Background
The objective of this study was to describe the first US‐based study to use the European Position Paper on Rhinosinusitis (EPOS) criteria to study the prevalence of chronic rhinosinusitis ...(CRS) in a general‐population sample.
Methods
A CRS symptom questionnaire was mailed to 23 700 primary care patients from Geisinger Clinic, a health system serving 45 counties in Pennsylvania. CRS cases were categorized into four unique subgroups based on EPOS symptoms: obstruction and discharge with no smell loss or pain/pressure; smell loss without pain/pressure; facial pain and/or pressure without smell loss; and both smell loss and pain/pressure. All cases were required to have nasal obstruction or discharge. Logistic regression was used to evaluate potential factors associated with CRS subgroups.
Results
We found that 11.9% of patients met criteria for CRS. Prevalence peaked at 15.9% between ages 50 and 59 years and then dropped to 6.8% after age 69. The odds of CRS was higher among patients who were white, younger, smokers, had a history of Medical Assistance, and had other diseases. When CRS subgroups were modeled separately, these associations were no longer significant for some CRS subgroups. Comorbid diseases were most strongly associated with CRS cases who reported smell loss and facial pain and/or pressure and had the weakest associations with CRS cases who did not report these symptoms.
Conclusions
CRS is a highly prevalent and heterogeneous condition. Differences in risk factors and health outcomes across symptom subgroups may be indicative of differences in etiology that have implications for disease management.
Summary
Chronic rhinosinusitis (CRS) has been known as a disease with strong infectious and inflammatory components for decades. The recent advancement in methods identifying microbes has helped ...implicate the airway microbiome in inflammatory respiratory diseases such as asthma and COPD. Such studies support a role of resident microbes in both health and disease of host tissue, especially in the case of inflammatory mucosal diseases. Identifying interactive events between microbes and elements of the immune system can help us to uncover the pathogenic mechanisms underlying CRS. Here we provide a review of the findings on the complex upper respiratory microbiome in CRS in comparison with healthy controls. Furthermore, we have reviewed the defects and alterations of the host immune system that interact with microbes and could be associated with dysbiosis in CRS.
Pathogenesis of nasal polyposis Hulse, K. E.; Stevens, W. W.; Tan, B. K. ...
Clinical & experimental allergy/Clinical and experimental allergy,
February 2015, Letnik:
45, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Summary
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large proportion of the population world‐wide and is associated with high cost of ...management and significant morbidity. Yet, there is a lack of population‐based epidemiologic studies using current definitions of CRSwNP, and the mechanisms that drive pathogenesis in this disease remain unclear. In this review, we summarize the current evidence for the plethora of factors that likely contribute to CRSwNP pathogenesis. Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL‐5, thymic stromal lymphopoietin and CCL11, that help to initiate and perpetuate this chronic inflammatory response. Together, these factors likely combine to drive the influx of a variety of immune cells, including eosinophils, mast cells, group 2 innate lymphoid cells and lymphocytes, which participate in the chronic inflammatory response within the nasal polyps. Importantly, however, future studies are needed to demonstrate the necessity and sufficiency of these potential drivers of disease in CRSwNP. In addition to the development of new tools and models to aid mechanistic studies, the field of CRSwNP research also needs the type of robust epidemiologic data that has served the asthma community so well. Given the high prevalence, costs and morbidity, there is a great need for continued research into CRS that could facilitate the development of novel therapeutic strategies to improve treatment for patients who suffer from this disease.
Chronic rhinosinusitis (CRS) is a complex disease consisting of several disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is ...possibly the greatest obstacle in understanding the causes of CRS and improving treatment. It is generally agreed that there are clinically relevant CRS phenotypes defined by an observable characteristic or trait, such as the presence or absence of nasal polyps. Defining the phenotype of the patient is useful in making therapeutic decisions. However, clinical phenotypes do not provide full insight into all underlying cellular and molecular pathophysiologic mechanisms of CRS. Recognition of the heterogeneity of CRS has promoted the concept that CRS consists of multiple groups of biological subtypes, or “endotypes,” which are defined by distinct pathophysiologic mechanisms that might be identified by corresponding biomarkers. Different CRS endotypes can be characterized by differences in responsiveness to different treatments, including topical intranasal corticosteroids and biological agents, such as anti–IL-5 and anti-IgE mAb, and can be based on different biomarkers that are linked to underlying mechanisms. CRS has been regarded as a single disease entity in clinical and genetic studies in the past, which can explain the failure to identify consistent genetic and environmental correlations. In addition, better identification of endotypes might permit individualization of therapy that can be targeted against the pathophysiologic processes of a patient's endotype, with potential for more effective treatment and better patient outcomes.
Summary
Background
B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic ...rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways.
Objective
We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation.
Methods
We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody‐secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT‐PCR.
Results
NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein–Barr virus‐induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody‐secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro.
Conclusions and Clinical Relevance
Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC‐mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell‐targeted therapies may provide new treatment options for CRSwNP.
It has become increasingly clear that airway epithelial cells are central participants in innate and adaptive immune responses as well as mucosal inflammation. Epithelial cells produce antimicrobial ...host defense molecules, proinflammatory cytokines and chemokines in response to activation via pathogen recognition receptors. Recruitment of immune cells including dendritic cells, T cells and B cells into the proximity of epithelium results in the enhancement of adaptive immunity through interactions with epithelial cells. Newly identified epithelial-derived cytokines, including TSLP, IL-33 and BAFF, help to shape the local accumulation and activation of Th2 responses and B cell immunoglobulin production. Epithelial cells are also downstream targets of molecules that activate IL-13R and EGFR and are responsible for mucus production in both protective immune responses and allergic airway inflammatory diseases. Improved understanding of epithelial immune and inflammatory responses will hopefully suggest new strategies for therapeutic intervention.
Background
Glucocorticoid resistance has been associated with Th17‐driven inflammation, the mechanisms of which are not clear. We determined whether human and mouse Th17 cells are resistant to ...glucocorticoid‐induced apoptosis.
Methods
Freshly isolated human blood Th17 cells and in vitro differentiated Th17 cells from IL‐17F red fluorescent protein reporter mice were treated with dexamethasone, a potent glucocorticoid. Apoptosis was measured using annexin V and DAPI staining. Screening of apoptosis genes was performed using the apoptosis PCR array. Levels of molecules involved in apoptosis were measured using quantitative RT‐PCR, flow cytometry, and Western blotting. Knockdown of BCL‐2 in murine Th17 cells was performed via retroviral transduction. Cytokines were measured using ELISA. A murine Th17‐driven severe asthma model was examined for Th17 glucocorticoid sensitivity in vivo.
Results
Human and mouse Th17 cells and mouse Th2 cells were resistant to glucocorticoid‐induced apoptosis. Th17 cells had glucocorticoid receptors levels comparable to those in other T effectors cells. Th17 cells had high levels of BCL‐2, knockdown of which sensitized Th17 cells to dexamethasone‐induced apoptosis. Production of IL‐22, but not IL‐17A and IL‐17F, was suppressed by glucocorticoids. STAT3 phosphorylation in Th17 cells was insensitive to glucocorticoid inhibition. Lung Th17 cells in the murine severe asthma model were enhanced, rather than suppressed, by glucocorticoids.
Conclusion
Th17 cells are resistant to glucocorticoid‐induced apoptosis and cytokine suppression, at least in part due to high levels of BCL‐2. These findings support a role of Th17 cells in glucocorticoid‐resistant inflammatory conditions such as certain endotypes of asthma.
Background
Chronic rhinosinusitis (CRS) is a disease characterized by inflammation of the nasal mucosa and paranasal sinuses. This inflammation may result in part from decreased epithelial barrier ...and innate immune responses, leading to frequent bacterial and fungal colonization. The objectives of this study were to investigate the expression of innate immune proteins of the palate lung and nasal epithelium clone (PLUNC) family in patients with CRS.
Methods
Nasal tissue samples were collected from control subjects and CRS patients with and without nasal polyps. Expression of the members of the PLUNC family was analyzed by real‐time PCR. Expression of SPLUNC1 and LPLUNC2 proteins was analyzed by ELISA, immunoblot, and immunohistochemical analysis.
Results
Levels of mRNA for most of the members of the PLUNC family were profoundly reduced in nasal polyps (NPs) compared to uncinate tissue from control subjects or patients with CRS. LPLUNC2 and SPLUNC1 proteins were decreased in NPs of patients with CRS compared to uncinate tissue from control subjects. Immunohistochemical data revealed that within submucosal glands of sinonasal tissues, SPLUNC1 and LPLUNC2 were differentially expressed, in serous and mucous cells, respectively. The decrease in the expression of these molecules is probably explained by a decrease in the number of glands in NPs as revealed by correlations with levels of the glandular marker lactoferrin.
Conclusions
Decreased SPLUNC1 and LPLUNC2 in NPs reflect a profound decrease in the number of submucosal glands. Decreased glands may lead to a localized defect in the production and release of glandular innate defense molecules.
Summary
Background
Eosinophilic and non‐eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) display distinct patterns of inflammation. However, the pathogenic mechanisms underlying the ...heterogeneity of CRSwNP need further investigation.
Objective
To investigate local immunoglobulin E (IgE) production and phenotype of mast cells in eosinophilic and non‐eosinophilic CRSwNP in Chinese.
Methods
Total and specific IgE levels were analysed by means of the ImmunoCAP system. The molecular steps involved in class‐switch recombination to IgE were investigated using RT‐PCR assays. Mast cell phenotypes, IgE‐ and high‐affinity IgE receptor (FcεRI)‐positive cells, and allergen binding to specific IgE in sinonasal mucosa were determined by means of immunohistochemistry.
Results
Compared with controls and non‐eosinophilic CRSwNP, local total IgE levels were increased, and local specific IgE to common aeroallergens was more frequently found, in Chinese eosinophilic CRSwNP independent of atopy and without significant association with Staphylococcus aureus enterotoxins. The ε germline gene transcript was also more frequently detected in eosinophilic CRSwNP. The number of IgE‐ and FcεRI‐positive cells was increased in eosinophilic CRSwNP. Most IgE‐ and FcεRI‐positive cells were mast cells. Dust mite antigens could bind to IgE on mast cells in situ. The number of mast cells positive for both tryptase and chymase and activated mast cells was increased in eosinophilic CRSwNP and the number of activated mast cells positively correlated with local IgE level, eotaxin‐1 level, and eosinophil count in CRSwNP.
Conclusions and Clinical Relevance
The local IgE induced by common aeroallergens may mediate mast cell activation and contribute to subsequent eosinophilic inflammation in Chinese CRSwNP. This study offers a rationale for considering intervention strategies designed to target ‘local allergy’ in eosinophilic CRSwNP.
Summary
Background
Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is ...excessive fibrin deposition, which is associated with down‐regulation of tissue plasminogen activator (t‐PA) in NPs. As t‐PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t‐PA would be a potential new strategy for the treatment of NPs.
Objective
The objective of this study was to determine whether short‐chain fatty acids (SCFAs) can induce t‐PA in airway epithelial cells via their known receptors GPR41 and GPR43.
Methods
We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein‐coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t‐PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA.
Results
Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t‐PA expression from two‐ to tenfolds. The strongest inducer of t‐PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t‐PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t‐PA by SCFAs was dependent upon both GPR41 and GPR43.
Conclusions and Clinical Relevance
Short‐chain fatty acids were shown to induce airway epithelial cell expression of t‐PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.
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