23 24 25 2 26 ABSTRACT 27 28 Eosinophils are the prominent inflammatory cell involved in allergic asthma, atopic dermatitis, 29 eosinophilic esophagitis, and hypereosinophilic syndrome and are found in high numbers in local tissue 30 and/or circulating blood of affected patients. There is recent interest in a family of alarmins, including 31 TSLP, IL-25 and IL-33, that are epithelial-derived and released upon stimulation of epithelial cells. Several 32 genome wide association studies have found SNPs in genes encoding IL-33 to be risk factors for asthma. 33 In two studies examining the direct role of IL-33 in eosinophils, there were differences in eosinophil 34 responses. We sought to further characterize activation of eosinophils with IL-33 compared to activation 35 by other cytokines and chemokines. We assessed IL-33 stimulated adhesion, degranulation, chemotaxis 36 and cell surface protein expression in comparison to IL-3, IL-5, and eotaxin-1 on human eosinophils. Our 37 results demonstrate that IL-33 can produce as potent or more eosinophil activation than IL-3, IL-5 and 38 eotaxin-1. Thus, when considering specific cytokine targeting strategies, IL-33 will be important to 39 consider for modulating eosinophil function. 40 41 42 111 Mg 2 + and washed with 3 times with HBSS. Cells, 1x10 4 eosinophils, were added to each well along with 112 the respective cytokines (1ng/ml final concentration). After 30 min at 37°C, wells were washed 3x with 113 HBSS to remove non adherent cells. 100ul of HBSS was added to sample wells and 100ul with 1x10 4114 eosinophils were added to untreated wells to provide "Total" eosinophils for comparison. Eosinophil
Eosinophils are the prominent inflammatory cell involved in allergic asthma, atopic dermatitis, eosinophilic esophagitis, and hypereosinophilic syndrome and are found in high numbers in local tissue and/or circulating blood of affected patients. There is recent interest in a family of alarmins, including TSLP, IL-25 and IL-33, that are epithelial-derived and released upon stimulation of epithelial cells. Several genome wide association studies have found SNPs in genes encoding IL-33 to be risk factors for asthma. In two studies examining the direct role of IL-33 in eosinophils, there were differences in eosinophil responses. We sought to further characterize activation of eosinophils with IL-33 compared to activation by other cytokines and chemokines. We assessed IL-33 stimulated adhesion, degranulation, chemotaxis and cell surface protein expression in comparison to IL-3, IL-5, and eotaxin-1 on human eosinophils. Our results demonstrate that IL-33 can produce as potent eosinophil activation as IL-3, IL-5 and eotaxin-1. Thus, when considering specific cytokine targeting strategies, IL-33 will be important to consider for modulating eosinophil function.
RATIONALE: Hypereosinophilia is defined as a peripheral blood absolute eosinophil count (AEC) of >0.5 x10 9 /L, while severe hypereosinophilia is defined as an AEC of >1.5x10 9 /L. Much has been published on hypereosinphilia in the adult literature; however, there is limited literature on pediatric patients with hypereosinophilia (especially severe eosinophila) or hypereosinophilic syndrome (HES). The goal of this study was to characterize children with severe hypereosinophilia hospitalized in a tertiary care center. METHODS: We reviewed the charts of allergy/immunology consults performed from January 2013-April 2016 at Saint Louis Children's Hospital. Children were included in this study if their AEC was >1.5x10 9 at the time of the allergy/immunology consult. Data was collected on demographics, comorbidities, treatment, laboratory data, and clinical outcomes. Patients were sorted into diagnostic groups that included: overlap hypereosinophilic syndrome, allergic/atopy, hypereosinophilic syndrome myeloproliferative subtype, immunodeficiency, and unknown. RESULTS: We reviewed that chart of 289 inpatient consults and 13 met our inclusion criteria. Mean age at presentation was 19.5 months (range 1-49 months). Mean peak peripheral blood AEC was 5.5x10 9 /L (range 1800-12,524x10 9 /L). Four patients were found to have atopic driven eosinophilia, three with an underlying primary immunodeficiency, two with HES myeloproliferative variant, one with overlap HES. Four patients had an unknown etiology. Mortality in our cohort was 23%. CONCLUSIONS: Severe hypereosinophilia was the reason for 4.5% of inpatient Allergy/Immunology consults. A variety of reasons caused underlying eosinophilia. As many life threatening conditions were identified, prompt recognition of the underlying pathology is critical for proper treatment.
RATIONALE: Tissue tropism is one key to understanding the pathogenesis of SARS-CoV-2, the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. We characterized the protein expression of the essential SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), and the critical SARS-CoV-2 entry factor, transmembrane protease, serine 2 (TMPRSS2), in human aerodigestive and ocular tissues to gain insights into initial SARS-CoV-2-host interactions. METHODS: Immunofluorescent staining was simultaneously performed on tissue microarrays consisting of normal human head & neck tissues. Tissues from SARS-CoV-2-infected patients were collected during autopsy. Imaging was performed using confocal microscopy, and quantification of fluorescent intensity was done using a custom open-source software in ImageJ. RESULTS: ACE2 and TMPRSS2 protein expression localize to a variety of human airway, ocular, and oral epithelial surfaces, suggesting that SARS-CoV-2 has the capability to enter through all mucosal surfaces of the face. Notably, ACE2 and TMPRSS2 are both very highly expressed in the motile cilia of the nasal mucosa. Finally, SARS-CoV-2 Spike transcripts are readily detected in the nasal epithelia of SARS-CoV-2-infected patients. CONCLUSIONS: ACE2 & TMPRSS2 are expressed on nasal, ocular, and oral epithelial surfaces, and are notably present within the motile cilia of the airway. As breathing occurs primarily through the nasal passage, the dense motile cilia in the nasal epithelia are predicted to readily encounter SARS-CoV-2 during viral transmission and serve as a predominant initial/ early site of infection. Prophylaxes and therapeutics for COVID-19 should, therefore, focus on a nasal route of administration. Similarly, proper eye protection should be worn during certain circumstances
RATIONALE: Eosinophils have an important role in asthma pathogenesis and are able to secrete exosomes which play a role in asthma pathogenesis that has not been fully defined. We hypothesized that exosomes released by eosinophils contribute to asthma pathogenesis by activating structural lung cells. METHODS: Eosinophils were purified from peripheral blood of asthmatic and healthy volunteers, and exosomes were isolated . Epithelial damage was evaluated in small airway epithelial cells in the presence of exosomes by two types of apoptosis assays, through flow cytometry and TUNEL assay by confocal microscopy. Also, wound healing assays were performed. Other functional studies such as proliferation were also carried out in bronchial smooth muscle cells. Gene and protein expression of several factors and pro-inflammatory molecules was studied in both kinds of cells after co-culture with exosomes. RESULTS: Asthmatic eosinophil-derived exosomes induced an increase in epithelial-cell apoptosis that impeded wound closure at 24 h and 48 h. In addition, muscle-cell proliferation was increased at 72 h after exosome addition and was correlated with higher phosphorylation of ERK1/2. We also found higher expression of several genes when both cell types were cultured in the presence of asthmatic exosomes: CCR3 and VEGFA in muscle cells, and CCL26, TNF, and POSTN in epithelial cells. Healthy eosinophil-derived exosomes did not exert any effect over these cell types. CONCLUSIONS: Exosomes of eosinophils from asthmatic patients participate actively in the development of the pathological features of asthma via structural lung cells. Interventions targeting exosomes could represent a new therapeutic approach in asthma.
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