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[ "Chronic rhinosinusitis (CRS) is a heterogeneous disease with an uncertain pathogenesis. Group 2 innate lymphoid cells (ILC2s) represent a recently discovered cell population which has been implicated in driving Th2 inflammation in CRS; however, their relationship with clinical disease characteristics has yet to be investigated. The aim of this study was to identify ILC2s in sinus mucosa in patients with CRS and controls and compare ILC2s across characteristics of disease. A cross-sectional study of patients with CRS undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies were obtained during surgery and control tissue from patients undergoing pituitary tumour resection through transphenoidal approach. ILC2s were identified as CD45(+) Lin(-) CD127(+) CD4(-) CD8(-) CRTH2(CD294)(+) CD161(+) cells in single cell suspensions through flow cytometry. ILC2 frequencies, measured as a percentage of CD45(+) cells, were compared across CRS phenotype, endotype, inflammatory CRS subtype and other disease characteristics including blood eosinophils, serum IgE, asthma status and nasal symptom score. 35 patients (40% female, age 48 ± 17 years) including 13 with eosinophilic CRS (eCRS), 13 with non-eCRS and 9 controls were recruited. ILC2 frequencies were associated with the presence of nasal polyps (P = 0.002) as well as high tissue eosinophilia (P = 0.004) and eosinophil-dominant CRS (P = 0.001) (Mann-Whitney U). They were also associated with increased blood eosinophilia (P = 0.005). There were no significant associations found between ILC2s and serum total IgE and allergic disease. In the CRS with nasal polyps (CRSwNP) population, ILC2s were increased in patients with co-existing asthma (P = 0.03). ILC2s were also correlated with worsening nasal symptom score in CRS (P = 0.04).", "yes. As ILC2s are elevated in patients with CRSwNP, they may drive nasal polyp formation in CRS. ILC2s are also linked with high tissue and blood eosinophilia and have a potential role in the activation and survival of eosinophils during the Th2 immune response. The association of innate lymphoid cells in CRS provides insights into its pathogenesis." ]

[ "yes. Our results indicate that both Th2 and Th17 lineages are involved in the pathogenesis of CSS, while CCR4-active chemokines contribute to eosinophilia in the active disease. These phenomena are down regulated by immunosuppressive therapy.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) or without nasal polyps (CRSsNP) is associated with expression of various cytokines. Suppressors of cytokine signaling (SOCS) regulate cytokine activity in a variety of cells, modulating inflammatory responses. We analyzed the expression and distribution pattern of SOCS1 and SOCS3 in CRSwNP and CRSsNP, and their cytokine-driven expression regulation in sinus mucosa. In addition, the expression levels of various cytokines were evaluated in CRSwNP and CRSsNP. The expression levels of SOCS1 and SOCS3 in CRSwNP and CRSsNP and in control samples were assessed by using real-time PCR, Western blot, and immunohistochemistry. Nasal epithelial cell culture was used to elucidate the effect of IL-4, IL-5, IL-6, IL-10, IL-13, IFN-γ, TNF-α, and TGF-β1 on SOCS1 and SOCS3 expression in sinus mucosa. The expression levels of these cytokines were also evaluated in normal and inflammatory sinus mucosa by using real-time PCR and Western blot. The expression levels of SOCS1 and SOCS3 were increased in CRS, irrespective of the presence of nasal polyp, and they were distributed in superficial epithelium, submucosal glands, and vascular endothelium in sinus mucosa. SOCS1 was induced by IL-4, IL-13, IFN-γ, and TNF-α, while SOCS3 expression was upregulated by IL-6, IL-13, IFN-γ, and TNF-α. IL-4 and IL-13 levels were increased in CRSwNP, while IL-4, IFN-γ, TNF-α, and TGF-β1 levels were increased in CRSsNP.", "Influx of inflammatory cells is one of the hallmarks of nasal polyposis. As glucocorticoids (GC) are known to exhibit strong anti-inflammatory effects, these drugs are frequently used in the treatment of the disease. Part of the anti-inflammatory effects of GC is attributed to their interference with prostanoid synthesis. As cyclooxygenases (COX) are key enzymes in the synthesis of both pro- (COX-1, COX-2) and anti-inflammatory prostanoids (COX-2), we investigated the role of topical GC on COX-1, COX-2 and inflammatory markers in nasal polyps (NP). Immunohistochemical analysis of inflammatory markers (CD68, CD117, MBP, elastase, IgE, BB-1, IL-4, IL-5 and IL-6), COX-1 and COX-2 was performed on normal nasal mucosa (NM) (n = 18), non-GC treated NP (n = 27) and topical GC treated NP (n = 12). NP groups were matched for allergy, asthma and ASA intolerance. Increased numbers of eosinophils, IL-5+ cells and IgE+ cells and decreased numbers of mastcells are striking features of NP inflammation (P < 0.05). In addition, increased numbers of COX-1+ cells are observed in NP epithelium compared to NM (P < 0.05).", "Pilot study examining toll-like receptor 9 (TLR9) expression by sinonasal epithelial cells in allergic rhinitis (AR) subjects with and without a history of recurrent acute rhinosinusitis (RARS). Cohort study. Outpatient clinic. Adult subjects were eligible for study if skin tested positive for inhalant allergens, and positive allergens were in season at time of study. Subjects were considered to have AR+RARS if they had four symptomatic episodes with major/minor factors in 12 months and CT evidence of sinusitis. Eight AR-only subjects and 13 AR+RARS subjects underwent endoscopic-guided cell brushing from the middle meatus. Flow cytometry for TLR9 expression was performed on collected fresh sinonasal epithelial cells. The AR+RARS group was found to have a significant increase in TLR9 expression in the sinonasal epithelium (66% +/- 30%) compared with that of AR-only patients (32% +/- 21%; P = 0.011).", "yes. Our results suggest that TSLP-mediated activation of human nasal mucosal CD1c(+) DCs triggers CCR7-dependent migration to the draining lymph nodes and enhances their capacity to initiate TH2 responses. However, the observation that TH2 cytokines abrogate the induction of CCR7 implies that during a TH2-mediated inflammatory reaction, TLSP-activated CD1c(+) DCs are retained in the inflamed tissue to further exacerbate local inflammation by activating local antigen-specific memory TH2 cells.", "Epidemiologic and clinical observations identify obesity as an important risk factor for asthma exacerbation, but the underlying mechanisms remain poorly understood. Type 2 innate lymphoid cells (ILC2s) and type 3 innate lymphoid cells (ILC3s) have been implicated, respectively, in asthma and adipose tissue homeostasis and in obesity-associated airway hyperresponsiveness (AHR). We sought to determine the potential involvement of innate lymphoid cells (ILCs) in allergic airway disease exacerbation caused by high-fat diet (HFD)-induced obesity. Obesity was induced by means of HFD feeding, and allergic airway inflammation was subsequently induced by means of intranasal administration of house dust mite (HDM) extract. AHR, lung and visceral adipose tissue inflammation, humoral response, cytokines, and innate and adaptive lymphoid populations were analyzed in the presence or absence of ILCs. HFD feeding exacerbated allergic airway disease features, including humoral response, airway and tissue eosinophilia, AHR, and T", "Innate lymphoid cells (ILCs) play important roles in innate immunity and tissue remodeling via production of various cytokines and growth factors. Group 2 ILCs (ILC2s) were recently shown to mediate the immune pathology of asthma even without adaptive immunity. However, little is known about possible interactions between ILC2s and other immune cells. We sought to investigate the capacity of ILC2s to regulate effector functions of T cells. We isolated ILC2s from the lungs of naïve mice. We cultured CD4(+) T cells with ILC2s in vitro and examined the functions of these cell types. The mechanisms were investigated using blocking antibodies and cells isolated from cytokine-deficient mice. For the in vivo study, we adoptively transferred ILC2s and CD4(+) T cells into Il7ra(-/-) mice and subsequently exposed the mice to ovalbumin and a cysteine protease. Lung ILC2s enhanced CD4(+) T-cell proliferation and promoted production of type 2 cytokines in vitro. The interaction between ILC2s and CD4(+) T cells involved costimulatory molecule OX40L and cytokine IL-4, which was mainly derived from ILC2s. Adoptive transfer of both ILC2 and CD4(+) T-cell populations, but not each population alone, into Il7ra(-/-) mice resulted in induction of a robust antigen-specific type 2 cytokine response and airway inflammation.", "yes. These findings suggest that the IL-13 polymorphisms at -1510A>C and 1055C>T are associated with the development of rhinosinusitis in AIA patients. IL-13 Arg110Gln may be associated with an increased eosinophil count and eotaxin-1 level and could increase eosinophilic inflammation in the upper and lower airways of patients with AIA.", "Nasal polyps (NPs) are characterized by eosinophilic inflammation and often coexist with asthma. However, the role of atopy and IgE in NP pathogenesis is unclear. We sought to determine whether there is an association between total and specific IgE to a variety of allergens in polyp and nonpolyp tissue and markers of eosinophilic inflammation or skin test results. Homogenates were prepared from nasal tissue of 20 patients with NPs and 20 patients without NPs and analyzed for concentrations of IL-5, IL-4, eotaxin, leukotriene (LT) C4/D4/E4, sCD23, and histamine (ELISA). Eosinophil cationic protein (ECP), tryptase, and total and specific IgE for inhalant allergens and Staphylococcus aureus enterotoxins were measured (ImmunoCAP). The concentrations of total IgE, IL-5, eotaxin, ECP, LTC4/D4/E4, and sCD23 were significantly higher in NP tissue compared with nonpolyp tissue. Total IgE was significantly correlated to IL-5, ECP, LTC4/D4/E4, and sCD23 and to the number of eosinophils in NPs. On the basis of the presence of specific IgE antibodies in tissue, 3 NP groups were defined. NP group 1 demonstrated no measurable specific IgE, and NP group 2 selected specific IgE. The third group demonstrated a multiclonal specific IgE, including IgE to S aureus enterotoxins, a high total IgE level, and a high prevalence of asthma.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL-1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. The objective of this study was to investigate the role of TSLP in patients with CRS. We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity.", "Eosinophilic pleural effusion (EPE) is characterized by greater than 10% eosinophilia and is frequently associated with air and/or blood in the pleural cavity. Primary spontaneous pneumothorax (PSP), defined as the spontaneous presence of air in the pleural space, is one of the most common causes of EPE. Recent studies have shown that type 2 immune responses play important roles in eosinophilic airway inflammation resulting in pleural pathology. To determine the predominant immune responses associated with PSP in humans, and to examine whether IL-33, thymic stromal lymphopoietin (TSLP), or type 2 innate lymphoid cell (ILC2)-mediated immune responses are associated factors. Eosinophil-associated cytokines were measured in the pleural fluid of patients with PSP and control subjects. Th2 cell and ILC2 responses in the pleural cavity and peripheral blood were also evaluated by in vitro restimulation and intracellular cytokine staining of T cells and ILC2s in patients with PSP (n = 62) and control subjects (n = 33). IL-33-mediated IL-5 production by ILC2s was also evaluated. Significantly higher concentrations of IL-5 and eotaxin-3 were detected in the pleural fluid of patients with PSP, in addition to significantly higher concentrations of IL-33 and TSLP. Although IL-5 production was induced by IL-33 treatment of ILC2s, other Th2 cell-mediated immune responses were not detected.", "Cystic fibrosis (CF) patients frequently suffer from chronic rhinosinusitis (CRS). The extent to which alterations in sinonasal innate immunity contribute to this disease process is unknown. Activation of sinonasal epithelial cell (SNEC) Toll-like receptors (TLRs), an important component of the innate immune system, may be associated with the hyperinflammatory state observed in sinonasal mucosa of CF patients with CRS. This study compares expression of Toll-like receptor 9 (TLR9), in SNRCs collected from CF subjects with CRS to that of normal control subjects. This was a prospective study measuring TLR9 on SNECs collected via endoscopic-guided middle meatal brushings from 8 adult controls and 14 adult subjects with CF-associated CRS. TLR9 expression was significantly elevated in CF subjects at 91% ± 6% when compared with 76% ± 10% in normal controls (p = 0.001).", "Nasal polyps often are associated with asthma. The phenotype of these patients is unknown. To identify the mucosal factors associated with asthma comorbidity, we analyzed the inflammatory patterns of nasal polyps. Nasal polyps from 70 Belgian patients, 34% with asthma, were analyzed for type of inflammation, T-cell cytokines, and IgE antibodies to Staphylococcus aureus enterotoxins. The same investigations were repeated in 93 Chinese patients with polyps, a group with a low asthma comorbidity rate (8%). In Belgian patients with polyps, 54% of samples showed eosinophilic inflammation. A classification tree evaluation identified IL-5 as the main positive determinant. Enterotoxin IgE in tissue (37%) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. Expression of enterotoxin IgE, total IgE at greater than 1,442 kU/L, and eosinophil cationic protein at greater than 17,109 μg/L in samples with a total IgE concentration of greater than 246 kU/L significantly predicted asthma (odds ratio, 5.8-13). Only 7.5% of the samples from Chinese patients with polyps showed eosinophilic inflammation. IL-5 was confirmed as a positive determinant of eosinophilic inflammation, and enterotoxin IgE in tissue (17% of patients) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. The expression of IL-5 or total IgE at greater than 790 kU/L in samples with an IL-5 concentration of greater than 194 pg/mL significantly predicted comorbid asthma (odds ratio, 17.2-96).", "yes. These data demonstrate that VEGF is a novel biomarker for chronic rhinosinusitis with hyperplastic sinonasal polyposis that functions in an autocrine feed-forward manner to promote nasal epithelial cell growth and to inhibit apoptosis. These findings implicate a previously unrecognized and novel role of VEGF functioning through neuropilin-1 on nonneoplastic primary human airway epithelial cells, to amplify cell growth, contributing to exuberant hyperplastic polyposis.", "yes. Children with chronic sinusitis have predominance of CD4+ cells in the sinus mucosa as compared with normal sphenoid tissue. This contrasts with published results in adults with chromic sinusitis, in whom CD8+ cells predominate in nasal polyps and the submucosa, possibly reflecting a difference in the immunologic response of children and adults.", "T-helper 2 (Th2) inflammation is a hallmark of chronic rhinosinusitis with nasal polyps (CRSwNP) although the pathogenesis is poorly understood. P-glycoprotein (permeability glycoprotein, P-gp) is an efflux pump that is capable of regulating cytokine transport and is expressed within sinonasal mucosa. The purpose of this study was to examine if the oversecretion of interleukin 5 (IL-5) and thymic stromal lymphopoietin (TSLP) in CRSwNP could be explained through P-gp-mediated secretory pathways. Fifteen ethmoid mucosal explants were harvested from patients with CRS (n = 10) and CRSwNP (n = 10) and stimulated with Staphylococcus aureus enterotoxin B (SEB). P-gp was inhibited using zosuquidar trihydrochloride (herein Zosuquidar). P-gp expression was measured using real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-5, IL-8, and TSLP secretion were quantified using ELISA. P-gp protein was overexpressed in CRSwNP (28.32 ± 25.94 ng/mL per mg explant) as compared to CRS (10.74 ± 8.61; p = 0.01, 2-tailed Mann-Whitney U test). There was no difference in messenger RNA (mRNA) expression. SEB induced a significant increase in IL-5 and TSLP but not IL-8 secretion relative to control in the CRSwNP explants only. Subsequent P-gp inhibition significantly reduced IL-5 and TSLP secretion (p = 0.04 for both, 2-tailed Student t test) to control levels. The concentration of IL-5 and TSLP secretion were strongly and significantly correlated to the concentration of P-gp within the same explant (IL-5: r = 0.791, p = 0.001; TSLP: r = 0.687, p = 0.003; 2-tailed Spearman's rank-order correlation).", "Data support the concept that nasal polyp lymphocyte subpopulations may be derived from both the local mucosal immune system as well as from random migration of peripheral blood lymphocytes secondary to adhesion molecules and chemokines, which are known to be present in nasal polyps.", "yes. Distinct T-helper and T-helper-like innate lymphoid cell (ILC) subsets are associated with different lesion topography in RRMS.", "Chronic rhinosinusitis (CRS) is characterized by a dysfunctional host-environment interaction at the nasal mucosa. Contributions of host susceptibility factors such as atopy and aspirin sensitivity to CRS pathophysiology are well established. However, clinical studies on the effects of environmental factors are limited. This study investigates the histological and immunological effects of allergen exposure duration in animal models. Animal study. A murine model for CRS with nasal polypoid lesions was induced by instilling ovalbumin/staphylococcal enterotoxin B (SEB) into murine nasal cavities for 12 (short term) or 24 weeks (long term). Histopathological changes were observed. Interleukin (IL)-4, IL-17A, IL-10, and interferon (INF)-γ levels from nasal lavage fluid were measured using enzyme-linked immunosorbent assay. Gene expressions of IL-25, thymic stromal lymphopoietin (TSLP), IL-4, IL-5, INF-γ, C-C motif chemokine ligand (CCL)-11, CCL-24, C-X-C motif chemokine ligand (CXCL)-1, CXCL-2, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, matrix metallopeptidase (MMP)-7, and tissue inhibitor of metalloproteinase (TIMP)-3 were analyzed from the nasal mucosa. Long-term CRS models exhibited increased polypoid lesions, edematous mucosal thickness, and eosinophil infiltration compared with short-term models and showed a higher IL-10 level but lower IFN-γ and IL-17A protein levels. Moreover, CCL-24 and MMP-7 gene expressions increased whereas TIMP-3 expression decreased in long-term models compared to controls and short-term models. IL-25 and TSLP expressions were upregulated at mRNA and protein levels in short-term and long-term CRS models, respectively. Furthermore, TSLP mRNA expression was positively associated with IL-5 (r = 0.8754) and inversely correlated to IFN-γ (r = -0.7212) in CRS models.", "yes. We revealed high levels of CCL24 in all patient groups showing a significant correlation with the degree of eosinophilia and clinical symptoms. A prolonged accumulation of CCL24 inside the nasal mucosa may sustain the process of unspecific self-perpetuating eosinophil recruitment pathognomonic of these patients.", "yes. Expression of multiple innate immune genes by HSNEC is reduced in CRSwNP. One mechanism appears to be a direct effect of the leukocyte-derived Th2 cytokines present in the sinonasal mucosa in CRSwNP. Impaired mucosal innate immunity may contribute to microbial colonization and abnormal immune responses associated with CRSwNP.", "Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness in association with airway inflammation under the influence of T(H)2 cytokines. Eosinophilic bronchitis has similar immunopathology to asthma but without disordered airway physiology. Whether eosinophilic bronchitis is associated with increased expression of T(H)2 cytokines is unknown. We sought to assess the expression of T(H)2 cytokines in eosinophilic bronchitis. Expression of activation markers and chemokine receptors from blood and bronchoalveolar lavage (BAL) fluid T cells and the T(H)2 cytokine expression from these T cells and bronchial mucosa biopsy specimens were assessed from subjects with eosinophilic bronchitis, subjects with asthma, and healthy control subjects. The proportion of resting (stimulated) CD4 BAL fluid T cells expressing intracellular IL-4 was significantly higher in the subjects with eosinophilic bronchitis 7.2% (11.4%) and subjects with asthma 5.3% (5.5%) than in healthy control subjects 2.8% (3.9%) (P =.03). The number of IL-4(+) (P <.001) and IL-5(+) (P =.003) cells per square millimeter of bronchial submucosa was significantly higher in the disease groups than in the healthy control subjects. Expression of intracellular IFN-gamma was significantly higher in stimulated blood CD8 T cells from subjects with eosinophilic bronchitis (24%) and asthma (17%) than in the healthy control subjects (5%; P =.003). There were no between-group differences in expression of IFN-gamma in the BAL fluid T cells or in the bronchial submucosa and no differences in expression of activation markers or chemokine receptors.", "yes. The increase in NF-kappaB activity after LPS and PGN stimulation suggests that stimulation through TLR2 and TLR4 may induce high cytokine expression and inflammatory cell migration in the paranasal sinus epithelial cells. In paranasal sinus epithelial cells GCs not only have anti-inflammatory effects through transcription factor inhibition but also enhance innate host defences.", "Toll-like receptors (TLRs) are important in sinonasal mucosal innate immunity. Previous studies demonstrate that sinonasal epithelial cell (SNEC) TLR9 expression is reduced in T-helper 2 (Th2) cytokine-predominant chronic rhinosinusitis with polyps, and with the in vitro application of Th2 cytokines. To further investigate in vivo modulation of TLR9 by the local cytokine environment, this study examines TLR9 expression in freshly isolated SNECs from subjects with and without active allergic rhinitis (AR). SNECs were gathered via endoscopic-guided middle meatal brushings from 9 AR subjects who were skin-prick test (SPT)-positive to environmental allergens in season at the time of study, and 8 controls. Flow cytometry was utilized to compare SNEC TLR9 expression in the 2 groups. TLR9 expression by SNEC in the AR group was significantly reduced compared to normals (35% ± 26% vs 76% ± 10%, p = 0.002).", "Despite improved surgical and medical therapies, recurrence remains a significant problem in chronic rhinosinusitis with nasal polyps (CRSwNP), given a recently-reported long-term revision rate of 15%-20%. In this prospective study uni- and multivariate statistical analyses were used to identify clinical, laboratory and conventional pathological parameters for pinpointing CRSwNP patients at higher risk of recurrence after functional endoscopic sinus surgery (FESS). The investigation concerned 179 consecutive patients undergoing FESS for CRSwNP, and 24 of them developed recurrent CRSwNP after FESS. A univariate statistical model disclosed significant associations between recurrent CRSwNP and serum basophil counts (p=0.03) and percentages (p=0.02). The recurrence rate was higher for patients with eosinophilic-type CRSwNP (p=0.01). In a multivariate logistic model, eosinophilic-type CRSwNP (p=0.025) and serum basophil percentage (statistical trend, p=0.079) retained their independent prognostic significance in relation to CRSwNP recurrence. The discriminatory power of a three-variable panel (age<65 years, serum basophil percentage and eosinophilic type) featured an AUC (ROC) of 0.7028 (an acceptable discriminatory power according to the Hosmer-Lemeshow scale).", "To quantitate lymphocyte subtypes in sinus tissues harvested from children with chronic sinusitis and coexisting asthma, allergies, and cystic fibrosis during functional endoscopic sinus surgery and compare them with those in normal adult sphenoid sinus mucosa. Immunohistochemical staining of surgical specimens with monoclonal antibodies against CD4 and CD8 surface antigens. Tertiary medical center. Thirty-two children who underwent functional endoscopic sinus surgery for chronic sinusitis refractory to medical treatment (median age, 8 years; range, 2-13 years) were divided into 3 groups: 10 with asthma, 15 without asthma, and 7 with cystic fibrosis. Sphenoid sinus mucosa obtained from 10 adults (median age, 70 years) undergoing transsphenoidal hypophysectomy was used as control tissue. Numbers of CD4+ and CD8+ cells in the lamina propria and epithelium of surgical specimens. Significantly more CD4+ cells were in the sinus mucosa of patients with chronic sinusitis than in the normal sinus mucosa (P < .01), but there was no significant difference in the number of CD8+ cells (P = 4). Patients with chronic sinusitis with asthma, without asthma, and with cystic fibrosis all had increased numbers of CD4+ cells compared with sphenoid mucosa, with the difference reaching statistical significance only in the subgroup with chronic sinusitis without asthma (P < .001). The numbers of CD4+ cells were higher in patients with chronic sinusitis than in the sphenoid mucosa irrespective of allergic status. Significantly more CD4+ than CD8+ cells were in tissues from the patients with chronic sinusitis irrespective of concomitant diseases or allergic status. CD4+ and CD8+ cells were more numerous in the apical portion of the submucosa (immediately beneath the epithelium) than in the basal portion both in patients with chronic sinusitis and in normal sphenoid tissue.", "In steady state, hemopoietic progenitors constantly egress from the bone marrow (BM) into the blood and circulate through the peripheral tissues. In allergic diseases, the BM releases increased numbers of CD34(+) progenitor cells that migrate to the site of allergic inflammation, where they differentiate into tissue-dwelling and classic effector cells of allergy, such as mast cells, eosinophils, and basophils. To examine whether peripheral blood CD34(+) cells in addition to being progenitors may also directly function as inflammatory effector cells. Highly purified neonatal or adult blood CD34(+) cells were examined for the expression of thymic stromal lymphopoietin (TSLP) and IL-33 receptors and for their response to these cytokines as well as to supernatants of primary small airway epithelial cells and nasal explants from rhinosinusitis and control subjects. Sputum of patients with asthma was examined before and after allergen inhalation for the presence of IL-5 and IL-13-containing CD34(+) cells. Circulating CD34(+) cells expressed receptors for TSLP and IL-33 and responded to these cytokines by rapidly releasing high levels of proinflammatory T(H)2-like cytokines and chemokines. These cells were activated in a TSLP-dependent manner by the supernatant fluids from activated primary human small airway epithelial cells and from nasal explants of patients with chronic rhinosinusitis. Moreover, activated CD34(+) cells containing IL-5 and IL-13 could be detected in the sputum of individuals with allergic asthma, with numbers increasing in response to specific allergen inhalation challenge.", "The role of atopy in chronic rhinosinusitis is unclear: it is particularly controversial in chronic rhinosinusitis with nasal polyps. A prospective study of 210 patients with chronic rhinosinusitis with nasal polyps was performed. Patient demographics, visual analogue scale scores, Lund-Kennedy endoscopy scores, Lund-Mackay computed tomography scores, serum total immunoglobulin E levels, serum eosinophil cationic protein (ECP) levels and Phadiatop test findings were analysed. There were no significant differences in age, sex, visual analogue scale score, Lund-Mackay computed tomography score, total serum immunoglobulin E level, serum ECP level or Phadiatop test results between patients with primary and recurrent chronic rhinosinusitis with nasal polyps. A total of 99 patients (47 per cent) had positive atopy tests. No significant differences in sex, visual analogue scale score, Lund-Kennedy endoscopy score, Lund-Mackay computed tomography score or recurrence rates were found between atopic and non-atopic patients; however, atopic patients were significantly younger than non-atopic patients. Atopy status did not correlate with disease severity.", "yes. These findings support the concept of asthma as a disease associated with activation of T(H)2 lymphocytes in the airway and provide evidence that these cytokines play a role in the development of airway inflammation in eosinophilic bronchitis but suggest that the release of T(H)2 cytokines is not sufficient for the elaboration of disordered airway physiology in asthma.", "Churg-Strauss syndrome (CSS) is a rare systemic vasculitis associated with eosinophilia and granuloma formation. The contribution of individual T-helper cell lineages in pathogenesis of CSS is unknown. We hypothesised that in CSS an imbalance of major effector T-cell subpopulations takes place, and is further influenced by the mode of treatment. We investigated the immunophenotype, cytokine production and transcriptome profile in peripheral blood lymphocytes (PBL) from 19 patients with stable CSS (10 were treated with glucocorticoids alone (CSS/GC), 9 with steroids and other immunosuppressive drugs (CSS/IS)), and 13 healthy controls. Furthermore, serum IL-5 and CCR4-active chemokines (CCL17, CCL22) were measured in six patients with active disease and upon remission. All CSS patients had decreased percentage of FoxP3+ regulatory T cells. In the CSS/GC group we found an increase in the Th17/Treg ratio and up-regulation of both Th2 and Th17 markers as evidenced by (1) over expression of Th2-related genes (GATA3, STAT6) in PBL, (2) elevated concentrations of serum IL-5 and CCL17, and (3) a concomitant increase in the number of Th17 cells, and secretion of IL-17A by stimulated PBL. The level of CCR4-active chemokines was increased in active-CSS, and correlated with blood eosinophilia. The combined treatment with steroids and other immunosuppressive drugs was associated with a significant decrease in both Th2-related chemokines and the number of Th17 cells.", "Defective innate immune functions can contribute to chronic rhinosinusitis (RS). Recently, it has been reported that chronic RS patients show impaired function of natural killer (NK) cells. We investigated the role of NK cells in eosinophilic inflammation in an allergic RS mouse model. Mice sensitized to ovalbumin (OVA) by intraperitoneal injection received nasal challenges with OVA for 5 weeks. NK cell depletion was achieved by intraperitoneal injections of anti-asialo ganglio-N-tetraosylceramide (ASGM1) antibodies 10 days before OVA sensitization and every 5 days thereafter until sacrifice. Sinonasal complex samples were evaluated histologically, and IL-4, IL-5, IL-13, IFN-γ, MIP-2, and eotaxin levels were measured in the nasal lavage fluid. Differential white blood cell counts were also obtained. Allergic RS mice showed significantly more eosinophilic inflammation in the sinonasal mucosa, elevated levels of IL-4, IL-5, IL-13, and eotaxin in the nasal lavage fluid, and peripheral blood eosinophilia compared to control mice. The depletion of NK cells by anti-ASGM1 treatment induced more prominent eosinophilic inflammation and increased secretion of IL-5 and peripheral blood eosinophilia in allergic RS mice.", "Sinonasal epithelial cells are recognized as drivers of inflammation in chronic sinusitis with nasal polyps (CRSwNP) through secretion of T helper 2 (Th2)-promoting cytokines. P-glycoprotein (P-gp) is overexpressed in nasal polyps and modulates epithelial cytokine secretion in healthy mucosa. The objective of this study is to determine whether P-gp overactivity promotes Th2-associated cytokine secretion in CRSwNP. Polyp explants (n = 4) and primary epithelial cell cultures (n = 5) were cultivated from patients with CRSwNP. Explant P-gp activity was determined using a calcein assay. In culture, P-gp was quantified by enzyme-linked immunosorbent assay (ELISA) and sensitivity to PSC-833 inhibition was determined using a calcein assay. Lipopolysaccharide (LPS)-stimulated cytokine secretion of interleukin 6 (IL-6), IL-8, IL-25, and granulocyte macrophage colony stimulating factor (GM-CSF) were quantified by ELISA and compared to secretion following P-gp inhibition. Differences in P-gp expression and cytokine secretion were compared using a Mann-Whitney U test. Secretion was correlated with P-gp expression using a Pearson correlation coefficient. Calcein retention is increased in P-gp inhibited vs uninhibited polyp explants (mean ± standard deviation [SD]; 5.17 ± 1.76 vs 2.55 ± 0.62; p < 0.05) but not in controls, indicating increased nasal polyp P-gp activity. P-gp is sensitive to dose-dependent P-gp inhibition with PSC-833 in vitro. LPS-stimulated secretion of normalized GM-CSF (45.21 ± 41.39) and IL-6 (63.16 ± 36.37) were significantly reduced following P-gp inhibition (8.47 ± 3.28; p < 0.01, and 39.94 ± 31.07; p < 0.05; respectively) and secretion was highly correlated with P-gp expression(r = 0.824, p < 0.05, and r = 0.833, p < 0.05; respectively).", "Chronic non-infectious sinusitis is an inflammatory disease sharing numerous features with both allergic and non-allergic rhinitis and asthma. In an attempt to analyse the underlying mechanisms of sinus and nasal inflammation, we assessed ICAM-1 immunoreactivity on maxillary sinus, nasal polyp and turbinate biopsies obtained surgically from 21 patients with sinusitis and chronic allergic rhinitis (AR), 23 patients with sinusitis and chronic non-allergic rhinitis (NAR) and 17 non-atopic control subjects. We compared ICAM-1 expression with both eosinophil (EG1) and neutrophil (NP57 elastase) infiltrates. In nasal turbinates and polyps, ICAM-1 was broadly distributed within the epithelium, on ciliated and basal epithelial cells and in the submucosa on endothelial and inflammatory cells. ICAM-1 was rarely expressed in the mucosa of the sinus, compared with polyps (P < 0.01) and turbinates (P < 0.0001). Submucosal and epithelial eosinophils were increased in both sinus and nasal biopsies from AR by comparison with NAR (P=0.003 and P=0.02) and non-atopic control subjects (P<0.0001 and P=0.014). Submucosal and epithelial neutrophil numbers were increased in the two chronic rhinitis groups and correlated with ICAM-1 submucosal expression in NAR only (P<0.01). On the other hand, epithelial eosinophil numbers correlated with ICAM-1 epithelial expression in AR only (P = 0.002).", "yes. SOCS1 and SOCS3 are increased in CRS, irrespective of nasal polyp presence. This may be a response to elevated levels of various cytokines increasingly expressed in inflammatory sinus mucosa.", "Early-life human rhinovirus infection has been linked to asthma development in high-risk infants and children. Nevertheless, the role of rhinovirus infection in the initiation of asthma remains unclear. We hypothesized that, in contrast to infection of mature BALB/c mice, neonatal infection with rhinovirus promotes an IL-25-driven type 2 response, which causes persistent mucous metaplasia and airways hyperresponsiveness. Six-day-old and 8-week-old BALB/c mice were inoculated with sham HeLa cell lysate or rhinovirus. Airway responses from 1 to 28 days after infection were assessed by using quantitative PCR, ELISA, histology, immunofluorescence microscopy, flow cytometry, and methacholine responsiveness. Selected mice were treated with a neutralizing antibody to IL-25. Compared with mature mice, rhinovirus infection in neonatal mice increased lung IL-13 and IL-25 production, whereas IFN-γ, IL-12p40, and TNF-α expression was suppressed. In addition, the population of IL-13-secreting type 2 innate lymphoid cells (ILC2s) was expanded with rhinovirus infection in neonatal but not mature mice. ILC2s were the major cell type secreting IL-13 in neonates. Finally, anti-IL-25 neutralizing antibody attenuated ILC2 expansion, mucous hypersecretion, and airways responsiveness.", "Nasal polyposis (NP) is considered a subgroup within chronic rhinosinusitis. NP can be further subdivided into aspirin sensitive- and aspirin tolerant types (ASNP/ ATNP). Although the true etiology of NP has not been identified so far, it is agreed that NP represents an inflammatory disease of the nasal mucosa. Alterations of cellular kinase activities including that of IKK-2 might play a role in this inflammatory process. Paraffin sections of ASNP, ATNP and controls were immunostained with Phospho-IkB-α antibody that detects the direct IKK-2 product (IkB-α. Intensity of epithelial staining was analysed semi-quantitatively by two independent observers. In cultured nasal polyp epithelial cells (NPECs) epithelial derived cytokines IL-8 and GRO α were induced by TNF-α or Staphylococcal supernatants and subsequently repressed by IKK-2 inhibitor TPCA-1. Significant Phospho-IkB-α staining was observed in the nasal epithelium of ASNP compared to ATNP and controls suggesting strong IKK-2 activation in patients with ASNP in vivo. In vitro, pro-inflammatory cytokines IL-8 and GRO-α in NPECs were significantly repressed by TPCA-1.", "Eosinophilic chronic rhinosinusitis (ECRS) is as a subgroup of chronic rhinosinusitis (CRS) with nasal polyps. ECRS is a refractory disease closely related to bronchial asthma. Fractionated exhaled nitric oxide (FeNO) levels were reportedly elevated in some asthmatics with CRS after adequate treatment, suggesting that residual eosinophilic airway inflammation or ECRS might affect FeNO levels. To investigate the association between asthma with ECRS and FeNO levels, we examined FeNO levels in 133 asthmatics (99 with ECRS and 34 without ECRS) and 13 patients with ECRS without asthma. The severity of asthma was defined by the Global Initiative for Asthma guidelines and that of sinusitis was evaluated by the sinus CT score based on the Lund-Mackay scale.", "Nasal polyps are benign mucosal protrusions into the nasal cavity of multifactorial origin and are characterized by chronic mucosal inflammation. The suggested multifactorial pathological mechanisms comprise several factors including cytokines and immunoglobulin E (IgE). The study was designed to examine the suggested roles of IgE, interleukin-5 (IL-5), and transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of nasal polyposis. Nasal polyps (n = 34) and healthy nasal mucosa samples (n = 9) were taken during routine endonasal surgeries. Immunoglobulin E (n = 13), IL-5 (n = 22), and TGF-beta1 (n = 27) concentrations were measured with enzyme-linked immunosorbent assay technique in homogenized polyp tissue and in control mucosa. Atopic and nonatopic groups were selected and compared. Histomorphological examination and immunohistochemical analysis to detect IL-5 and TGF-beta1 were performed in five specimens. The level of tissue-bound IgE was significantly higher in polyps compared with control specimens and in atopic compared with nonatopic polyps, but between nonatopic polyps and control specimens the difference was not significant. However, significant correlation was found between tissue and serum IgE in the complete polyp (P =.001) and atopic polyps group (P =.05). Tissue IL-5 concentration was significantly higher in polyps compared with control specimens, in which it was below the limit (15 pg/mL), and there was no difference between atopic and nonatopic polyps. In atopic polyps there was significant correlation between tissue IgE and IL-5. Transforming growth factor-beta1 concentration proved to be significantly higher in control mucosa than in polyps, with no difference between atopic and nonatopic polyps. Immunohistochemical analysis revealed numerous IL-5-positive eosinophil cells and TGF-beta1 positivity in the lamina propria of polyp samples, but none in control specimens.", "Free light chain (FLC) concentrations are demonstrated to be increased in different inflammatory disorders and are proposed to mediate mast cell-dependent immune responses. A role for mast cells is suggested in chronic rhinosinusitis with nasal polyposis (CRSwNP), which is characterized by a local Th2 inflammatory response. However, clear mast cell-activating factors are not always apparent. In this study, the presence of FLCs in CRS patients with or without nasal polyps (CRSw/sNP) was investigated and the effect of different treatments on FLC expression was analyzed. Nasal tissue, nasal secretion, and serum of control patients, patients with CRSwNP, and CRSsNP were analyzed for the presence of kappa and lambda FLC. The expression of FLCs in nasal polyp tissue was investigated using immunohistochemistry. In addition, FLC was measured in serum and nasal secretion of nasal polyp patients treated with methylprednisolone, doxycycline, anti-IL-5, or placebo. Free light chain concentrations were increased in nasal secretion and mucosal tissue homogenates in patients with chronic rhinosinusitis, and this effect was most prominent in CRSwNP patients. Immunohistochemical analysis confirmed the increased FLC concentrations in nasal polyp tissue. In CRSwNP patients, treatment with methylprednisolone or anti-IL-5 resulted in the reduction in systemic or local FLC concentrations, respectively.", "yes. These studies suggest that there is an association between increased levels of total IgE, specific IgE, and eosinophilic inflammation in NPs, which may be of relevance in the pathophysiology of nasal polyposis. Similarly, the presence of specific IgE to staphylococcal enterotoxins A and B also points to a possible role of bacterial superantigens.", "yes. The relative increase of IL-4-positive cells in the presence of an eosinophilic infiltrate might thus reflect an imbalance between a type 1 and type 2 response, in favor of the latter. Since a type 1 response stimulates an adequate cellular response which is negatively regulated by type 2 cytokines, these findings might explain the worse clinical outcome seen in cervical cancer patients with an eosinophilic tumor infiltrate. These results may have implications when developing immunotherapeutical strategies for cervical cancer.", "yes. Infiltration of inflammatory effector cells such as eosinphils and chronic inflammatory changes of the nasal mucosa might play a role in nasal polyps sprouting.", "yes. The present work suggests a disequilibrium of TH1 and TH2, together with a down-regulation of regulatory T lymphocytes and up-regulated TH17 in NP. Moreover, elevated levels of diverse mediators represent the activation of various inflammatory cells in this disease entity. The inflammation in CRSsNP, however, is only weakly depicted in nasal secretions. Therefore, cytokines in nasal secretions may provide helpful information for differential diagnosis.", "The mechanisms and immune pathways associated with chronic rhinosinusitis (CRS) are not fully understood. Immunological changes during acute exacerbation of CRS may provide valuable clues to the pathogenesis and perpetuation of the disease. To characterize local and systemic immune responses associated with acute worsening of sinonasal symptoms during exacerbation in CRS with nasal polyps (CRSwNP) compared to controls. This was a non-interventional prospective study of individuals with CRSwNP and normal controls. Subjects underwent a baseline visit with collection of nasal secretions, nasal washes, and serum specimens. Within 3 days of acute worsening of sinonasal symptoms, subjects underwent a study visit, followed by a post-visit 2 weeks later. The sinonasal outcome test-22 (SNOT-22) scores and immunological parameters in the specimens were analysed using a novel, unsupervised learning method and by conventional univariate analysis. Both CRSwNP patients and control subjects showed a significant increase in SNOT-22 scores during acute exacerbation. Increased nasal levels of IL-6, IL-5, and eosinophil major basic protein were observed in CRSwNP patients. A network analysis of serum specimens revealed changes in a set of immunological parameters, which are distinctly associated with CRSwNP but not with controls. In particular, systemic increases in VEGF and GM-CSF levels were notable and were validated by a conventional analysis.", "yes. The observation that eosinophil products upregulate ICAM-1 on HNECs suggests a positive feedback mechanism, in which the products released from migrating eosinophils might promote additional HNEC-leukocyte adherence by enhancing interactions between leukocyte beta 2 integrins (CD11/18) and nasal epithelial ICAM-1.", "Non-eosinophilic nasal polyps (NPs) show less inflammatory changes and are less commonly associated with lower airway inflammatory disorders such as asthma, compared with eosinophilic NPs. However, the development of non-eosinophilic NPs which is a predominant subtype in Asian population still remains unclear. A total of 81 patients (45 with non-eosinophilic NPs and 36 with eosinophilic NPs) were enrolled. Clinical information and computed tomography (CT), endoscopic, and histological findings were investigated. Tissue samples were analyzed for total IgE levels and for mRNA expression levels of interleukin (IL)-4, IL-5, IL-13, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-17A, IL-22, IL-23p19, transforming growth factor (TGF)-β1, TGF-β2, TGF-β3, and periostin. Immunostaining assessment of Ki-67 as a proliferation marker was performed. We found that epithelial in-growing patterns such as pseudocysts were more frequently observed in histological and endoscopic evaluations of non-eosinophilic NPs, which was linked to increase epithelial staining of Ki-67, a proliferating marker. Eosinophilic NPs were characterized by high infiltration of inflammatory cells, compared with non-eosinophilic NPs. To investigate the developmental course of each subtype, CT was analyzed according to CT scores and subtypes. Non-eosinophilic NPs showed more localized pattern and maxillary sinus involvement, but lesser olfactory involvement in early stage whereas eosinophilic NPs were characterized by diffuse ethmoidal and olfactory involvement. In addition, high ethmoidal/maxillary (E/M) CT scores, indicating ethmoidal dominant involvement, were one of surrogate markers for eosinophilic NP. E/M CT scores was positively correlated with levels of TH2 inflammatory markers, including IL-4, IL-5, periostin mRNA expression and total IgE levels in NPs, whereas levels of the TH1 cytokine, IFN- γ were inversely correlated. Moreover, if the combinatorial algorithm meet the three of the four markers, including IL-5 (<2.379), periostin (<3.889), IFN-γ (>0.316), and E/M ratio (<2.167), non-eosinophilic CRSwNP are diagnosed with a sensitivity of 84.4% and a specificity of 84.8%.", "Eosinophilic lung diseases comprise a group of heterogeneous pulmonary disorders linked by increased eosinophils in bronchoalveolar lavage fluid (BALF). There is supporting evidence that natural killer (NK) cells participate in the regulation of eosinophilic inflammation. Our aim was to investigate the relationship between eosinophils and NK cells in BALF in patients with different interstitial lung diseases (ILDs) focusing on eosinophilic pneumonias. Of 114 patients who presented with increased BALF eosinophils (>5%), 74 patients were classified into the following groups: 27 had eosinophilic pneumonia (EP), 17 had idiopathic pulmonary fibrosis (IPF), 16 had hypersensitivity pneumonitis (HSP) and 14 had cryptogenic organizing pneumonia (COP/BOOP). Total BALF cells, cell density and cell differential counts were assessed and lymphocyte subsets CD3+, CD4+, CD8+, CD19+, CD3-CD16/56+ (NK) and CD3+CD16/56+ (NKT) were determined by flow cytometry. Significant differences were observed in the percentages of lymphocytes (p < 0.001) and CD3+CD16/56+ cells (p = 0.023) among patient groups. In patients with EP, the percentage of eosinophils correlated positively with the number of CD3-CD16/56+ cells (r = 0.522, p = 0.005), the percentage of CD3-CD16/56+ cells (r = 0.690, p < 0.001), and the absolute count of CD3+CD16/56+ absolute cells (r = 0.609, p = 0.001). However, in patients with IPF, HSP or COP/BOOP, no correlation between the percentage of eosinophils and CD3-CD16/56+ or CD3+CD16/56+ cells was observed.", "Eosinophils are thought to play a significant role in nasal polyposis, but the exact mechanism by which they contribute to polyposis remains unclear. Therefore, we proposed to test the hypothesis that peripheral blood eosinophilia (PBE) is a surrogate and biomarker for polyp load. To do this, we examined whether PBE levels correlate with nasal polyp load in a longitudinal manner. We retrospectively analyzed the fluctuation of PBE and nasal polyp load in each patient (n = 61) assessed preoperatively, 1-2 months postoperatively, and 3-12 months postoperatively. Nasal polyp load was assessed using computed tomography (CT) scan preoperatively and nasal endoscopy postoperatively. Correlation coefficients were analyzed using parametric statistics. There was a positive correlation between initial preoperative baseline PBE and CT scan staging of polyp load (r = 0.35, p < 0.01). When patients were analyzed longitudinally, we found that the change in PBE correlated with the change in nasal endoscopy scores obtained at or near the same timepoint (r = 0.82, p < 2.0 × 10(-10) ). When nasal polyp load increased with time, we observed a stepwise increase in eosinophil counts (r = 0.37, p < 0.02).", "yes. P-gp overactivity promotes Th2-associated epithelial cytokine secretion in nasal polyps, suggesting a novel mechanism for maintaining chronic inflammation in CRSwNP.", "The key features of aspirin-exacerbated respiratory diseases (AERDs) include chronic, severe asthma and a high prevalence (60-80%) of chronic rhinosinusitis with nasal polyps, all of which are exacerbated by exposure to aspirin and other NSAIDs. Although the pathogenic mechanisms of AERD are not completely understood, repeated instances have shown intense eosinophilic infiltrations of upper and lower airway mucosa, and dysregulation of arachidonate metabolisms. Here, recent updates on the pathogenic mechanisms of chronic rhinosinusitis with nasal polyps in aspirin-exacerbated respiratory diseases are summarized. Intense eosinophilic infiltration is closely related to the elevated production of cytokines and chemokines such as IL-5 and eotaxin. The response of local immunoglobulin E to staphylococcal enterotoxins contributes to eosinophilic inflammation in nasal polyp tissue. Other characteristics include the overproduction of cysteinyl leukotrienes and increased expression of cysteinyl leukotriene receptor-1, reduced production of prostaglandin E2, and the down-regulation of cyclooxygenase-2 and E-prostanoid receptor subtype-2. A recent gene expression profiling study has also suggested that periostin is the most up-regulated gene in the nasal polyp tissue of AERD patients.", "yes. These finding suggests that lung IL-33, through innate activation of ILC2s and their production of IL-5, plays a key role in promoting acute reactive eosinophilopoiesis in the bone marrow when naïve animals are exposed to airborne allergens. Therefore, bone marrow eosinophilopoiesis may be affected by atmospheric environmental conditions.", "In most nasal polyps, tissue eosinophilia is a striking finding, the pathologic mechanism of which is not understood. This study was performed to investigate a possibly distinct cytokine and chemokine pattern that could explain the characteristic tissue eosinophilia in nasal polyps. Polyps from 23 patients and turbinate tissue from 18 control subjects were investigated. The cytokine protein content (IL-1 beta, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, IL-1RA, RANTES, GRO-alpha) of tissue homogenates was measured by ELISA. Immunohistochemistry was performed in selected samples to detect IL-5+, major basic protein-positive, and EG2+ cells. IL-5 was detectable in only one sample of tissue from 18 control subjects but was found in 18 of 23 nasal polyps. Immunohistochemistry revealed an abundant number of IL-5+ cells, of which 69.5% could be identified as eosinophils by morphology. IL-6, IL-8, IL-10, tumor necrosis factor-alpha, GRO-alpha, and RANTES were detected in all specimens, without significant differences between groups (p > or = 0.05), whereas significnatly higher concentrations of IL-1 beta and IL-1RA were found in turbinate mucosa (p < or = 0.05). IL-3 was not detectable: granulocyte-macrophage colony-stimulating factor could only occasionally be found.", "yes. High tissue TGF-beta1 quantity in healthy nasal mucosa without its active form on the cell surface and its low quantity in polyps may reflect its essential role in the inhibitory mechanisms of nasal polyposis. Interleukin-5 plays a key role in the eosinophil recruitment and activation, and both atopic and nonatopic pathways might activate this process. The main sources of IL-5 and TGF-beta1 are the eosinophils and macrophages. Immediate hypersensitivity, besides other mechanisms, might be related to atopic polyps, but the involvement of other, local allergic mechanisms in IgE production of nonatopic polyp tissue cannot be excluded.", "We have previously demonstrated that persistent symptoms following functional endoscopic sinus surgery for chronic rhinosinusitis (CRS) is associated with Gram-negative bacterial carriage. Mechanisms for this remain unknown. We wished to determine whether Gram-negative carriage in patients with CRS with nasal polyposis is associated with a more severe inflammatory phenomenon. Three hundred and thirty-seven patients with CRS with nasal polyposis (CRSwNP) previously phenotyped for genetic association studies with questionnaire, serum biomarkers, and endoscopically-obtained swab cultures were studied. These were separated according to the presence (wGN) or absence (sGN) of Gram-negative bacterial carriage; demographic parameters and available serum biomarkers (complete blood count [CBC], total immunoglobulin E [IgE]) were then compared. Subgroup analysis for Pseudomonas aeruginosa (GNwPa) and non-Pseudomonas Gram-negative bacteria (GNsPs) was performed in order to explore potentially differential roles of these bacteria. Gram-negative bacterial carriage was not associated with a difference in demographic parameters or serum biomarkers. However, P. aeruginosa carriage was associated with a higher self-reported incidence of asthma (GNwPa 79%, sGN 57%; p = 0.048). Interestingly, serum IgE was increased in the non-Pseudomonas Gram-negative population (GNsPs: 338 IU/mL, sGN: 195 IU/mL; p = 0.026).", "Macrophages are major producers of inflammatory cytokines; however, their role in chronic rhinosinusitis (CRS) has not been clearly defined. The aim of this study was to quantify macrophages in sinus tissue of patients with various subtypes of CRS and determine the impact of atopic status on macrophage infiltrate. Prospective immunohistochemical study of human sinonasal tissue. Academic medical center. Human sinonasal tissue was taken from patients with CRS with nasal polyposis (CRSwNP, n = 8), CRS without nasal polyposis (CRSsNP, n = 8), and controls (n = 8) undergoing surgery for CSF leak repair or endoscopic excision of non-secreting pituitary tumor. Samples were immunohistochemically stained for macrophage/monocyte markers Mac387 and CD68. CRSwNP patients had significantly increased numbers of Mac387 and CD68 cells compared to control patients (P < .05) or CRSsNP patients (P < .01). CRSsNP had significantly increased number of cells staining for CD68 compared to controls (P < .05). The increased presence of macrophages measured by either marker in CRSwNP was independent of atopic status.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disorder of the sinonasal mucosa that is frequently associated with microbial colonization. Innate defense mechanisms at the mucosal surface are critical in protecting the host from airborne environmental pathogens. Recent studies of skin and gastrointestinal tract inflammatory diseases have shown that stimulation of the interleukin-22 receptor (IL-22R1) nonspecifically increases innate immune responses. The potential role of IL-22R1 in the pathogenesis of CRSwNP has never been explored. Prospective. Nine controls and 19 subjects with CRS were prospectively enrolled prior to undergoing endoscopic sinus surgery. Nasal epithelial cells were cultured from surgically obtained ethmoid mucosa and IL-22R1 protein expression was examined via flow cytometry. RNA was extracted from whole mucosal samples and real-time polymerase chain reaction (PCR) was employed to determine expression of IL22 and IL-22R1. Subjects were followed for at least 6 months postoperative to assess for recurrence or persistence of polyps. Flow cytometry demonstrated the expression of IL-22R1 protein on the surface of cultured nasal epithelial cells. IL-22R1 mRNA was expressed in 100% of the controls and CRSsNP. However, IL-22R1 was only expressed in 55% of patients with recalcitrant CRSwNP. Additionally, levels of IL22R1 were significantly lower in recalcitrant CRSwNP compared to controls and CRSsNP. IL22 levels did not reach statistical significance.", "To study the relation between inflammatory cells infiltration in nasal polyp tissues and it's pathogenesis. Nasal mucosa from 10 normal individual and 4 patients of nasal polyps were studied with immunohistochemical technique and histopathologic examination. The number of eosinophils, CD68 positive cells and monocytes was significantly higher (P < 0.05) in nasal polyps tissues than in the normal controls.", "The CC-chemokine eotaxin plays a key role in the pathologic mechanism of tissue eosinophilia in nasal polyposis. In this study, we investigated a possible role of eotaxin-2 and eotaxin-3, the recently discovered members of the eotaxin family. Nasal polyps from 24 patients (non allergic/allergic/aspirin-intolerant patients) and turbinate tissue from 8 controls were investigated. Chemokine protein content (eotaxin, eotaxin-2, and -3) of tissue homogenates was measured by ELISA. Paraffin sections of samples were stained to determine the extent of eosinophilia. Protein expression of eotaxin, eotaxin-2 and eotaxin-3 was significantly higher in nasal polyps than in controls. There was a direct correlation between the protein concentrations of all three eotaxins. Further, protein levels of all chemokines were significantly correlated to the amount of eosinophilia. In aspirin-sensitive polyps the number of eosinophils was significantly higher than in the other patient groups and they had significantly higher eotaxin, eotaxin-2, and -3 protein levels than non-allergic and significantly higher amounts of eotaxin-3 compared with allergic patients.", "yes. These results suggest that the regulatory effects of LPS on eosinophilic airway inflammation are controlled via the COX-2/PGE(2) axis. For clinical implications, indiscreet use of non-steroidal anti-inflammatory drugs should be avoided in patients with chronic rhinosinusitis with nasal polyps.", "yes. The results of this study show that TSLP expression could be induced in nasal fibroblasts by exposure to Alternaria and that TLR2 may be involved in the process. The promotion of TSLP production in nasal fibroblasts by airborne fungi may facilitate the development or exacerbation of Th2-type nasal inflammation, especially in CRS with nasal polyps.", "Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinuses and mucosa with unclear pathogenesis. Interleukin (IL)-21 is mainly expressed in activated cluster of differentiation (CD)4(+) T cells and has potent regulatory effects on the immune system. This study is to determine whether IL-21 in the blood is correlated with CRS. The blood samples from CRS patients and normal controls were analyzed in correlation with clinical features. The eosinophil percentage was counted, and serum levels of total immunoglobulin E (IgE) and IL-21 were analyzed by enzyme-linked immunosorbent assay (ELISA). In addition, IL-21 and interferon (IFN)-γ secreted from stimulated peripheral blood mononuclear cells (PBMCs) were measured by ELISA, and their mRNA expression levels were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Disease severity was scored based on computed tomography (CT) scan, nasal endoscopy, and global osteitis scoring scale (GOSS). A total of 55 CRS and 37 healthy subjects were recruited. The average levels of serum total IgE were 20 kU/L in normal group, 290 kU/L in CRS with nasal polys (CRSwNP), and 187 kU/L in CRS without nasal polys (CRSsNP). IL-21 levels were 28 pg/mL in normal group, 54 pg/mL in CRSwNP, and 71 pg/mL in CRSsNP. Both IgE and IL-21 were significantly elevated in both CRS patient subgroups. However, no significant difference was found between these two patient subgroups. The serum IL-21 levels correlated well with the disease severity in the patients. In addition, the secreted IL-21 was enhanced significantly in the patient's PBMCs stimulated by phytohemagglutin (PHA).", "Being one of the most common nasal diseases, chronic rhinosinusitis (CRS) is subdivided into CRS with nasal polyps (NP) and CRS without nasal polyps (CRSsNP). CRSsNP presents itself with a TH1 milieu and neutrophil infiltration, while NP is characterised by a mixed TH1/TH2 profile and an influx of predominantly eosinophils, plasma cells and mast cells. For the purpose of discovering disease-specific cytokine profiles, the present study compares levels of mediators and cytokines in nasal secretions between CRSsNP, NP, and healthy controls. The study included 45 participants suffering from NP, 48 suffering from CRSsNP and 48 healthy controls. Allergic rhinitis constituted an exclusion criterion. Nasal secretions, sampled using the cotton wool method, were analysed for IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, IL-8, GM-CSF, G-CSF, IFN-γ, MCP-1, MIP-1α, MIP-1β, eotaxin, and RANTES, and for ECP and tryptase, using Bio-Plex Cytokine assay or ELISA, respectively. Elevated levels of IL-5, IL-17, G-CSF, MCP-1, MIP-1α, MIP-1β, ECP, and tryptase, as well as decreased levels of IL-10, IL-12, IL-13, and IFN-γ were detected in NP. CRSsNP presented increased levels of RANTES and MIP-1β while IL-13 was decreased. No differences between the three groups were found for IL-4, IL-8, GM-CSF, and eotaxin.", "yes. Mucosal inflammation in nasal polyps orchestrated by T(H)2 cytokines and amplified by S aureus enterotoxins is characterized by an increased eosinophilic inflammation and formation of IgE antibodies. This phenotype is associated with comorbid asthma in white and Asian patients with nasal polyps.", "yes. The depletion of NK cells aggravates allergen-induced sinonasal eosinophilic inflammation, suggesting that impaired NK cell activity may be an exacerbating factor in eosinophilic chronic RS.", "Nasal polyposis demonstrates histological features of epithelial remodeling and variable inflammatory cellular infiltration. We studied a large series of Chinese nasal polyp (NP) samples to characterize these histological features and their associations with clinical characteristics. A detailed histological study of nasal polyposis was performed employing various histopathological techniques. A total of 153 intraoperative NP biopsies were analyzed histologically. Sections were examined under microscopy to determine the percentages of different types of inflammatory cells, and types of epithelial remodeling. Two systems of subtyping NPs based on inflammatory cell infiltration were assessed. These were correlated with patient characteristics. Epithelial remodeling patterns include epithelial hyperplasia (87.8% of specimens), goblet cell hyperplasia (53.2%), and squamous metaplasia (44.6%). Smoking was a strong independent association of squamous metaplasia (adjusted odds ratio [OR] 9.9; 95% confidence interval [CI], 4.2 to 22.9; p < 0.01). The most common inflammatory cells were neutrophils (median of 12.8%) and CD8+ T cells (12.8%), followed by macrophages (11.0%), CD4+ T cells (9.7%), eosinophils (8.6%), and mast cells (7.6%). We defined 2 systems to classify NPs based on proportions of eosinophils and neutrophils. The majority of NP samples were neutrophilic. The first classification system has greater histological correlation. Based on the first classification, eosinophilic nasal polyposis was associated with epithelial hyperplasia (OR 3.7, p = 0.019) and goblet cell hyperplasia (OR 3.4, p < 0.001).", "Chronic rhinosinusitis with nasal polyps is a chronic inflammatory disease with markedly increased eosinophils, Th2-type lymphocytes, fibroblasts, and goblet cells. Fungi are commonly associated with airway inflammatory diseases, and thymic stromal lymphopoietin (TSLP) is important in the development of Th2 inflammatory responses. The aim of this study was to investigate the interaction between airborne fungi and nasal fibroblasts in TSLP mRNA and protein expression. Inferior turbinate and nasal polyp fibroblasts were stimulated with Alternaria and Aspergillus, respectively, for 48 hours, and TSLP mRNA and protein expressions were measured. The reverse transcriptase polymerase chain reaction was performed for the Toll-like receptor (TLR) mRNA expression of the nasal fibroblasts. To determine the role of TLR in the induction of TSLP, the fibroblasts were transfected with siRNA against TLR2 and TLR5. Alternaria induced TSLP mRNA and protein expression in both inferior turbinate and nasal polyp fibroblasts. The nasal polyp fibroblasts responded more strongly to the fungi. TLR2 and TLR5 mRNA expressions were significantly increased with fungal stimulation and TSLP production was significantly inhibited by siRNA against TLR2.", "This study aimed to predict eosinophilic chronic rhinosinusitis prognosis by investigating changes in the blood eosinophil count and other disease biomarkers after surgery. Blood eosinophil numbers and serum interleukin-5 levels were measured in 22 eosinophilic chronic rhinosinusitis patients before and after functional endoscopic sinus surgery, and compared with equivalent measures in non-eosinophilic chronic rhinosinusitis patients and chronic rhinosinusitis without polyps patients. Differences between well-controlled eosinophilic chronic rhinosinusitis patients and those who experienced recurrence were also assessed. Blood eosinophil numbers and serum interleukin-5 level decreased after surgery in eosinophilic chronic rhinosinusitis patients. In this patient group, blood eosinophil counts before surgery were significantly higher in patients who experienced recurrence (825.7 ± 26.1 vs 443.9 ± 76.6 cells/μl, p < 0.05), and decreased significantly after surgery (825.7 ± 26.1 vs 76.7 ± 25.8 cells/μl, p < 0.05).", "Asthmatic patients are highly susceptible to air pollution and in particular to the effects of ozone (O3) inhalation, but the underlying mechanisms remain unclear. Using mouse models of O3-induced airway inflammation and airway hyperresponsiveness (AHR), we sought to investigate the role of the recently discovered group 2 innate lymphoid cells (ILC2s). C57BL/6 and BALB/c mice were exposed to Aspergillus fumigatus, O3, or both (3 ppm for 2 hours). ILC2s were isolated by means of fluorescence-activated cell sorting and studied for Il5 and Il13 mRNA expression. ILC2s were depleted with anti-Thy1.2 mAb and replaced by means of intratracheal transfer of ex vivo expanded Thy1.1 ILC2s. Cytokine levels (ELISA and quantitative PCR), inflammatory cell profile, and AHR (flexiVent) were assessed in the mice. In addition to neutrophil influx, O3 inhalation elicited the appearance of eosinophils and IL-5 in the airways of BALB/c but not C57BL/6 mice. Although O3-induced expression of IL-33, a known activator of ILC2s, in the lung was similar between these strains, isolated pulmonary ILC2s from O3-exposed BALB/c mice had significantly greater Il5 and Il13 mRNA expression than C57BL/6 mice. This suggested that an altered ILC2 function in BALB/c mice might mediate the increased O3 responsiveness. Indeed, anti-Thy1.2 treatment abolished but ILC2s added back dramatically enhanced O3-induced AHR.", "yes. Mucosal innate immunity likely plays an important role in CRSwNP pathogenesis. A definitive link between infectious triggers and the development of Th2 inflammation has been elusive. We have found constitutive IL-33 expression by SNECs in recalcitrant CRSwNPs, which can be further induced by a bacteria-associated molecular pattern. Dysregulated epithelial cell immune interactions between host and environment may contribute to Th2 inflammation in CRSwNPs.", "Any relationship between atopy and nasal polyposis remains to be further studied to determine the contribution of atopy to the pathogenesis of nasal polyps. We have compared the inflammatory cellular infiltrate in nasal polyp tissue taken during resection from 10 atopic and 11 non-atopic subjects. We have used immunohistochemistry to enumerate the individual inflammatory cell types using monoclonal antibodies against tryptase (AA1) to identify mast cells, the secreted forms of eosinophil cationic protein (EG2) to identify activated eosinophils, neutrophil elastase (NE+) to demonstrate neutrophils, and T cell surface markers (CD3) to identify pan T cells. The number of AA1+ and NE+ cells tended to be higher in atopics, but no statistical significance was found (p = 0.06, p = 0.12). Eosinophil numbers (EG2) were abundant in both groups and found to be not different between them (p = 0.65). Some subjects had CD3+ cells with no significant difference between atopic and non-atopic subjects (p = 0.21). Significant correlation was found between NE+ and AA1+ or EG2 cells (r = 0.59, r = 0.63, p < 0.05, respectively).", "The role of myeloid and plasmacytoid dendritic cells and its consequences for the T(H)2 skew in chronic rhinosinusitis (CRS) with nasal polyps (CRSNP(+)) should be detailed. In 18 CRS patients without nasal polyps (CRSNP(-)), 35 CRSNP(+) patients and 22 patients with nasal structural abnormalities without rhinosinusitis (controls), dendritic cells (DC) were differentiated into myeloid (mDC) and plasmacytoid (pDC) subtypes using an antibody cocktail including CD1c (BDCA-1) and CD303 (BDCA-2) in peripheral blood mononuclear cells (PBMC) and single cell preparations of sinonasal mucosa by flow cytometry. Moreover, cells were analysed for expression of CD45, CD3, CD4, CXCR3 (T(H)1) and CCR4 (T(H)2) and IFN-gamma, IL-5, TGF-beta1, TGF-beta2, ECP and total IgE in nasal secretions were determined. As a possible confounder, Staphylococcus aureus in nasal lavages was detected. The tissue mDC/pDC-ratio was 1.7 (1.0-2.4) in controls, 3.0 (1.8-4.0) in CRSNP(-) and 0.8 (0.6-1.0) in CRSNP(+) (P < 0.01). In tissue samples, the T(H)1/T(H)2 ratio was 12.6 (6.4-16.0) in controls, 12.5 (6.9-21.2) in CRSNP(-) and 1.8 (1.3-3.6) in CRSNP(+) (median and interquartile range, P < 0.001). Less pronounced differences were found in PBMC. S. aureus detection rates or TGF-beta levels did not differ between patient groups and S. aureus detection had no influence on the parameters investigated.", "Nasal polyps (NPs) are hallmark inflammatory lesions of sinusitis. Despite the spectrum of NP conditions, cellular differences between NPs from patients with chronic rhinosinusitis with NPs (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) are poorly understood. NPs are associated with abundant eosinophils; the contributions of neutrophil and basophil granulocytes are less defined. We therefore sought to assess granulocyte subpopulations, and differential effects following prednisone pretreatment, within NPs of CRSwNP and AERD patients. NPs, adjacent ethmoid sinus tissue, and peripheral blood mononuclear cells (PBMCs) were obtained from patients undergoing endoscopic sinus surgery. Samples from 5 cohorts: CRSwNP ± prednisone (n = 6 each), AERD ± prednisone (n = 6 each), and controls (n = 9), were analyzed by high-dimensional flow cytometry to gate granulocyte populations. Specimens were also assessed using immunohistochemistry (IHC) staining. Systemic prednisone administration was associated with a lower frequency of eosinophils (p < 0.0001, n = 6) in NPs in both CRSwNP and AERD patients, whereas a decrease in neutrophils (p = 0.0070, n = 6) in NPs was only observed in CRSwNP patients after prednisone treatment. In contrast, steroids do not alter basophil proportions (p = 0.48, n = 6) within NPs from either group. No significant shift in granulocyte subsets after steroid treatment was identified in the adjacent ethmoid mucosa or PBMCs from the same patients. Immunohistochemistry (IHC) staining supported these findings.", "Chronic rhinosinusitis (CRS) with nasal polyps (NP) represents a persistent inflammation often characterized by local hyper-immunoglobulinaemia and the presence of specific IgE to Staphylococcus aureus enterotoxins (SAEs). We aimed to study the systemic and local production of Igs in relation to plasma cells, B cells and specific IgE to SAEs. Concentrations of IgE, IgG, IgM, IgA, IgG subclasses and specific IgE to SAE were determined on tissue homogenates and serum from 15 CRS patients with NP, 15 CRS without NP and 10 control patients. Tissue cryo-sections were stained for CD19, CD20 and CD138 to demonstrate B and plasma cells. IgA, IgG and IgE concentrations were significantly higher in tissue homogenates, but not in serum, of NP compared with CRS and control subjects. NP with specific IgE to SAEs had significantly higher concentrations of IgG and IgE, and also showed a significantly higher fraction of IgG4 (P=0.003) and a lower fraction of IgG2 (P=0.04) than those without specific IgE production. Furthermore, naïve CD19(+) B cell and plasma cell counts (CD138(+)) were significantly higher in NP tissue compared with controls or CRS.", "Abnormalities in host mucosal immunity exist in chronic rhinosinusitis with nasal polyps (CRSwNPs), but it is unclear whether this is a cause or an effect of the eosinophilic inflammation and frequent microbial colonization that characterizes the disease. Sinonasal epithelial cells (SNECs) are critical participants in healthy antimicrobial innate immune defense. They also can promote Th2 inflammation with various mediators, including interleukin (IL)-33, which induces T helper cells to produce Th2 cytokines. CRSwNP SNECs were obtained during sinus surgery and stored. Patients were subsequently classified as either treatment responsive or treatment recalcitrant, based on long-term outcomes of medical and surgical therapy. Epithelial cells from these patients were grown in air-liquid interface (ALI) culture and treated with IL-13, as well as the bacteria-associated molecule, CpG. Expression of IL-33 mRNA was determined by real-time polymerase chain reaction. Recalcitrant CRSwNP epithelial cells had increased baseline expression of IL-33 compared with responsive CRSwNPs, which was further increased by 24-hour exposure to CpG. Treatment-responsive epithelial cells were not induced by CpG to express IL-33. Prolonged treatment with IL-13 during differentiation at the ALI diminished the baseline expression of IL-33 and prevented the subsequent induction of IL-33 by CpG.", "Smoking negatively affects postoperative evolution in patients with chronic rhinosinusitis (CRS); however, the mechanism remains incompletely described. In the lung, smoking increases expression of proinflammatory genes and is associated with an elevation of inflammatory serum markers. Our objective is to determine the impact of smoking on these biomarkers in CRS. Two existing populations of patients previously phenotyped for genetic association studies (206 patients with refractory CRS and 408 patients with CRS and nasal polyposis) were stratified according to self-reported smoking status and available serum biomarkers (complete blood count [CBC], total immunoglobulin E [IgE]). Asthma and bacterial cultures were evaluated. Active smoking was low in both groups (genetics of chronic rhinosinusitis 1 [GCRS1]: 11.2%; genetics of chronic rhinosinusitis 2 [GCRS2]: 9.4%). Total white blood cell (WBC) count was significantly higher in active smokers than in those who had never smoked and ex-smokers. Serum eosinophilia and prevalence of self-reported asthma was lower in active smokers than never-smokers. In the GCRS2 population, endoscopically-collected cultures trended toward a lower recovery rate of Staphylococcus aureus in smokers (p = 0.07). Never-smokers and ex-smokers had similar levels of WBCs and eosinophils.", "yes. Our data demonstrate that SEB-induced generation of Th1 and Th2 cytokines is increased in the presence of human blood and airway eosinophils. Thus, eosinophils can have an immunoregulatory function in pathogen-associated allergic diseases such as atopic dermatitis, chronic sinusitis, and asthma exacerbations.", "yes. This study further characterizes sinus and nasal granulocyte inflammation in chronic non-infectious sinusitis and rhinitis and suggests a differential role for ICAM-1 in neutrophil and eosinophil recruitment according to the allergic status.", "Despite advances in the diagnosis and treatment of chronic rhinosinusitis with nasal polyps (CRSwNP), their recurrence rate remains significant. There is a need for promptly-obtainable, inexpensive, minimally-invasive prognostic parameters to enable rhinologists to identify patients at higher risk of recurrent CRSwNP. The prognostic role of the neutrophil-to-lymphocyte ratio (NLR) and eosinophil-to-lymphocyte ratio (ELR), previously discussed as potential markers of inflammation, has already been investigated in CRSwNP. The aim of the present study was to test the prognostic value of the NLR and ELR, and also of the basophil-to-lymphocyte ratio (BLR) (given the emerging role of basophils in CRSwNP) in a large series of CRSwNP. The study concerned 240 patients who underwent FESS for CRSwNP from 2009 to 2014 and had a postoperative follow-up longer than 12months. We considered patients with recurrences as those with endoscopic evidence of at least grade I polyposis. In our series, the mean NLR, ELR and BLR were significantly higher in patients whose disease recurred than in those remaining recurrence-free (p=0.03, p=0.0001, and p=0.0002, respectively), but the discriminatory power of the NLR, ELR, or BLR in terms of disease recurrence was unacceptable (AUCs=0.600, 0.678, and 0.662, respectively).", "Asthmatic nasal polyps primarily exhibit eosinophilic infiltration. However, the identities of the immune cells that infiltrate non-asthmatic nasal polyps remain unclear. Thus, we thought to investigate the distribution of innate immune cells and its clinical relevance in non-asthmatic chronic rhinosinusitis (CRS) in Korea. Tissues from uncinate process (UP) were obtained from controls (n = 18) and CRS without nasal polyps (CRSsNP, n = 45). Nasal polyps (NP) and UP were obtained from CRS with nasal polyps (CRSwNP, n = 56). The innate immune cells was evaluated by immunohistochemistry such as, eosinophil major basic protein (MBP), tryptase, CD68, CD163, CD11c, 2D7, human neutrophil elastase (HNE) and its distribution was analyzed according to clinical parameters. In comparisons between UP from each group, CRSwNP had a higher number of MPB(+), CD68(+), and CD11c(+) cells relative to CRSsNP. Comparisons between UP and NP from CRSwNP indicated that NP have a higher infiltrate of MBP(+), CD163(+), CD11c(+), 2D7(+) and HNE(+) cells, whereas fewer CD68(+) cells were found in NP. In addition, MBP(+) and CD11c(+) cells were increased from UP of CRSsNP, to UP of CRSwNP, and to NP of CRSwNP. Moreover, in UP from CRSwNP, the number of MBP(+) and CD11c(+) cells positively correlated with CT scores. In the analysis of CRSwNP phenotype, allergic eosinophilic polyps had a higher number of MBP(+), tryptase(+), CD11c(+), 2D7(+) cells than others, whereas allergic non-eosinophilic polyps showed mainly infiltration of HNE(+) and 2D7(+) cells.", "Nasal polyposis associated with chronic rhinosinusitis (CRS) is a chronic inflammatory disease that is characterized by infiltration of many inflammatory cells. Meanwhile, interleukin (IL)-17A is a well-known proinflammatory cytokine that induces both eosinophilic and neutrophilic inflammation. We investigated the role of IL-17A in the development of nasal polyps in the CRS murine model. Eosinophilic CRS with nasal polyps was induced by using ovalbumin (OVA) and Staphylococcus aureus enterotoxin B (SEB) in wild-type BALB/c and IL-17A knockout (KO) mice. Histopathologic changes of the sinonasal cavity were evaluated using hematoxylin and eosin, Periodic acid-Schiff, Sirius red, Masson's trichrome, and immunohistochemistry. The levels of total and OVA-specific immunoglobulin Es (IgEs) in sera were measured using enzyme-linked immunosorbent assay. The expression levels of IL-4, IL-5, and interferon-γ (IFN-γ) in the nasal mucosa were assessed by quantitative real-time polymerase chain reaction. Under the IL-17A deficiency, total and OVA-specific IgEs in sera were reduced significantly. Infiltration of both eosinophils and neutrophils into the nasal mucosa, subepithelial fibrosis, and goblet cell count also decreased significantly in IL-17A KO mice treated with both OVA and SEB compared with those in the wild-type counterpart. However, there were no significant differences in the number of polypoid lesions among groups. Meanwhile, IL-4 increased and IFN-γ decreased in the nasal mucosa in IL-17A KO mice treated with both OVA and SEB.", "Innate and adaptive immune responses change with increasing age and affect the course of diseases. Previous study investigated immunologic alteration in Western nasal polyps (NP) which is mostly eosinophilic. However, there are no reports regarding age-related immune changes of non-eosinophilic NP (NE-NP) which is a predominant subtype in Asian population. A total of 153 subjects, including 20 with control, 63 with chronic rhinosinusitis (CRS) without NP (CRSsNP), and 70 with CRS with NP were enrolled. Age-related changes in computed tomography (CT), cytokines and clinical information were investigated. Tissue samples were analyzed for protein levels of IL-5, IL-17A, IL-23, interferon (IFN)-γ, CCL-11, and CXCL-8, using Luminex immunoassay and for mRNA expression levels of interleukin (IL)-5, IL-17A, IL-23p19, IFN-γ, CCL-11, CXCL-1, CXCL-2, CXCL-8, and CXCR2 by quantitative RT-PCR. Immunohistochemistry (IHC) was performed for the number of inflammatory cells. We observed that Lund-Mackay CT scores decreased with age in NE-NP. The number of human neutrophil elastase-positive cells and myeloperoxidase gene expression decreased in older patients with NE-NP, but not in control subjects, CRSsNP, and E-NP. Neutrophil-associated cytokines including IL-17A and IL-23, were negatively correlated with age in NE-NP at the protein and mRNA levels. Additionally, the expression of CXCR2, a receptor for CXCL-1 and CXCL-2, was decreased with age in NE-NP. However, there were no age-related changes in blood neutrophil count, and neutrophil-recruiting chemokines such as CXCL-1, CXCL-2, and CXCL-8. Elderly NE-NP patients showed better endoscopic scores at 12 months after surgery compared with the non-elderly.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by the accumulation of inflammatory cells; however, an eosinophil predominance is seen in white (Belgian), but not Asian (south Chinese), patients with polyps. We sought to investigate the association of inflammatory cell predominance with regulatory T-cell and T-effector cell patterns. Nasal mucosal tissue was obtained from 26 consecutive Belgian patients with CRSwNP and 21 Belgian control subjects and 29 south Chinese patients with CRSwNP and 29 south Chinese control subjects, who all underwent phenotyping, including nasal endoscopy and computed tomographic scanning. Tissues were investigated for granulocytes and their products and T-effector/regulatory T cells and related cytokines. Both CRSwNP groups were comparable in terms of symptoms, computed tomographic scan results, and nasal endoscopy results, but asthma comorbidity was significantly higher in white patients. Tissue from white patients with CRSwNP was characterized by eosinophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio > 2), whereas samples from Asian patients were biased toward neutrophilic inflammation (eosinophil cationic protein/myeloperoxidase ratio = 0.25). Both CRSwNP groups demonstrated significant upregulation of the T-cell activation marker soluble IL-2 receptor alpha and significant downregulation of Foxp3 expression and TGF-beta1 protein content versus their respective control groups. However, whereas white patients displayed a significant increase in T(H)2 cytokine and related marker levels versus control subjects and versus Asian patients, the latter showed a T(H)1/T(H)17 cell pattern versus control tissue.", "yes. This study indicates that IL-5 plays a key role in the pathophysiology of eosinophilic nasal polyps and may be produced by eosinophils.", "The aim of our study was to measure CCL24 (eotaxin-2) levels in nasal lavage fluid of patients with different forms of sinonasal chronic eosinophilic inflammation to verify the relationship with nasal hypereosinophilia and symptoms. Patients with nasal hypereosinophilia were randomly recruited and grouped in persistent allergic rhinitis, non-allergic rhinitis with eosinophilia syndrome (NARES) and chronic rhinosinusitis with polyps. Non rhinitic volunteers were recruited as controls. CCL24 concentration was measured by `Quantikine Human CCL24 Immunoassay`. Differential cell counts were performed by microscopic cytological examination of nasal tissue scraped by inferior turbinate. CCL24 levels measured in patient groups were significantly higher compared to control group with the highest levels in NARES patients. Eotaxin- 2 levels were significantly correlated to severity of symptoms and to the percentage of eosinophils in nasal tissue.", "yes. Chronic rhinosinusitis with nasal polyps is a major comorbid condition of AERD patients that is closely associated with severe asthmatic symptoms. Significant pathologic findings in nasal polyp tissues include intense eosinophilic inflammation, which is caused by elevated production of eosinophil-related cytokines and chemokines, specific immunoglobulin E responses to staphylococcal enterotoxins, and altered arachidonic acid metabolism. This could affect the current treatments and methodologies that are used to control asthma, leading to a more severe and intractable AERD phenotype.", "yes. Similar to observations in eosinophilic chronic rhinosinusitis, this study shows that active AR is associated with decreased SNEC TLR9 expression. These findings are consistent with the concept that Th2 cytokines suppress expression of TLR9 and other innate immune genes. Multiple endogenous and microbial factors likely modulate sinonasal innate immunity to maintain homeostasis and prevent infection in AR.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized as a Th2-driven disease. Activated dendritic cells (DCs) are the main T-cell activators; their role in the chronic inflammatory process of nasal polyposis is still unclear. The regulation of DC subsets was analyzed in nasal polyp tissue from CRSwNP patients and compared to inferior turbinate tissue from healthy subjects. Tissue localization and expression of both plasmacytoid and myeloid DCs were assayed by means of immunohistochemistry and flow cytometry. Plasmacytoid DCs were also assayed by PCR, and tissue homogenates were assayed for various inflammatory markers. The number of plasmacytoid (pDCs) and myeloid (mDCs) dendritic cells was significantly increased in nasal polyp tissue when compared to non-inflamed nasal mucosa. The number of pDCs, but not mDCs, was down-regulated in more severe cases (nasal polyps with asthma) and varied with the cytokine milieu. The amount of pDCs was significantly decreased in IL5+IFNγ - nasal polyp tissue compared to tissues with high IFNγ levels (IL5+IFNγ+). Furthermore, levels of indoleamine 2,3-dioxygenase were increased in nasal polyp compared to inferior turbinate tissue and correlated negatively with the number of pDCs.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disorder characterized by eosinophilic inflammation and local T-helper 2 (Th2) cytokine production. Innate lymphoid cells that elaborate Th2 cytokines have recently been characterized within nasal polyps. These cells can be activated by the epithelial cell-derived cytokine interleukin-33 (IL-33). The objective of this study is to determine whether 2 molecules associated with tissue damage (high mobility group box-1 [HMGB-1] and adenosine triphosphate [ATP]) elicit expression of IL-33 in sinonasal epithelial cells (SNECs) derived from recalcitrant CRSwNP patients. Ethmoid tissue was obtained from 8 recalcitrant CRSwNP and 9 control subjects during endoscopic sinus surgery (ESS). Tissue was prepared for immunohistochemistry and for SNEC air-liquid interface culture. After exposure to either HMGB1 or ATP in vitro, SNECs were processed for messenger RNA (mRNA) extraction and immunocytochemistry. IL-33 levels were determined by real-time polymerase chain reaction (PCR) and by immunochemical staining with anti-IL-33 antibody. Intranuclear IL-33 is normally expressed in basal epithelial cells, but is present in more apical cells and outside the nucleus in CRSwNP. Exposure of SNECs to HMGB-1 or ATP resulted in a statistically significant increase in IL-33 mRNA expression in SNECs derived from recalcitrant CRSwNP patients. This increase was reflected at the protein level by immunochemical staining of IL-33.", "The pathogenesis of chronic hyperplastic rhinosinusitis with massive nasal polyposis is still not entirely known. The present study evaluates the lymphocyte subpopulations and their production of cytokines using a technique for detection of intracytoplasmic cytokines by flow cytometry. This information may allow us to determine whether the source of these lymphocytes is from peripheral blood, the common mucosal immune system, or both. Detection of intracytoplasmic cytokines by flow cytometry was performed using a fluoresceinated monoclonal antibody directed against CD4+ and CD8+ lymphocytes and a rhodamine-labeled intracytoplasmic monoclonal antibody directed against four cytokines. In this way, the percentage of lymphocytes synthesizing TH1 and TH2 cytokines were identified in nasal polyp lymphocytes and the corresponding peripheral blood lymphocytes of 13 patients. Lymphocytes producing interferon-gamma and IL-2, as well as IL-4 and IL-5, were found in the nasal polyps, suggesting that the nasal polyp possesses both TH1 and TH2 cytokine expression. There are also significant differences between the percentage of lymphocytes producing these cytokines between nasal polyps and peripheral blood, suggesting that nasal polyp lymphocytes derive from at least another source than only peripheral blood lymphocytes. Statistical analysis of four groups of patients demonstrated that no statistically significant difference in the lymphocyte subpopulations in atopic versus non-atopic patients, nor aspirin-intolerant versus aspirin-tolerant patients. In general, CD8 cells always produce more interferon-gamma than IL-2 in both peripheral blood and nasal polyps. In contrast with this data, CD4 cells produce more IL-2 in the peripheral blood than in nasal polyps.", "Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with aberrant host defense responses. However, whether innate immunity is similarly impaired in patients with eosinophilic and those with noneosinophilic CRSwNP remains unclear. We sought to evaluate the expression and possible modulation of short palate, lung, and nasal epithelium clone 1 (SPLUNC1), an innate immune molecule, in the 2 CRSwNP subsets. Polyp tissue and uncinate processes were collected from 40 patients with CRSwNP, 27 patients with chronic rhinosinusitis without nasal polyps (CRSsNP), and 22 control subjects. Expression of SPLUNC1; Toll-like receptor (TLR) 2, TLR3, and TLR4; and the proinflammatory cytokines IL-1α, IL-4, IL-13, IL-17A, and IFN-γ was examined in nasal tissues. Additionally, SPLUNC1 expression in response to specific inflammatory stimulation was measured in cultured polyp epithelial cells and A549 cells. Polyp tissues exhibited significantly decreased expression of SPLUNC1 and other innate immune molecules compared with uncinate process tissues from patients with CRSwNP (P < .05), patients with CRSsNP, and healthy control subjects. Moreover, the eosinophilic CRSwNP subset exhibited significantly decreased SPLUNC1 expression and numbers of submucosal glands, as well as significantly increased IL-4 and IL-13 mRNA levels, compared with the noneosinophilic subset (P < .05). Accordingly, SPLUNC1 expression in polyp epithelial cells was significantly inhibited by IL-4 and IL-13 stimulation in vitro but was significantly upregulated after stimulation with TLR agonists and glucocorticoids (P < .05).", "Despite the high prevalence and morbidity of chronic rhinosinusitis (CRS), little is known about the mechanisms that underlie its pathogenesis. Recent studies have suggested that B cells might play an important role in CRS. We sought to thoroughly characterize B lineage cells within sinus tissues of patients with CRS and healthy control subjects and to determine whether levels of EBV-induced protein 2, which is known to play an important role in the development of B-cell responses, were increased in patients with CRS. Cells isolated from sinus tissues of patients with CRS and healthy control subjects were characterized by means of flow cytometry and immunohistochemistry. Local production of antibodies was measured in tissue extracts, nasal lavage fluid, and sera by using multiplex bead arrays and ELISA. Quantitative RT-PCR, ELISA, and Western blotting were used to assess gene and protein expression from tissue extracts. Nasal polyps (NPs) from patients with CRS had increased levels of both B cells and plasma cells compared with uncinate tissue from healthy control subjects (P<.05). NPs also contained significantly increased levels of several antibody isotypes compared with normal uncinate tissue (P<.05), but no differences in circulating antibody levels were found. Interestingly, levels of EBV-induced protein 2 were also increased in NPs (P<.05) and were positively correlated with expression of plasma cell markers (CD138 and B lymphocyte-induced maturation protein) in sinus tissue.", "yes. The significantly greater expression of sinonasal epithelial TLR9 in CF likely reflects increased antimicrobial innate immune activity in chronically colonized and frequently infected CF individuals. However, this finding contrasts with previously reported decreased epithelial TLR9 expression in eosinophilic CRS with nasal polyposis and may indicate differential modulation of innate immunity in Th1-predominent CF versus Th2-dominated CRS with nasal polyps, despite both being diseases of sinonasal mucosal inflammation.", "Group 2 Innate lymphoid cells (ILC2s) are innate cells that produce the TH2 cytokines IL-5 and IL-13. The importance of these cells has recently been demonstrated in experimental models of parasitic diseases but there is a paucity of data on ILC2s in the context of human parasitic infections and in particular of the blood dwelling parasite Schistosoma haematobium. In this case-control study human peripheral blood ILC2s were analysed in relation to infection with the helminth parasite Schistosoma haematobium. Peripheral blood mononuclear cells of 36 S. haematobium infected and 36 age and sex matched uninfected children were analysed for frequencies of ILC2s identified as Lin-CD45+CD127+CD294+CD161+. ILC2s were significantly lower particularly in infected children aged 6-9 years compared to healthy participants. Curative anti-helminthic treatment resulted in an increase in levels of the activating factor TSLP and restoration of ILC2 levels.", "yes. These data suggest a role for sinonasal epithelial cell-derived IL-33 and an IL-33-responsive innate lymphoid cell population in the pathophysiology of CRSwNP demonstrating the functional importance of innate lymphoid cells in Th2-mediated inflammatory disease.", "Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a disorder characterized by persistent eosinophilic Th2 inflammation and frequent sinonasal microbial colonization. It has been postulated that an abnormal mucosal immune response underlies disease pathogenesis. The relationship between Th2 inflammatory cytokines and the innate immune function of sinonasal epithelial cells (SNECs) has not been explored. Human SNECs (HSNECs) isolated from control subjects and patients with CRS were assessed for expression of antimicrobial innate immune genes and proinflammatory cytokine genes by real-time polymerase chain reaction, ELISA, and flow cytometry. A model of the Th2 inflammatory environment was created by exposure of primary HSNEC to the Th2 cytokine interleukin (IL)-4 or IL-13 for 36 hours, with subsequent assessment of innate immune gene expression. HSNEC obtained from CRSwNP patients displayed decreased expression of multiple antimicrobial innate immune markers, including toll-like receptor 9, human beta-defensin 2, and surfactant protein A. Baseline expression of these genes by normal and CRS HSNEC in culture is significantly down-regulated after incubation with IL-4 or IL-13.", "Chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP) are associated with Th1 and Th2 cytokine polarization, respectively; however, the pathophysiology of CRS remains unclear. The importance of innate lymphoid cells in Th2-mediated inflammatory disease has not been clearly defined. The objective of this study was to investigate the role of the epithelial cell-derived cytokine IL-33 and IL-33-responsive innate lymphoid cells in the pathophysiology of CRS. Relative gene expression was evaluated using quantitative real-time polymerase chain reaction. Innate lymphoid cells in inflamed ethmoid sinus mucosa from patients with CRSsNP and CRSwNP were characterized using flow cytometry. Cytokine production from lymphoid cells isolated from inflamed mucosa of patients with CRS was examined using ELISA and intracellular cytokine staining. Elevated expression of ST2, the ligand-binding chain of the IL-33 receptor, was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP and healthy control subjects. An increased percentage of innate lymphoid cells was observed in inflamed sinonasal mucosa from CRSwNP compared with CRSsNP. ST2(+) innate lymphoid cells are a consistent source of IL-13 in response to IL-33 stimulation. Significant induction of IL-33 was observed in epithelial cells derived from patients with CRSwNP compared with patients with CRSsNP in response to stimulation with Aspergillus fumigatus extract.", "Chronic rhinosinusitis (CRS) is a heterogeneous disease with an uncertain pathogenesis. Group 2 innate lymphoid cells (ILC2s) represent a recently discovered cell population which has been implicated in driving Th2 inflammation in CRS; however, their relationship with clinical disease characteristics has yet to be investigated. The aim of this study was to identify ILC2s in sinus mucosa in patients with CRS and controls and compare ILC2s across characteristics of disease. A cross-sectional study of patients with CRS undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies were obtained during surgery and control tissue from patients undergoing pituitary tumour resection through transphenoidal approach. ILC2s were identified as CD45(+) Lin(-) CD127(+) CD4(-) CD8(-) CRTH2(CD294)(+) CD161(+) cells in single cell suspensions through flow cytometry. ILC2 frequencies, measured as a percentage of CD45(+) cells, were compared across CRS phenotype, endotype, inflammatory CRS subtype and other disease characteristics including blood eosinophils, serum IgE, asthma status and nasal symptom score. 35 patients (40% female, age 48 ± 17 years) including 13 with eosinophilic CRS (eCRS), 13 with non-eCRS and 9 controls were recruited. ILC2 frequencies were associated with the presence of nasal polyps (P = 0.002) as well as high tissue eosinophilia (P = 0.004) and eosinophil-dominant CRS (P = 0.001) (Mann-Whitney U). They were also associated with increased blood eosinophilia (P = 0.005). There were no significant associations found between ILC2s and serum total IgE and allergic disease. In the CRS with nasal polyps (CRSwNP) population, ILC2s were increased in patients with co-existing asthma (P = 0.03). ILC2s were also correlated with worsening nasal symptom score in CRS (P = 0.04).", "yes. As ILC2s are elevated in patients with CRSwNP, they may drive nasal polyp formation in CRS. ILC2s are also linked with high tissue and blood eosinophilia and have a potential role in the activation and survival of eosinophils during the Th2 immune response. The association of innate lymphoid cells in CRS provides insights into its pathogenesis." ]

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["Secretory phospholipases A2 (sPLA2) initiate the biosynthesis of eicosanoids, are increased in the(...TRUNCATED)

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