-stored pools of MBP are available for agonist-elicited secretion of MBP from human Eosinophils. The recognition of PMD as a secretory process to release MBP is important to understand the pathological basis of allergic and other Eosinophil-associated inflammatory diseases.
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Activated human Eosinophils.
International archives of allergy and immunology, 2005Co-Authors: Rossana C N Melo, Peter F. Weller, Ann M. DvorakAbstract:Eosinophils are leukocytes which, when stimulated with cytokines or chemokines, become activated and release mediators stored in their dominant population of cytoplasmic granules (termed specific or secondary granules) [1]. The morphology of activated Eosinophils is quite distinct. In a range of inflammatory and allergic disorders or upon physiological stimulation, activated Eosinophils are generally seen as cells full of granules, but these structures are undergoing progressive losses of their contents with retention of granule outer membranes, a process known as ‘piecemeal degranulation’ [2, 3] (fig. 1a). As a result, a mixed population of intact (fig. 1a, asterisks) and enlarged, emptying (fig. 1a, arrows) granules is always visualized in cell sections [3]. Also, a decrease of specific granule numbers can occur [3]. A rare view of an activated Eosinophil is shown in figure 1b taken from a hyperEosinophilic subject. While a single specific granule (Gr) is seen in the cytoplasm in conjunction with an osmiophilic lipid body (LB), the cell surface shows elaborate projections indicative of activation. Vesiculotubular structures (fig. 1b, arrowheads), termed ‘Eosinophil sombrero vesicles’ (EoSV) and recently associated with the Eosinophil secretory pathway [4, 5] reside in the cytoplasm. This vesicle population is unique to Eosinophils and allows the prompt identification of these cells by electron microscopy when specific granules are not present [3]. Fig. 1 Different views of activated Eosinophils. a Eotaxin-stimulated Eosinophils show piecemeal degranulation (arrows). Intact granules are indicated by asterisks. b Eosinophil from a hyperEosinophilic subject. Arrowheads indicate Eosinophil sombrero vesicles. ... Shape changes are another hallmark of activated human Eosinophils. In parallel with the morphological alterations of specific granules, Eosinophils are able to change their morphology in response to different agonists. Figure 2 shows shape changes in Eosinophils stimulated by eotaxin, a potent Eosinophil activator. Fig. 2 Shape changes in eotaxin-activated Eosinophils. a The Eosinophil shows a narrow constriction at the midpoint of the cell. b The cell shows a broadened cytoplasmic area filled with granules and displaying broad surface processes. c Granule-free uropod ...
Gerald J. Gleich - One of the best experts on this subject based on the ideXlab platform.
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Extracellular Eosinophil Granule Protein Deposition in Ringed Esophagus with Sparse Eosinophils
Digestive diseases and sciences, 2015Co-Authors: Kathryn A. Peterson, William J. Cobell, Frederic Clayton, Chaya Krishnamurthy, Jian Ying, Leonard F. Pease, Hedieh Saffari, Ann Georgelas, John C. Fang, Gerald J. GleichAbstract:Background Eosinophilic esophagitis (EoE) remains difficult to classify because of varying presentations. Not uncommonly, patients present with symptoms of esophageal dysfunction and have esophageal changes on endoscopy resembling EoE but without[15 Eosinophils/HPF. Patients with low numbers of Eosinophils in esophageal biopsy specimens may have esophageal changes and symptomatic disease brought about by Eosinophil granule protein deposition without recognizable intact cells. Aim To determine whether extracellular Eosinophil granule protein deposition is present in the esophagi of patients with low Eosinophil numbers who have clinical symptoms and characteristic endoscopic esophageal changes of EoE including ringed esophagus (RE). Methods Esophageal biopsy specimens were studied from eight EoE patients with[15 Eosinophils per high power field (HPF) and nine patients with RE (\15 Eosinophils/HPF). The specimens were analyzed for Eosinophil granule proteins, major basic protein 1 (eMBP1) and Eosinophil-derived neurotoxin (EDN), by indirect immunofluorescence. Results Both EoE and RE showed positive EDN and eMBP1 extracellular deposition; control esophagus showed minimal or none. Comparing EoE and RE, extracellular EDN and eMBP1 were similar except that EDN in EoE was greater in the distal esophagus. Conclusions This study highlights the importance of assessing Eosinophil granule protein deposition in esophageal disease with potential Eosinophil involvement. Persistent/progressive esophageal changes may be brought about by Eosinophil granule proteins despite low numbers of intact cells. The meaning of ‘‘resolution’’ in EoE may need to be redefined based on numbers of esophageal Eosinophils, extracellular Eosinophil granule protein deposition, and subsequent clinical course of patients.
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Allergen-specific IgG1 and IgG3 through FcRIl Induce
2014Co-Authors: Eosinophil Degranulation, Gerald J. Gleich, Masayuki Kaneko, Mark C. Swanson, Hirohito KitaAbstract:Evidence suggests that Eosinophils contribute to inflammation in bronchial asthma by releasing chemical mediators and cytotoxic granule proteins. To investigate the mechanism of Eosinophil degranulation in asthma, we established an in vitro model of allergen-induced degranulation. We treated tissue culture plates with short ragweed pollen (SRW) extract and sera from either normal donors or SRW-sensitive patients with asthma. Eosinophils were incubated in the wells and degranulation was assessed by measurement of Eosinophil-derived neurotoxin in supernatants. We detected degranulation only when sera from SRW-sensitive patients were reacted with SRW. Anti-IgG and anti-FcRII mAb, but not anti-IgE or anti-FcRU mAb, abolished the degranulation. IgG-depleted serum did not induce degranulation; IgE-depleted serum triggered as much degranulation as untreated serum. Furthermore, serum levels of SRW-specific IgG1 or IgG3 correlated with the amounts of released Eosinophil-derived neurotoxin. When Eosinophils were cultured in wells coated with purified IgG or IgE, Eosinophil degranulation was observed only with IgG. Finally, human IgGl and IgG3, and less consistently IgG2, but not IgG4, induced degranulation. Thus, sera from patients with SRW-sensitive asthma induce Eosinophil degranulation in vitro through antigen-specific IgG1 and IgG3 antibodies. These antibodies may be responsible for degranulation of Eosinophils in inflammatory reactions, such as bronchial asthma. (J. Clin. Invest. 1995.95:2813-2821.) Key words: bronchial asthma. Eosinophils * immunoglobulin. allergen-degranulatio
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blood Eosinophil count is a useful biomarker to identify patients with severe Eosinophilic asthma
Annals of the American Thoracic Society, 2014Co-Authors: Lynn Katz, Gerald J. Gleich, Benjamin Hartley, Steven W Yancey, Hector OrtegaAbstract:Rationale: Measurement of sputum or blood Eosinophils may allow identification of a severe Eosinophilic asthma population responsive to mepolizumab.Objectives: The primary objective was assessment of a single blood Eosinophil measurement to predict future Eosinophil measurements in the following year versus using multiple blood Eosinophil measurements. In addition, we examined whether a single sputum or blood Eosinophil measurement was a useful biomarker for predicting treatment response to mepolizumab.Methods: Based on data from placebo subjects (n = 155), we determined whether a blood Eosinophil count of 150/μl or greater at screening remained on average above this level during the following year. The rate of exacerbation reduction in the sputum substudy population based on the screening blood Eosinophil count and sputum Eosinophils was evaluated.Measurements and Main Results: Of 115 patients with Eosinophils 150/μl or greater at screening, 98 (85%) remained above this level in their post-screening aver...
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Eosinophil major basic protein first identified natural heparanase inhibiting protein
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Vladislav Temkin, Gerald J. Gleich, Ilaria Puxeddu, Helena Aingorn, Orit Goldshmidt, Eyal Zcharia, Israel Vlodavsky, Francesca LevischafferAbstract:Abstract Background Heparanase and Eosinophils are involved in several diseases, including inflammation, cancer, and angiogenesis. Objective We sought to determine whether Eosinophils produce active heparanase. Methods Human peripheral blood Eosinophils were isolated by immunoselection and tested for heparanase protein (immunocytochemistry, Western blot), mRNA (RT-PCR) and activity (Na 2 [ 35 S]O 4 -labeled extracellular matrix degradation) before and after activation. Heparanase intracellular localization (confocal laser microscopy) and ability to bind to Eosinophil major basic protein (MBP) were also evaluated (immunoprecipitation). A model of allergic peritonitis resulting in Eosinophilia was induced in TNF knockout and wild-type mice for in vivo studies. Results Eosinophils synthesized heparanase mRNA and contained heparanase in the active (50-kd) and latent (65-kd) forms. Heparanase partially co-localized with and was bound to MBP. No heparanase enzymatic activity was detected in Eosinophils resting or activated with various agonists, including GM-CSF/C5a. Eosinophil lysates and MBP inhibited recombinant heparanase activity in a concentration-dependent manner (100%, 2×10 –7 mol/L). Eosinophil peroxidase and Eosinophil cationic protein, but not myelin basic protein or compound 48/80, partially inhibited heparanase activity. Poly-l-arginine at very high concentrations caused an almost complete inhibition. In allergic peritonitis, heparanase activity in the peritoneal fluid inversely correlated with Eosinophil number. Conclusions MBP is the first identified natural heparanase-inhibiting protein. Its presence in the Eosinophil granules might indicate a protective function of these cells in diseases associated with inflammation and cancer progression.
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Eosinophil granule proteins in peripheral blood granulocytes.
Journal of leukocyte biology, 1992Co-Authors: R Abu-ghazaleh, H Kita, David A. Loegering, S. L. Dunnette, James L. Checkel, L L Thomas, Gerald J. GleichAbstract:Eosinophils contain four principal cationic proteins, major basic protein (MBP), Eosinophil-derived neurotoxin (EDN), Eosinophil cationic protein (ECP), and Eosinophil peroxidase (EPO). To determine the quantities of these proteins in granulocytes and whether they are specific to Eosinophils, their concentrations in ly- sates of human granulocytes were measured using specific radioimmunoassays. The effect of different methods for Eosinophil lysis on the recovery of the proteins was also studied. Maximal recovery occurred at pH 2 for MBP and pH 5.6 for the other granule proteins. The proteins cosedimented with Eosinophils and their concentrations (X± SEM) in ng/106 Eosinophils (and in nM/106 eo- sinophils) were: MBP, 8,982 ± 611 (641.6); EDN, 3,283 ± 116 (178.4); ECP, 5,269 ± 283 (250.9); and EPO, 12,174 ± 859 (171.5). Basophils from a normal per- son contained (in ng/106 cells) MBP, 2,374; EDN, 214; ECP, 77; and EPO, 17. Highly purified neutrophils con- tamed (in ng/106 cells) MBP, 3 ± 0.5; EDN, 72 ± 9; and ECP, 50 ± 12. Therefore we conclude that these proteins are mainly expressed in Eosinophils, but that certain ones are present in basophils and neutrophils. J. Leukoc. Biol. 52: 611-618; 1992.
Marc E. Rothenberg - One of the best experts on this subject based on the ideXlab platform.
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Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies.
Annual review of immunology, 2021Co-Authors: Elizabeth A. Jacobsen, David J. Jackson, Enrico Heffler, Sameer K. Mathur, Albert J. Bredenoord, Ian D. Pavord, Praveen Akuthota, Florence Roufosse, Marc E. RothenbergAbstract:The enigmatic Eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating Eosinophils in vivo, initially in mice and more recently in humans. Eosinophil knockout mice have identified a contributory role for Eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of Eosinophils in Eosinophil-associated diseases, a series of anti-Eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete Eosinophils, provide a valuable opportunity to characterize the consequences of Eosinophil knockout humans. Herein, we comparatively describe mouse and human Eosinophil knockouts. We put forth the view that human Eosinophils negatively contribute to a variety of diseases and, unlike mouse Eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of Eosinophils remains an ongoing pursuit. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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targeting Eosinophils in allergy inflammation and beyond
Nature Reviews Drug Discovery, 2013Co-Authors: Patricia C. Fulkerson, Marc E. RothenbergAbstract:Eosinophils can regulate local immune and inflammatory responses, and their accumulation in the blood and tissue is associated with several inflammatory and infectious diseases. Thus, therapies that target Eosinophils may help control diverse diseases, including atopic disorders such as asthma and allergy, as well as diseases that are not primarily associated with Eosinophils, such as autoimmunity and malignancy. Eosinophil-targeted therapeutic agents that are aimed at blocking specific steps involved in Eosinophil development, migration and activation have recently entered clinical testing and have produced encouraging results and insights into the role of Eosinophils. In this Review, we describe recent advances in the development of first-generation Eosinophil-targeted therapies and highlight strategies for using personalized medicine to treat Eosinophilic disorders.
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Eosinophils biological properties and role in health and disease
Clinical & Experimental Allergy, 2008Co-Authors: Simon P. Hogan, Helene F Rosenberg, R Moqbel, Simon Phipps, Paul S Foster, Paige Lacy, Barry A Kay, Marc E. RothenbergAbstract:Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of Eosinophils is summarized, focusing on transcriptional regulation of Eosinophil differentiation, characterization of the growing properties of Eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of Eosinophil degranulation. New views on the role of Eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in Eosinophil-mediated mucosal diseases are conceptualized.
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a central regulatory role for Eosinophils and the eotaxin ccr3 axis in chronic experimental allergic airway inflammation
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Patricia C. Fulkerson, Simon P. Hogan, Christine A Fischetti, Melissa Mcbride, Lynn M Hassman, Marc E. RothenbergAbstract:To clarify the role and regulation of Eosinophils, we subjected several key Eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in Eosinophil development (Δdbl-GATA) and Eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1/2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced Eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1/2 double knockout, CCR3 knockout, and Δdbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of Eosinophil- and CCR3-deficient mice. The absence of Eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was Eosinophil- and CCR3-dependent; pathways downstream from Eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that Eosinophils via CCR3 have a central role in chronic allergic airway disease.
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The alpha4bbeta7-integrin is dynamically expressed on murine Eosinophils and involved in Eosinophil trafficking to the intestine.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2006Co-Authors: Eric B. Brandt, Yoshiyuki Yamada, Nives Zimmermann, Emily E. Muntel, Samuel M. Pope, Anil Mishra, Simon P. Hogan, Marc E. RothenbergAbstract:BACKGROUND Of the numerous adhesion molecules expressed by Eosinophils, the alpha4-integrin has been identified as critically involved in Eosinophil trafficking in the lung. Most studies have focused on the role of the alpha4beta1-adhesion complex, but Eosinophils also express the alpha4beta7-integrin complex. OBJECTIVE To investigate the role of alpha4beta7, by assessing its membrane expression on Eosinophils from different compartments using allergen-challenged mice and IL-4/IL-5 bi-transgenic mice. In addition, we aim to determine the impact of beta7-integrin deficiency on Eosinophil recruitment to the lungs and intestine in specific experimental allergic models. RESULTS Evaluation of alpha4beta7 expression on bronchoalveolar lavage fluid (BALF) and lung tissue Eosinophils revealed a down-regulation of this integrin as Eosinophils migrate through the lungs. Indeed Eosinophils isolated from the BALF and lung of allergic mice had low expression of the alpha4beta7-complex. While expression of the alpha4-chain remained unchanged, a significant decrease in beta7-surface expression was observed. Intestinal Eosinophils, isolated from Peyer's patches, also displayed a down-regulation of the alpha4beta7-integrin, albeit only modest. In contrast, circulating Eosinophils, isolated from the blood and spleen, expressed high levels of the alpha4beta7-integrin. However, Eosinophil trafficking into the lungs of beta7-integrin-deficient mice was not significantly impaired in response to respiratory allergen challenges. In contrast, beta7-deficient mice had impaired Eosinophil recruitment to the intestine. CONCLUSION Taken together, these results identify differential expression of the alpha4beta7-integrin on Eosinophils and its critical role in regulating Eosinophil responses in the intestine.
Hirohito Kita - One of the best experts on this subject based on the ideXlab platform.
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Allergen-specific IgG1 and IgG3 through FcRIl Induce
2014Co-Authors: Eosinophil Degranulation, Gerald J. Gleich, Masayuki Kaneko, Mark C. Swanson, Hirohito KitaAbstract:Evidence suggests that Eosinophils contribute to inflammation in bronchial asthma by releasing chemical mediators and cytotoxic granule proteins. To investigate the mechanism of Eosinophil degranulation in asthma, we established an in vitro model of allergen-induced degranulation. We treated tissue culture plates with short ragweed pollen (SRW) extract and sera from either normal donors or SRW-sensitive patients with asthma. Eosinophils were incubated in the wells and degranulation was assessed by measurement of Eosinophil-derived neurotoxin in supernatants. We detected degranulation only when sera from SRW-sensitive patients were reacted with SRW. Anti-IgG and anti-FcRII mAb, but not anti-IgE or anti-FcRU mAb, abolished the degranulation. IgG-depleted serum did not induce degranulation; IgE-depleted serum triggered as much degranulation as untreated serum. Furthermore, serum levels of SRW-specific IgG1 or IgG3 correlated with the amounts of released Eosinophil-derived neurotoxin. When Eosinophils were cultured in wells coated with purified IgG or IgE, Eosinophil degranulation was observed only with IgG. Finally, human IgGl and IgG3, and less consistently IgG2, but not IgG4, induced degranulation. Thus, sera from patients with SRW-sensitive asthma induce Eosinophil degranulation in vitro through antigen-specific IgG1 and IgG3 antibodies. These antibodies may be responsible for degranulation of Eosinophils in inflammatory reactions, such as bronchial asthma. (J. Clin. Invest. 1995.95:2813-2821.) Key words: bronchial asthma. Eosinophils * immunoglobulin. allergen-degranulatio
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a novel il 1 family cytokine il 33 potently activates human Eosinophils
The Journal of Allergy and Clinical Immunology, 2008Co-Authors: Brett W Cherry, Juhan Yoon, Kathleen R Bartemes, Koji Iijima, Hirohito KitaAbstract:Background Eosinophils are likely key cells involved in the pathogenesis of asthma and allergic diseases; however, the mechanisms that regulate Eosinophil dynamics and functions in mucosal tissues are incompletely understood. IL-33, which is produced by mucosal cells, is a new member of the IL-1 cytokine family. Mice injected with IL-33 display profound mucosal Eosinophilia with associated pathologic changes. Although mast cells and T H 2 cells express the IL-33 receptor, ST2, the roles of IL-33 and ST2 in Eosinophil biology are unknown. Objectives We investigated the effects of IL-33 on human Eosinophils in vitro . Methods Eosinophils and neutrophils were isolated from blood of normal individuals and mildly atopic patients. Real-time RT-PCR and flow cytometry were used to detect ST2. Granulocyte responses to IL-33 were monitored by superoxide anion production and by degranulation; IL-5, IL-1β, and TNF-α served as controls. Eosinophil survival and cytokine production were assessed by flow cytometry and ELISA, respectively. Results ST2 mRNA and protein were detected on Eosinophils. IL-33 induced Eosinophil superoxide anion production and degranulation as potently as IL-5. IL-33 also increased Eosinophil survival and induced production of IL-8. Anti-ST2 inhibited Eosinophil responses to IL-33. Neutrophils did not express ST2, nor did they respond to IL-33. Conclusion IL-33 and its receptor, ST2, may play important roles in Eosinophil-mediated inflammation; they may provide new therapeutic targets for controlling mucosal Eosinophilic inflammation.
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The chemotactic behavior of Eosinophils in patients with chronic rhinosinusitis
The Laryngoscope, 2003Co-Authors: Julie L. Wei, Hirohito Kita, David A. Sherris, Eugene B. Kern, Amy L. Weaver, Jens U. PonikauAbstract:Objective: To characterize peripheral Eosinophil migration in patients with chronic rhinosinusitis in the presence of nasal mucin and nasal tissue extracts. Study Design: Prospective, controlled, ex-vivo. Methods: Peripheral blood Eosinophils, nasal mucin, and nasal tissue were harvested at the time of sinus surgery in 10 patients, as well as obtained in 10 healthy control subjects. Extracts were prepared from nasal mucin and nasal tissue. A modified Boyden chamber was used to study Eosinophil migration from both patients and healthy control subjects in the presence of both extracts. Results: Patients with chronic rhinosinusitis and all healthy control subjects demonstrated a concentration-dependent increased migration of Eosinophils in the presence of both nasal mucin and nasal tissue extracts. The percentage of migration was consistently higher for Eosinophils from patients with chronic rhinosinusitis compared with control subjects. The difference attained statistical significance in the presence of 50% tissue extract (median percentage of migration, 23.3% vs. 7.8% [P = .033]). Conclusions: Nasal mucin and nasal tissue in chronic rhinosinusitis contains chemoattractants, which can induce active Eosinophil migration. The Eosinophil migration from patients with chronic rhinosinusitis was consistently higher compared with Eosinophils from healthy control subjects. Because the Eosinophils were obtained from the peripheral blood, this finding suggests activation of Eosinophils in the systemic circulation in chronic rhinosinusitis.
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Eosinophil Signal Transduction
1998Co-Authors: Hirohito KitaAbstract:Eosinophils are important effector cells in host defense against parasites, in allergic diseases such as bronchial asthma and atopic dermatitis, and in diseases associated with Eosinophilia (1,2). The Eosinophil is an important source of cytotoxic proteins, lipid mediators, and oxygen metabolites, which have the potential to induce pathology in disease. However, little is known about the mechanisms coupling receptors and effector functions of Eosinophils. Studies in Eosinophils have been hampered because Eosinophils represent only a small fraction of peripheral white blood cells, and the isolation of large numbers of cells for biochemical studies has been difficult. However, recent advances in procedures have enabled us to isolate Eosinophils from normal individuals with high purity and reasonable recovery. Furthermore, techniques have become available to analyze intracellular events at a single-cell level. This chapter will review recent advances in the studies of Eosinophil signal transduction, in the hope of finding ways to modulate Eosinophil activation therapeutically in patients with Eosinophil-associated diseases.
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Effect of steroids on immunoglobulin-induced Eosinophil degranulation.
Journal of Allergy and Clinical Immunology, 1991Co-Authors: Hirohito Kita, R Abu-ghazaleh, C J Sanderson, Gerald J. GleichAbstract:Abstract Because glucocorticoids are a mainstay in the treatment of asthma and other allergic diseases, we tested the effect of various steroid hormones on secretory IgA- and IgG-induced Eosinophil degranulation in vitro. Human normodense Eosinophils were purified by discontinuous Percoll density gradient, and hypodense Eosinophils were obtained by culture of normodense cells with recombinant human interleukin (rIL)-5. Eosinophils were incubated with various steroids, including dexamethasone, hydrocortisone, methylprednisolone, estradiol, or dihydrotestosterone at concentrations from 10 −9 to 10 −4 mol/L. Sepharose 4B beads coupled to ovalbumin, secretory IgA, or IgG were added as targets of degranulation and incubated at 37 ° C for 4 hours. In some experiments, rIL-5 was added to Eosinophils before addition of beads to activate the cells. The release of Eosinophil-derived neurotoxin was measured by radioimmunoassay as an index of degranulation. Dexamethasone (10 −9 to 10 −4 mol/L), hydrocortisone (10 −9 to 10 −4 mol/L), estradiol (10 −9 to 10 −7 mol/L), and dihydrotestosterone (10 −9 to 10 −4 mol/L) had no effect on normodense Eosinophil degranulation. Methylprednisolone, 10 −5 mol/L, inhibited degranulation of normodense Eosinophils up to 20%, whereas 10 −4 mol/L inhibited degranulation of hypodense Eosinophils, up to 30%, Overall, no difference in inhibition by steroids was observed between normodense and hypodense Eosinophils. rIL-5 enhanced immunoglobulin-induced Eosinophil degranulation, but this effect of rIL-5 was not blocked by any of the steroids tested. These results suggest that Eosinophil degranulation and rIL-5-mediated Eosinophil activation are not direct targets of glucocorticoids and that the beneficial effects of glucocorticoids on allergic inflammation in vivo are not likely due to direct effects on Eosinophil degranulation.
Paul M Obyrne - One of the best experts on this subject based on the ideXlab platform.
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effects of allergen challenge on Eosinophils Eosinophil cationic protein and granulocyte macrophage colony stimulating factor in mild asthma
American Journal of Respiratory and Critical Care Medicine, 1995Co-Authors: K L Woolley, E Adelroth, M J Woolley, Russ Ellis, Manel Jordana, Paul M ObyrneAbstract:Allergen inhalation challenge is associated with increases in Eosinophil number and activation, and provides a useful model for investigating airway inflammation in asthma. Limited information, however, is available on the effect of allergen challenge on cytokines regulating Eosinophil function. We investigated allergen-induced changes in Eosinophil number and activation and in granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine known to regulate Eosinophil function in vitro. Seven subjects with mild atopic asthma and late asthmatic responses completed diluent- and allergen-inhalation challenges. Blood, bronchoalveolar lavage fluid (BALF), and biopsy samples were collected 24 h after challenge. Allergen inhalation caused a significant increase in Eosinophils in BALF and biopsy samples. Eosinophil activation, as assessed by secretion of Eosinophil cationic protein, and GM-CSF levels were significantly increased in BALF and bronchoalveolar lavage (BAL) cells. Allergen inhalation did not cause a significant change in Eosinophil activation in biopsy tissue but did result in a significant decrease in GM-CSF in the tissue. Significant correlations were shown between the concentration of GM-CSF in BALF and the percentage of BAL Eosinophils (Rs = 0.75, p = 0.05), severity of the late asthmatic response, and number of BAL Eosinophils (Rs = 0.82, p = 0.02). A trend was seen between the late response and the concentration of GM-CSF in BALF. These results are consistent with the hypothesis that Eosinophils, regulated by GM-CSF, contribute to allergen-induced decreases in airway function.
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granulocyte macrophage colony stimulating factor Eosinophils and Eosinophil cationic protein in subjects with and without mild stable atopic asthma
European Respiratory Journal, 1994Co-Authors: K L Woolley, E Adelroth, M J Woolley, Russ Ellis, Manel Jordana, Paul M ObyrneAbstract:Increasing evidence implicates the Eosinophil as an important effector cell in asthma, but little is known regarding its regulation in vivo. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to regulate Eosinophil function in vitro. We investigated the in vivo role of Eosinophils and GM-CSF in mild asthma. We compared the number and function of Eosinophils and the presence of GM-CSF in blood, bronchoalveolar lavage (BAL) and biopsy tissue obtained from eight mild, stable, atopic asthmatics and 10 nonasthmatics, five of whom were atopic and five nonatopic. Eosinophils were significantly increased in the blood, BAL and biopsy tissue from asthmatics. Activated Eosinophils, assessed by immunostaining for the secreted form of Eosinophil cationic protein (EG2), were also increased in asthmatic BAL cells and biopsy tissue. Significant increases in GM-CSF in BAL cells and biopsy tissue from asthmatics were also evident. Significant positive correlations existed between GM-CSF in BAL and EG2, and GM-CSF in biopsy tissue and BAL and biopsy Eosinophils. Airway responsiveness was also significantly positively correlated with Eosinophil number and activation, and with GM-CSF. These results demonstrate that there are increased numbers of activated Eosinophils and GM-CSF is increased in patients with mild asthma. Furthermore, GM-CSF is correlated with Eosinophil number and function in vivo and these indices are significantly correlated with airway function. These findings emphasize the importance of Eosinophils, potentially regulated in vivo by GM-CSF, in contributing to the disordered airway function evident even in mild asthma.