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Journal ListTher Clin Risk Managv.3(4); 2007 AugPMC2374942
Logo of tcriskman
Ther Clin Risk Manag. 2007 Aug; 3(4): 613–619.
Published online 2007 Aug.
PMCID: PMC2374942
PMID: 18472983
A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma
Gennaro D'Amato, Antonello Salzillo, Amedeo Piccolo, Maria D'Amato, and Gennaro Liccardi
Author information Copyright and License information Disclaimer
Division of Respiratory and Allergic Diseases, High Speciality Hospital "A.Cardarelli", Napoli, Italy
Correspondence: Prof Gennaro D'Amato Director, Division of Respiratory and Allergic Diseases, High Speciality Hospital "A.Cardarelli", Rione Sirignano, 10–80121 Napoli, Italy Email ti.tfosibuq@otamadg
This article has been cited by other articles in PMC.
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Abstract
Bronchial asthma is recognized as a highly prevalent health problem in the developed and developing world with significant social and economic consequences. Increased asthma severity is not only associated with enhanced recurrent hospitalization and mortality but also with higher social costs. The pathogenetic background of allergic-atopic bronchial asthma is characterized by airway inflammation with infiltration of several cells (mast cells, basophils, eosinophils, monocytes, and T-helper (Th)2 lymphocytes). However, in atopic asthma the trigger factors for acute attacks and chronic worsening of bronchial inflammation are aeroallergens released by pollens, dermatophagoides, and pets, which are able to induce an immune response by interaction with IgE antibodies. Currently anti-inflammatory treatments are effective for most asthma patients, but there are asthmatic subjects whose disease is not completely controlled by inhaled or systemic corticosteroids and who account for a signific ant portion of the healthcare costs of asthma. A novel therapeutic approach to asthma and other allergic respiratory diseases involves interference in the action of IgE, and this antibody has been viewed as a target for novel immunological drug development in asthma. Omalizumab is a humanized recombinant monoclonal anti-IgE antibody approved for treatment of moderate to severe IgE-mediated (allergic) asthma. This non-anaphylactogenic anti-IgE antibody inhibits IgE functions, blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade, omalizumab represents a new class of mast cells stabilizing drugs; it is a novel approach to the treatment of atopic asthma. Omalizumab therapy is well tolerated and significantly improves symptoms and disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids. Moreover, omalizu mab improves quality of life of patients with severe persistent allergic asthma which is inadequately controlled by currently available asthma medications. In conclusion omalizumab may fulfil an important need in patients with moderate to severe asthma.

Keywords: airway hyper-reactivity, asthma, allergic respiratory diseases, atopic respiratory diseases, anti-IgE therapy, hypersensitivity, monoclonal anti-IgE antibody, omalizumab
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Introduction
Bronchial asthma is a chronic disease of airways which is recognized as a highly prevalent health problem in the developed and developing world. Asthma is characterized by bronchial inflammation, airway hyper-responsiveness induced by specific and nonspecific stimuli, and reversible bronchial obstruction with the appearance of respiratory symptoms such as dyspnea, chest tightness, wheezing, and cough. Airway inflammation plays a central role in the pathogenesis of bronchial asthma and is associated with an increase in airway responsiveness to several trigger factors such as aeroallergens which induce bronchoconstriction in atopic asthma patients.

The pathogenesis of bronchial asthma is not completely understood and it is well known that this clinical condition has a multifactorial etiology (D'Amato and Holgate 2002; Loddenkemper et al 2003; Masoli et al 2004; Rabe et al 2004). Although some asthmatic subjects exhibit a pathogenesis in which immunoglobulin E (IgE)-mediated mechanisms are not evident, asthma is almost always associated with some type of IgE-related reaction and therefore has an allergic basis (Holt et al 1999). Allergic bronchial asthma is a Th2 mediated chronic inflammatory disease of the airways, and IgE antibodies, Th2 derived cytokines, and eosinophils play a major role in the development of chronic airway inflammation, which is observed even in subjects with very mild disease (Wenzel et al 1991; Busse et al 1995; Novak and Bieber 2003). In other words the development of inflammation in asthma involves a complex array of several inflammatory mediators that promote the recruitment and activation of various different immune cells (T-lymphocytes of the T-helper type 2 phenotype, eosinophils, macrophages/monocytes, and mast cells) and regulate inflammatory cell trafficking into the lungs.

Activation of chemokine receptors triggers multiple cascades of intracellular signaling events that lead to recruitment and activation of immune effector cells. The inhibition of specific chemokines and receptors could prevent the excessive recruitment of inflammatory cells into the airways.

A number of selective chemokine receptor antagonists or anti-inflammatory chemokines are currently at various stages of development, but there are no products yet ready for clinical use.

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From IgE antibodies to therapy with monoclonal anti-IgE (omalizumab)
Elevated serum levels of specific IgE in response to common environmental aeroallergens are a key component in the pathogenesis of allergic asthma. IgE antibodies cause chronic airway inflammation through effector cells such as mast cells and basophils activated via high-affinity (FcεRI) or low-affinity (FcεRI) IgE receptors which bind these antibodies.

IgE is an immunoglobulin, consisting, like the other four antibody classes, of a variable antigen-binding fragment (Fab) region and a receptor-binding constant (Fc) region. The whole molecule consists of two heavy (H) ε chains and two light (L) chains of the k or λ type.

There is also high association between serum IgE levels and FcεRI receptors on precursor dendritic cells, and the expression of these receptors on antigen presenting cells such as dendritic cells is increased in asthmatic patients (Hollowaj 2001).

Since the discovery of IgE this antibody has been viewed as a target for novel immunological drug development in asthma, and a number of strategies to inhibit its proinflammatory action have been developed.

Current treatment for asthma suggested by the Global Initiative for Asthma (GINA) guidelines includes several drugs (relievers and controllers), in particular corticosteroids able to reduce recruitment and activation of inflammatory cells, in particular eosinophils, in the airways (NHLBI -GINA 2006).

Previous GINA documents subdivided asthma into four categories by severity based on the level of symptoms, airflow limitation, and lung function variability: Intermittent, Mild Persistent, Moderate Persistent, or Severe Persistent.

The GINA 2006 update recognizes, however, that asthma severity involves both the severity of the underlying disease and its responsiveness to treatment. In addition, severity is not an unvarying feature of an individual patient's asthma, but may change over months or years. Therefore GINA, for this purpose, suggests that a periodic assessment of asthma control is more relevant and useful.

The burden of asthma is greatest in patients with inadequately controlled severe persistent asthma symptoms, limitations in normal daily activities, medical resource utilization, and both direct and indirect costs.

The available treatments are effective for most of these asthma patients, but there are subjects affected by severe asthma who continue to experience debilitating disease, because their control is incomplete by inhaled or systemic corticosteroids associated with other drugs such as beta-2 bronchodilators (short- and long-acting), leukotriene receptor antagonists (Bateman 2004; Partridge 2006).

These patients are at high risk of life-threatening exacerbation, hospitalization, and mortality (Tough 1998; Serra-Batles et al 1998; Guite 1999) and are most affected in terms of quality of life (Turk 2005).

The economic impact of asthma is considerable. Approximately US$13 billion were spent in the United States in 1998 (for indirect and direct cost) (Redd 2002) and €18 billion in Europe in 2003 (European Lung white book 2003).

Several studies have also indicated that asthma severity is associated not only with poor control, such as symptoms, recurrent hospitalization, lower quality of life (QoL), but also with higher social costs (Strunk and Bloomberg 2006), and that the economic burden of asthma increases with asthma severity and is greatest in this patient group (Antonicelli et al 2004).

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Omalizumab in the treatment of IgE-mediated (allergic) asthma
Omalizumab, an anti-IgE monoclonal antibody, can reduce free IgE levels avoiding the binding of IgE to FcεRI without the following development of allergic reaction (Boulet et al 1997; Fahy et al 1997; Chang 2000; Fahy 2000; Holgate et al 2001; Godard et al 2002; Kuehr et al 2002; Mankad et al 2003; D'Amato et al 2004, 2006). Omalizumab acts as a neutralizing antibody by binding IgE at the same site (Cε3 domain of Fc fragment) as the high affinity receptor (FcεRI) binds IgE. Consequently, IgE effector functions (cross linking IgE and triggering degranulation and synthesis of new-generated chemical mediators of IgE-sensitized cells) and the following activation of mast cells and basophils are inhibited (Buhl et al 2002a, b; Ayres et al 2004; Deniz and Gupta 2005; Holgate et al 2005) (Table 1). In other words in allergic subjects, and in the elderly (Milgrom et al 2001), omalizumab prevents the activation of cellular response and reduces occurrence of asthma symptoms (see Table 2).

Table 1
Biological characteristics of omalizumab

Omalizumab expresses a high degree of isotype specificity and can neutralize serum free IgE without affecting other antibody classes.

Omalizumab binds to serum free IgE and reduces IgE serum concentration, but does not bind to high- or low-affinity IgE receptors on inflammatory cells. However, it blocks IgE binding to these receptors and the IgE effector cells of inflammation are "disarmed".

Long-term treatment (3 months or more) with omalizumab induced down-regulation of the high-affinity receptors on basophils and dendritic cells.

Omalizumab does not induce extensive immune complex formation, but only microcomplexes (thrimeric or exameric) which are not able to induce immune-complex pathology.

Omalizumab activity does not depend on the allergic-atopic sensitization to various types of aeroallergens (seasonal and/or perennial).

Omalizumab is active in case of IgE-mediated sensitization to one or more aeroallergens.

Table 2
Omalizumab in clinical studies in allergic asthma patients

Omalizumab has been shown to:
Decrease IgE-induced bronchoconstriction during both the early- and late-phase responses to inhaled allergen during the bronchial provocation tests.

Reduce skin prick test response to allergenic extracts.

Reduce asthma exacerbations regardless of the type of seasonal or perennial allergic sensitization.

Have a corticosteroid sparing effect.

Reduce the use of bronchodilators.

Improve also the nasal symptoms in subjects with allergic rhinitis associated with asthma.

Improve quality of life in patients with asthma, and also in those with severe persistent allergic asthma that is inadequately controlled by currently available asthma medication.

Have a reassuring safety profile similar to that of placebo. In malignant neoplasms observed in patients treated with omalizumab, blinded and unblended expert oncologist review showed that the neoplasms were most likely pre-existent and there was no evidence that any of neoplasms were linked causally to omalizumab treatment.

Studies in patients with atopic asthma showed that anti-IgE antibodies decrease serum IgE levels in a dose-dependent manner and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen (Chang 2000; Fahy 2000).

Serum free IgE is dramatically reduced after omalizumab administration and the expression of high-affinity receptors is significantly reduced after 3 months' treatment (MacGlashan et al 1997). Also, skin test reactivity is reduced by omalizumab (Togias et al 1998).

In patients who experience asthma associated with allergic rhinitis there is an improvement also in nasal symptoms (Casale et al 1999; Adelroth et al 2000; Kopp et al 2002; Plewako et al 2002; Vignola et al 2004). Omalizumab administered together with specific immunotherapy can help to reduce risk of serious adverse events such as anaphylaxis and the need for epinephrine and corticosteroid use to treat adverse reactions (Casale 2006). However, omalizumab is useful also if used without contemporaneous administration of specific immunotherapy.

In several clinical controlled trials omalizumab reduced asthma-related symptoms, decreased corticosteroid use, and improved quality of life of asthmatic patients (Buhl et al 2002a, b; Ayres et al 2004; Deniz and Gupta 2005; Niebauer et al 2006). Recent studies show the benefits of anti-IgE as add-on therapy in patients with moderate and severe persistent asthma who are inadequately controlled by antiasthma pharmacological therapy. The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases (allergic conjunctivitis and rhinitis, atopic dermatitis, and food allergy) and a favorable side-effect profile regardless of the type of allergic sensitization (seasonal or perennial) (Casale et al 1999; Adelroth et al 2000; Buhl et al 2002b; Plewako et al 2002; Kopp et al 2002; Ayres et al 2004; Vignola et al 2004; Deniz and Gupta 2005). Omalizumab was shown not only to inhibit mast cell and basophil responses but also to have an inhibiting effect on inflammatory cells, such as eosinophils, T lymphocytes, and B lymphocytes which are fundamental to the chronic inflammatory response in allergic diseases such as asthma. This increased understanding places anti-IgE therapy firmly in the domain of an anti-inflammatory treatment for chronic allergic disease, with effect on multiple cell types (Chang and Shiung 2006; D'Amato 2006).

Severe or refractory asthma remains a frustrating disease for both patients and the clinicians treating them (Busse et al 2000; Humbert et al 2005; Wenzel 2005; Moore et al 2007).

Severe asthma has been defined as persisting symptoms due to asthma despite high-dose inhaled steroids (1000 μg beclometasone dipropionate or equivalent) plus long- acting beta-2 agonist (LABA), with the requirement for either maintenance systemic steroids or at least two rescue courses of steroids over 12 months and despite trials of add-ons such as leukotriene-receptor antagonist or theophylline.

The Global Initiative for Asthma (GINA) document for patients with uncontrolled asthma (step 5) recommends the use of high-dose inhaled corticosteroids plus a LABA, and, if required, one more additional controller such as omalizumab.

Response to treatment can take several weeks to appear and it is suggested that patients should be treated for at least 12 weeks before efficacy is assessed (Bousquet et al 2005).

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Experimental and controlled clinical studies
During the clinical trial on omalizumab 7 pivotal studies were performed on patients with moderate to severe IgE-mediated allergic asthma. One of these, the INNOVATE (INvestigatioN of Omalizumab in seVere Asthma TrEatment) study, was specifically designed to evaluate the efficacy and safety of add-on therapy with omalizumab in this difficult-to-treat asthma population (Humbert et al 2005).

In the INNOVATE trial were enrolled patients aged 12–75 years with severe persistent allergic asthma (GINA step 3 or 4 clinical features despite step 4 therapy). 108 centers in 14 countries participated in the study. Subjects enrolled had reduced lung function and not adequate symptom control despite therapy with a high dose of inhaled corticosteroids (ICS) (>1000 μg/day beclometasone dipropionate equivalent) and LABA stimulant bronchodilators, with a recent history of clinically significant exacerbation. After a run-in phase, patients were randomized to receive double-blind therapy with omalizumab or placebo for 28 weeks.

The primary efficacy variable was the rate of clinically significant asthma exacerbations (defined as a worsening of asthma symptoms requiring treatment with systemic corticosteroids). Other efficacy variables included the rate of severe exacerbations (peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1) <60% of personal best, requiring treatment with systemic corticosteroids), total emergency visits for asthma, asthma-related quality of life (Juniper Adult Asthma Quality of Life Questionnaire; AQLQ), clinical symptom score, morning PEF, rescue medication use, and global evaluation of treatment effectiveness by patients and investigators. Safety was evaluated by observing adverse events and by monitoring laboratory parameters and vital signs. A total of 419 patients were included in the efficacy analyses (omalizumab, n = 209; placebo, n = 210). All patients were receiving ICS and LABA and two-thirds were receiving additional controller medications (including 22% oral corticosteroids). Patients had experienced an average of 2.1 exacerbations per year requiring systemic corticosteroids and 67% were considered at high risk of asthma-related death (based on previous history of emergency department or hospital visits or intubations).

After adjusting for an observed imbalance in asthma exacerbation history prior to randomization, the rate of clinically significant asthma exacerbations was significantly reduced by 26.2% with omalizumab versus placebo (0.68 and 0.91, respectively; p = 0.042).

Treatment with omalizumab significantly reduced the rate of severe asthma exacerbations in comparison with placebo (0.24 vs 0.48, p = 0.002) and the rate of total emergency visits for asthma (0.24 vs 0.43, p = 0.038). Significantly greater improvements were obtained with omalizumab compared with placebo in AQLQ scores, with a significantly greater proportion of patients receiving omalizumab achieving a clinically meaningful (>0.5-point) improvement from baseline compared with placebo treated patients (61% and 48%, respectively; p = 0.008).

The overall changes from baseline in mean morning PEF (p = 0.042) and total asthma symptom score (p = 0.039) during the treatment period were also significantly greater with omalizumab, which was considered more effective than placebo (p < 0.001) by both investigators and patients.

The pooled data from all clinical studies in patients with severe persistent asthma show that omalizumab is highly efficacious as add-on treatment to concomitant asthma therapy, as shown by the consistent reduction in asthma exacerbation rates compared with control-treated patients. Overall, exacerbations were significantly reduced (p < 0.0001) by 38.3% (annualized rate: 0.910 vs 1.474) with omalizumab compared with the control group (Table 3).

Table 3
Reduction in asthma exacerbation rates across studies

Rate per year P-Value for rate ratio Exac. rate treatment difference
Omalizumab Control
INNOVATE study 1.37 1.86 0.042 0.49
ETOPA study1 0.98 2.47 <0.001 1.49
SOLAR study2 0.49 0.79 0.027 0.29
Busse study3,4 0.59 0.99 <0.001 0.40
Solèr study5,6 0.51 1.21 <0.001 0.70
Holgate study7 1.18 1.60 0.165 0.42
ALTO safety study 1.02 1.20 0.077 0.18
Pooled 0.91 1.47 <0.001 0.56
1 Ayres et al 2004
2 Vignola et al 2004
3 Busse et al 2001
4Lanier et al 2003
5Solèr et al 2001
6 Buhl et al 2002
7Holgate et al 2004
Omalizumab significantly reduced the rate of emergency visits for asthma care by 47% compared with control therapy (p < 0.0001). Hospital admissions were reduced by 52%, emergency room visits by 61%, and unscheduled doctor visits by 47% (Bousquet 2005).

The clinical study showed also that side-effects following treatment with omalizumab were mild to moderate and did not differ significantly from placebo with the exception of injection site reactions, and no anti-omalizumab antibody response has been observed (Walker 2006).

A recent exploratory study on allergic subjects living in poor urban areas of Brazil, at high risk of helminthes infections, showed that omalizumab appeared to be effective and safe, but may be associated with a possible slightly increased risk of infections (not statistically significant) (Cruz 2007).

Further studies will need to focus on the utility of long-term treatment with anti-IgE to reduce the risk of life-threating reactions in subjects with food allergy, latex allergy, or stinging insect hypersensitivity.

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Preparation for use
Omalizumab is administered by subcutaneous injection. The appropriate dose and dosing frequency of omalizuamb is determined by baseline IgE (IU/mL) measured before start of treatment, and body weight (kg). Based on these measurements, 75–375 mg of omalizumab in 1–3 injections may be needed for each administration.

Omalizumab is supplied as a lyophilized, sterile powder in single-use, 5-mL vials designed to deliver either 150 or 75 mg on reconstitution with sterile water for injection. The powder requires 15–20 minutes or more to dissolve. The solution is viscous and must be carefully drawn up into the syringe before it is administered. Usually the injection needs 5–10 seconds for administration. Once prepared, omalizumab must be injected within 4 hours if at room temperature or 8 hours if refrigerated. It is important to schedule appointment for injection, avoiding preparing injection until the patient arrives. This results in visits that take 1 hour or more, since 30 minutes of observation after the injection are recommended.

Total serum IgE levels are generally increased during treatment, since there are circulating IgE-antiIgE complexes (Hamilton et al 2005).

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Conclusions
Studies of patients with allergic asthma show that anti-IgE treatment with omalizumab has a reassuring safety profile. The drug was approved for commercial use in allergic asthma by the Federal Drug Administration in June 2003 and by the European Agency for Evaluation of Medicinal Products in July 2005.

Analysis of data from controlled clinical trials carried with patients affected by severe allergic asthma showed that omalizumab is well-tolerated and safe both in short-term and long-term studies. It is well tolerated, and its overall adverse event profile is similar to that of placebo.

Several clinical studies have shown no evidence that omalizumab enhanced the risk of anaphylactic reactions, infections or parasitic infestations, or bleeding-related or any immune complex diseases or similar syndromes. As for malignant neoplasms observed in patients treated with omalizumab during a pivotal trial, blinded and unblended expert oncologists review showed that the neoplasms were most likely pre-existent and there was no evidence that any of neoplasms were linked causally to omalizumab treatment.

Because omalizumab is administered infrequently, with twice-monthly or monthly dosing, anti-IgE therapy may be useful in patients who have difficulty in complying with daily treatment.

Since omalizumab treatment induces a reduction in FcεRI and IgE+ cells in the airways of asthma patients and because a relationship between FcεRI expression and fatal asthma has been hypothesized (Fregonese et al 2004), the possible effect of omalizumab in reducing the risk of mortality induced by severe asthma should be considered.

A recent study demonstrated that omalizumab add-on in patients with severe allergic asthma results in a cost-per-quality-adjusted life year ratio that compares favorably with other uses of scarce healthcare resources that are recommended by national reimbursement bodies and could be considered cost-effective. In the current climate of scarce healthcare resources, it is important to demonstrate both economic value as well as therapeutic value of a treatment (Brown 2007). Omalizumab offers both therapeutic and economic value and represents a major advance for the treatment of patients with inadequately controlled severe persistent allergic asthma.

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Η ομαλιζουμάμπη (omalizumab) είναι εξανθρωποποιημένο μονοκλωνικό αντίσωμα που προκύπτει από ανασυνδυασμένο DNA, το οποίο δεσμεύει εκλεκτικά την ανθρώπινη ανοσοσφαιρίνη Ε (IgE). Η ομαλιζουμάμπη δεσμεύεται με την IgE και εμποδίζει τη σύνδεση της IgE με τον FcsRI (υποδοχέας IgE υψηλής συγγένειας) και κατά συνέπεια μειώνει την ποσότητα ελεύθερης IgE που είναι διαθέσιμη για να δώσει το έναυσμα για τον αλλεργικό καταρράκτη. Η αγωγή των ατοπικών ατόμων με ομαλιζουμάμπη είχε ως αποτέλεσμα μια σημαντική προς τα κάτω ρύθμιση των υποδοχέων FcsRI στα βασεόφιλα.

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Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2021 Feb 3;56(2):150-152. doi: 10.3760/cma.j.cn115330-20201112-00864. Online ahead of print.

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PMID:33548945 | DOI:10.3760/cma.j.cn115330-20201112-00864

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Journal ListHHS Author ManuscriptsPMC2904676
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Am J Rhinol. Author manuscript; available in PMC 2010 Jul 15.
Published in final edited form as:
Am J Rhinol. 2008 Mar–Apr; 22(2): 115–121.
doi: 10.2500/ajr.2008.22.3136
PMCID: PMC2904676
NIHMSID: NIHMS212987
PMID: 18416964
Th2 cytokines associated with chronic rhinosinusitis with polyps down-regulate the antimicrobial immune function of human sinonasal epithelial cells
Murugappan Ramanathan, Jr., M.D.,* Won-Kyung Lee, M.S.,* Ernst W. Spannhake, Ph.D.,# and Andrew P. Lane, M.D.*
Author information Copyright and License information Disclaimer
* Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
# Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
Address correspondence and reprint requests to Andrew P. Lane, M.D., Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Outpatient Center, 6th Floor, 601 North Caroline Street, Baltimore, MD 21287-0910, ude.imhj@3enala
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Abstract
Background
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.

Methods
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.

Results
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.

Conclusion
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.

Keywords: Chronic, epithelial, innate, innate immunity, nasal polyps, polyps, rhinosinusitis, Th2 cytokines, TLR9
Although significant progress has been made in the treatment of sinonasal inflammatory disease, chronic rhino-sinusitis with nasal polyps (CRSwNP) remains an entity that is particularly difficult to treat.1–3 The clinical behavior of CRSwNP often defies the classic concepts underlying current management strategies in rhinosinusitis. Specifically, surgical reestablishment of sinus ostial patency and clearing of infection within the sinus cavities does not necessarily reverse the disease process and restore normal function in CRSwNP. Although, in general, the majority of sinusitis cases do respond to this proven therapeutic approach, those that fail tend to be characterized by persistence of mucosal inflammation, despite widely patent sinus openings, and a continued microbial presence, despite adequate antimicrobial coverage. For these recalcitrant forms of sinusitis, research is clearly needed to understand the basic pathophysiology and to develop novel treatment alternatives.

In many respects, recalcitrant CRSwNPs appears to be an inflammatory disorder of the local mucosal immune system. The sinonasal mucosa is a first site of contact between the host and the outside environment and consequently has a critical role in host defense.4 Many microorganisms enter the sinonasal tract during the act of breathing, but multiple innate immune mechanisms normally serve to remove potential pathogens.5–7 Through secretion of antimicrobial products, mucociliary clearance, and activation of appropriate adaptive immune processes, the sinonasal epithelial lining is able to create an environment that is inhospitable to infecting organisms. However, in CRSwNP, these protective functions seem to be diminished, permitting microbial colonization within the nose and sinus cavities. This perceived persistence of infection in CRSwNPs is frequently the impetus for repeated medical and surgical therapy. Although several factors might contribute to impaired mucosal immunity, our p revious research suggests that there is a relative decrease in expression of innate immune genes related to microbial recognition by sinonasal epithelial cells. Failure of epithelial cells to identify potential pathogens at the mucosal surface and respond vigorously and immediately to them may contribute to the development of microbial colonization in CRSwNP. In turn, epithelial "barrier defects" have been postulated to activate proinflammatory adaptive immune mechanisms in other mucosal-based human diseases.8,9

In previous studies, we have shown that messenger RNA for pattern recognition receptors known as toll-like receptors (TLRs) is expressed in sinonasal mucosa, both in health and in sinus disease.10,11 Activation of TLRs on sinonasal epithelial cells (SNECs) induces expression of innate immune effector genes and signaling molecules such as defensins, complement components, and interleukin-8 (IL-8).12 TLRs are transmembrane receptors that interact with pathogen ligands through an extracellular domain and signal the presence of the microbial products through an intracellular domain.13 At least 10 TLRs that recognize specific pathogen molecules are expressed in the sinonasal mucosa, each of which is thought to play a role in the innate immune response to both innocuous microbes in the sinonasal cavity as well as airborne bacterial, fungal, or viral pathogens.14 Among the TLRs, we have been particularly interested in TLR9, in which its ligand is bacterial or viral unmethylated CpG DNA. TLR 9 is strongly expressed in normal nasal epithelium, and its expression is significantly down-regulated in the SNEC of patients with CRSwNP.15,16 In addition, activation of TLR9 by CpG is known to be Th1 polarizing and capable of suppressing Th2 inflammation. Given that CRSwNP is a Th2-biased eosinophilic inflammatory condition characterized by bacterial colonization, these features of TLR9 biology suggest a possible role in CRSwNP pathogenesis. We have hypothesized that underactivity of the innate immune system in the sinonasal mucosa may play a role in the perpetuation of Th2 inflammation and the failure to restore Th1–Th2 balance in CRSwNP. Moreover, relative down-regulation of TLR9 in recalcitrant CRSwNP may contribute to the colonization of the sinonasal cavities with bacteria and fungi.

A distinguishing feature of CRSwNP is the predominance of eosinophils and a Th2 cytokine profile in the sinus mucosa.3 The basis for this immune phenotype is unknown, and both host and exogenous mechanisms have been proposed. The effect of an established Th2-biased inflammatory mediator environment on the function of the human sinonasal epithelium has not been investigated directly. There is increasing evidence that a Th2 cytokine milieu may inhibit innate antibacterial activity at mucosal surfaces. For example, in human intestinal epithelial cells, Mueller et al. indicated that Th2 cytokines suppress antimicrobial immunity.17 Similarly, Beisswenger et al. showed that pulmonary antibacterial host defense was inhibited in a murine model of allergic airway inflammation.18 Further evidence of a down-regulation of innate immunity in Th2 nasal inflammation is provided by a study by Kirtsreesakul et al. examining clearing of Streptococcus pneumoniae infection in allergic mice.19 It was fou nd that nasal allergen-sensitized BALB/c mice (in which a Th2 inflammatory response is favored) were less able to clear infection than C57BL/6 mice (which favor a Th1 response). Our previous observation that TLR and immune effector genes are down-regulated in recalcitrant CRSwNP patients is consistent with a similar suppression of epithelial innate immune function by Th2 cytokines within the sinonasal mucosa. At the same time as antibacterial innate immune genes are down-regulated in recalcitrant CRSwNP, we also have found that "antiparasite" or proeosinophilic genes, such as acidic mammalian chitinase, are up-regulated.20 We propose that Th2 cytokines present in CRSwNPs direct the innate immune activity of epithelial cells into an antiparasite program of gene expression at the expense of the Th1-induced antimicrobial pattern. In this way, Th2 inflammation within the sinonasal epithelium may create a permissive environment for microbial colonization.

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METHODS
Human Subjects
Thirty-two patients with CRS and 10 control subjects were enrolled in the study. The research protocol was approved through the Johns Hopkins Institutional Review process, and all subjects gave signed informed consent. The CRS subjects were classified into CRSwNP and chronic rhinosinusitis without nasal polyps (CRSsNP) groups as defined by historical, endoscopic, and radiographic criteria and by meeting the definition of the American Academy of Otolaryngology–Head and Neck Surgery Chronic Rhinosinusitis Task Force.3 Specifically, the patients had continuous symptoms of rhino-sinusitis as defined by the Task Force report for >12 consecutive weeks, associated with computed tomography of the sinuses revealing isolated or diffuse sinus mucosal thickening or air–fluid levels. CRSwNP patients had at least one sinonasal polyp present on nasal endoscopy before or at the time of endoscopic sinus surgery. Surgery was performed only if a patient's symptoms and radiographic findings failed to resolve, despite at least 6 weeks of treatment with oral antibiotics, topical corticosteroids, decongestants, and mucolytic agents, as well as 4 weeks of systemic corticosteroid.

After surgery, CRSwNP patients underwent endoscopic surveillance at regular intervals as per the normal practice of the senior investigator. Patients with recurrence or persistence of polyps after at least 6 months after the surgery, despite a standard postoperative medical regimen including topical corticosteroids, saline lavage, and allergy therapy as indicated, were further subclassified as having "recalcitrant" disease.

The control subjects had no evidence of sinus disease and were undergoing endoscopic approaches for orbital decompression, cerebrospinal fluid leak repair, or sphenoidotomy for biopsy of an isolated, noninflammatory sphenoid sinus process. Before surgery, both the CRS patients and the control subjects received 1 week of oral methylprednisolone and oral antibiotics. All tissue specimens were taken from the resected uncinate process and anterior ethmoid sinus. The specimens were immediately placed in saline on ice and transported to the laboratory for epithelial cell isolation and culture.

Epithelial Cell Dissociation from Human Sinus Mucosal Tissue
Mucosal tissue removed during endoscopic sinus surgery was collected into sterile cold saline and transferred to phosphate-buffered saline (PBS) supplemented by penicillin (100 U/mL; Gibco, Gaithersburg, MD), streptomycin (100 μg/mL; Gibco), amphotericin B (2.5 μg/mL; Gibco), and gentamicin (50 μg/mL; Gibco). The samples were placed through a cell strainer (BD Falcon, Sigma, St. Louis, MO) into Ham's F12 media containing 0.01% protease Sigma type XIV (Sigma) and supplemented with antibiotics as above. Digestion in protease was performed at 4°C overnight, with separation of cells by agitation the following day. The cells were separated by straining into a conical tube to which fetal bovine serum (FBS) was added to a final concentration of 10%, inactivating the protease. The cells were centrifuged twice at 1300 rpm for 10 minutes, after which the supernatant was aspirated and discarded. The washed passage 0 (P0) epithelial cells were then seeded, at a density of ≥1.5 × 104 cel ls/cm2, onto Vitrogen 100-coated (1:75 in sterile water; Cohesion, Palo Alto, CA) P-100 dishes in bronchial epithelium growth medium (BEGM) as previously described.21 The cells were then grown at 37°C for 24 hours and then washed with Hanks Balanced Salt Solution (HBSS; Biofluids, Rockville, MD) to remove debris. The media was then changed every 48 hours until the cells reached confluence.

SNEC Culture at the Air–Liquid Interface (ALI)
Confluent cells were washed with HBSS before trypsinization and then treated at 37°C for 4 minutes with a solution containing 0.2% Trypsin (Sigma), 1% polyvinylpyrrolidone (Sigma), and 0.02% EGTA (Sigma) in HBSS. The trypsin was then neutralized by the addition of an equal volume of cold soybean trypsin inhibitor at a concentration of 1 mg/mL in Ham's F12 media. Dissociated cells were washed and resuspended into BEGM media and plated into human type IV placental collagen (type VI; Sigma) coated 6-well Falcon filter inserts (0.4 μm pore size; Becton Dickinson, Franklin Lakes, NJ). The P1 cells were grown to confluence with BEGM, above (1 mL) and below (2 mL) the cells. When confluent, medium is removed from above the cultures and the medium below the inserts was changed to ALI medium consisting of LHC Basal Medium/DMEM-H (50:50; Gibco) containing the same concentrations of additives as BEGM with the exception that the concentration of epidermal growth factor is reduced to 0.63 ng/ mL, and amphotericin B is omitted. Each set of cultures came from a separate patient source and was maintained at the ALI with the apical surfaces remaining free of medium for at least 3 weeks before study.

Stimulation of Cells
Ciliated epithelial cells at the ALI were stimulated apically with 5–25 ng/mL of IL-4 or IL-13 or with 50 ng/mL of IFN-γ diluted in ALI medium for 36 hours. In other experiments, cells were exposed to 10 μmol of TLR9 agonist (invivogen). Control wells were stimulated with 0.5 mL of ALI medium alone. In the flow cytometry experiment, cells were treated with 10 ng/mL of IL-4 and IL-13.

Flow Cytometric Analysis of Intracellular TLR9 Expression
Adherent cells at the ALI were detached from 6-well inserts as described previously and transferred into 1.5-mL microfuge tubes at a concentration of 1 × 106 cells/tube. Cells were first fixed and permeabilized using a kit from eBiosciences (San Diego, CA). Briefly, cells were fixed using 100 μL of fixation buffer for 20 minutes at room temperature followed by two washed in permeabilization buffer. Permeabilized cells were then incubated with either 0.5 μg of phycoerythrin-conjugated TLR9 or rat anti-human IgG isotype control (eBiosciences) for 30 minutes at 4°C. Cells were then centrifuged and washed twice with cold PBS with sodium azide and 2% FCS and resuspended in PBS. All cells were also stained with FITC antiepithelial cell antigen (Dako, Carpinteria, CA) to verify purity of epithelial cells. Analysis was performed on a FACScalibur flow cytometer and data were analyzed using CellQuest software (BD Biosciences, San Jose, CA). Cell surface protein is expressed as the increase in mean fluorescence intensity over background (species-specific isotype-matched control) or percentage of positive staining cells.

RNA Extraction/Reverse Transcription
Total RNA was isolated with RNeasy Mini kit (Qiagen, Valencia, CA) using the manufacturer's protocol. RNA was quantified spectrophotometrically and absorbance ratios at 260/280 nm were >1.80 for all samples studied. Five hundred nanograms of total RNA was reverse transcribed in a 20-μL volume with random hexamer primers (Invitrogen, Carlsbad, CA), 20 U of RNase inhibitor (Applied Biosystems, Foster City, CA), and Omniscript RT kit (Qiagen) under conditions provided by the manufacturer.

Real-Time Polymerase Chain Reaction (PCR)
Real-time PCR was performed in a Light-Cycler 1.2 (Roche Applied Science, Indianapolis, IN) using the SYBR Green PCR Kit (Qiagen). The 18S (sense, 5′-GTAACCCGTTGAAC-CCCATT-3′; antisense, 5′-CCATCCAATCGGTAGTAGCG-3′) was used as a internal control. The reaction mix consisted of 50 ng of cDNA (target genes) or 5 ng of cDNA (18S RNA), 10 μL of QuantiTect SYBR Green PCR, and 0.5 mol/L of primers in a total volume of 20 μL. All primers were commercially synthesized by Invitrogen. The cycle parameters used were 95°C for 15 minutes to activate Taq polymerase, followed by 35 cycles at 94°C for 15 seconds, 60°C for 30 seconds, and 72°C for 30 seconds. Amplicon expression in each sample was normalized to its 18S RNA content. The level of expression of target mRNA was determined as ΔCT. The ΔCT method uses the difference in CT value obtained between normalizing housekeeping gene (18S) and target gene to calculate relative quantification (ΔCT = the difference in threshold cycles for target and housekeeping gene). This normalization reduces sample-to-sample variations in signal strength. A decrease in the ΔCT by 1 U equals a doubling of the level of the target gene. Consistent use of cDNA described previously (50 and 5 ng for target molecules and 18S RNA, respectively) resulted in highly reproducible real-time PCR cycle thresholds for each of the amplicons across all cell samples. Negative controls, consisting of reaction mixtures containing all components except target cDNA, were included in each PCR run.

ELISA of IL-6, IL-8, Eotaxin-3, and Human β-Defensin 2 (HBD-2)
HBD-2, eotaxin-3, IL-6, and IL-8 released to culture medium were quantified using ELISA according to the manufacturer's instructions (IL-6, IL-8, and eotaxin-3 from BD Biosciences; HBD-2 from Peprotech, Rocky Hill, NJ).

Statistical Analysis
Raw data from real-time PCR were entered into a spreadsheet (Excel; Microsoft Corp., Redmond, WA). Statistical analysis was performed using software (Excel). Data are expressed as mean ± SEM. Statistical significance of differences was determined using either a two sample t-test assuming unequal variances for parametric data, or a Wilcoxon signed rank test for nonparametric paired data. Differences were considered statistically significant at p < 0.05.

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RESULTS
SNECs were obtained from 9 control subjects and 19 CRSwNP patients in the initial set of experiments. mRNA was extracted after growth in culture at the ALI. The CRSwNP patients were subdivided into recalcitrant and responsive groups (10 subjects and 9 subjects, respectively) based on endoscopic evidence of recurrence or persistence of polyps at least 6 months after surgery. Real-time PCR analysis revealed decreased expression of mRNA for the innate immune proteins HBD-2, mannose binding lectin, and surfactant protein A in the recalcitrant CRS groups versus controls (Fig. 1). In addition, flow cytometry showed decreased basal expression of TLR9 in cultured HSNEC from CRSwNP patients when compared with controls (Fig. 2).

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Figure 1
Cultured SNECs from patients with recalcitrant CRSwNP have diminished baseline mRNA expression of HBD-2, surfactant protein A, and mannose binding lectin. SNECs isolated from patients with and without CRSwNP were grown in cell culture for 2–3 weeks before harvesting of cells for flow cytometry and extraction of mRNA. The level of expression of mRNA for mannose-binding lectin, HBD-2, and SPA was measured by real-time PCR. In each case, expression was reduced in recalcitrant CRS versus controls. (A) SPA, *0.08; (B) HBD-2, *0.04; (C) MBL, *0.04. Columns represent means ± standard error of the mean.

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Figure 2
Cultured SNECs from patients with recalcitrant CRSwNP have diminished baseline expression of TLR9 protein. In fixed and permeabilized SNECs from control subjects, intracellular TLR9 was evident in 49–91% of cells. In contrast, TLR9 expression was shown in 11–16% of cultured sinonasal cells from 10 CRSwNP patients. This difference was statistically significant (p = 0.005).

To investigate the impact of the cytokine milieu in CRSwNP on the expression of TLR9 by HSNEC, we used an epithelial cell culture model system. We obtained HSNEC from control subjects and from grossly uninflamed regions of sinus mucosa in CRSsNP patients. We first examined the effect of IFN-γ, a prototypical Th1 cytokine on TLR9 protein expression. When cultured HSNECs from five control subjects were stimulated with IFN-γ, there was an increase in TLR9 by an average of 49.8%, as detected by flow cytometry, compared with unexposed cells from the same patient (Fig. 3). We assessed the functionality of the TLR9 receptor on HSNECs from five control subjects by exposure to its agonist, CpG DNA (10 μmol) for 36 hours. Evaluation of supernatents for HBD-2 and IL-8 protein revealed induction of both genes after TLR9 stimulation (Fig. 4). The induction of HBD-2 achieved statistical significance (p = 0.03), whereas IL-8 did not (p = 0.1).

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Figure 3
IFN-γ stimulation increases TLR9 expression in cultured HSNECs. The Th-1 promoting cytokine, IFN-γ, increases TLR9 expression by SNECs derived from control subjects by an average of 49.9%. This figure depicts an example of a flow cytometry histogram plot from one subject.

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Figure 4
Expression of HBD-2 and IL-8 by cultured HSNECs is increased by exposure to TLR9 agonist. Exposure to TLR9 agonist in vitro induces expression of HBD-2 and IL-8 protein as assessed by ELISA (*p = 0.03, Wilcoxon signed rank; columns represent means ± standard error of the mean).

In additional experiments designed to simulate the cytokine milieu in CRSwNP, cultured HSNECs from four control and four CRSsNP subjects were exposed to a combination of IL-4 and IL-13. These Th2 cytokines had the opposite effect to interferon-γ, with an average decrease in TLR9 expression by 46.6% (Fig. 5). Supernatants from these cultures were collected and analyzed by ELISA along with an additional four control and nine CRSsNP patient cultures. The expression of secreted IL-6, IL-8, HBD-2, and eotaxin 3 proteins was assessed by ELISA in HSNECs exposed to IL-4 and IL-13 alone or in combination. Pilot experiments revealed that both cytokines had approximately the same effect (data not shown); therefore, the remaining experiments used IL-4 only. In both control and CRSsNP patients (n = 10), it was found that IL-4 reduced expression of IL-6, IL-8, and HBD-2, while very significantly inducing expression of eotaxin 3 (Fig. 6). The magnitude of the effect did not vary between HSNECs der ived from control and CRS subjects (data not shown). In 10 HSNEC cultures from individual subjects, real-time PCR was used to determine the effect of IL-4 on expression of surfactant protein A and TLR9 mRNA. This analysis revealed a significant decrease in the expression of TLR9 mRNA (p = 0.01) and a trend toward decreased SPA mRNA after IL-4 treatment (p = 0.2; Fig. 7).

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Figure 5
Exposure of cultured HSNECs to IL-4 decreases expression of TLR9 protein. Th2 cytokines IL-4/IL-13 (25 μg/mL) decreased TLR9 expression in SNECs from both CRS and control patients at ALI by 50%, as determined by flow cytometry. The figure depicts a representative flow cytometry histogram plot from a single subject.

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Figure 6
Exposure of cultured HSNECs to IL-4 decreases expression of TLR9 protein, HBD-2, IL-6, and IL-8, while increasing expression of eotaxin. Cultured HSNEC were exposed to IL-4 at the ALI for 36 hours, and the supernatants were collected for analysis by ELISA. The expression of HBD-2, IL-8, and IL-6 was reduced over baseline (p = 0.05, 0.07, and 0.003, respectively), while eotaxin 3 expression was greatly increased (p = 0.03). Columns represent means from 10 different subjects ± standard error of the mean.

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Figure 7
Exposure of cultured HSNECs to IL-4 decreases expression of TLR9 protein and surfactant protein A mRNA. Cultured HSNEC from 10 subjects were exposed to IL-4 at the ALI for 36 hours and then processed for mRNA extraction. Real-time PCR was used to assess expression of surfactant protein A and TLR9 mRNA before and after IL-4 exposure. Expression of both innate immune genes was reduced, with TLR9 reaching statistical significance (p = 0.01, Wilcoxon signed rank). Columns represent means ± standard error of the mean.

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DISCUSSION
In this study, we presented a novel discovery that Th2 cytokines, in particular IL-4, can modulate the expression of innate immune genes by SNECs. Our findings suggest that IL-4 acts on SNECs in vitro to down-regulate production of TLR9, SPA, HBD-2, IL-6, and IL-8. Epithelial cells derived from patients with recalcitrant CRSwNP displayed decreased expression of SPA, HBD-2, and mannose binding lectin. In contrast, the Th1 cytokine IFN-γ increases TLR9 expression, and CpG DNA (TLR9 ligand) stimulates production of multiple innate immune effectors and pro-Th1 chemokines. Thus, the antimicrobial immune activity of HSNECs may be directed, at least in part, by the local cytokine milieu. Because CRSwNP is characterized by Th2-biased inflammation, the resulting down-regulation of antimicrobial mucosal immunity could then contribute to the chronic state of sinonasal infection or microbial colonization. Although Th2 cytokines blunt the antimicrobial response of SNECs, they also induce express ion of proeosinophilic mediators, such as eotaxin and acidic mammalian chitinase.20 Taken together, these relationships suggest that an interaction exists between the adaptive immune system and the innate immune function of the epithelial cells that line the sinonasal mucosa. The local Th1/Th2 cytokine environment influences the nature of the innate immune response, perhaps helping to explain the permissive environment for microbial colonization found in CRSwNP.

The initiating factors that underlie persistent inflammation and microbial colonization in CRSwNP are not well understood. Although Th2 inflammation is a central characteristic of the active disease process, what triggers the local production of Th2 cytokines and infiltration of lymphocytes and eosinophils in the first place is unknown. Multiple groups have proposed that CRS results from an abnormal immune response to microorganisms or their products, including fungi, Staphylococci, Pseudomonal biofilms, or viruses.22–29 Innocuous or ubiquitous agents do not ordinarily generate a vigorous immune response in healthy hosts, and normal mucosal immune activity against potential microbial pathogens typically involves elaboration of innate immune effectors and Th1-like inflammatory mediators. In CRSwNP, the mucosal immune abnormality appears to be twofold: on the one hand, there is a failure to prevent or eliminate microbial colonization of the sinonasal cavities, and on the other hand, there is a seemingly inappropriate Th2-biased immune response perpetuated within the mucosa. The results of this study would suggest that these issues are related, i.e., that the latter contributes to the former. Whether or not the opposite is true—that exogenous agents or microorganisms can drive the mucosal immune response in a Th2 direction—is an area of current investigation.

As an initial point of contact between the host and the outside world, the sinonasal tract is constantly exposed to microorganisms. There are constitutively active mechanisms that serve to keep the growth of "normal flora" in check and clear microbes to the nasopharynx. The transitory presence of organisms generally is tolerated by the mucosal immune system, and this does not elicit a significant inflammatory reaction. In an analogous manner, multiple bacterial species colonize the mucosa of the intestines, where they coexist commensally with the host. In both the intestine and the airway, experimental evidence suggests that Th2 cytokines inhibit innate immune activity of the epithelium and may promote bacterial overgrowth. In vitro experiments with human intestinal epithelial cells reveal that Th2 cytokines down-regulate TLR expression and inhibit TLR signaling function.17 In human bronchial epithelial cells, exposure to Th2 cytokines also blunts the innate immune response to Ps eudomonas.18 Although no mouse model currently exists for CRSwNP, mice with allergic Th2 inflammation of the upper and lower airways have been generated. In both cases, airway Th2 inflammation leads to decreased expression of innate immune genes and reduced capacity to clear experimentally induced infection.18,19 Taken together, these studies strongly support the validity of the in vitro findings with HSNECs that we have described.

Multiple lines of evidence suggest that dysregulation of the complex interaction between the host and microbial agents at the sinonasal mucosal surface may underlie CRSwNP. A cause-and-effect relationship between Th2 inflammation and microbial colonization might explain the presence of chronic infection and biofilms within the nose and sinuses in polypoid rhinosinusitis. The opposite causal relationship is conceivable also, although to date there is little evidence that infectious agents can directly elicit Th2-type inflammation of the type seen in CRSwNP. Nonetheless, because epithelial cell innate immune function may be modulated by cytokines, it is possible that dysregulation of this same pathway may result in diminished antimicrobial function even in the absence of Th2 cytokines. We speculate that exogenous stimuli exist that bind to yet unidentified pattern recognition receptors on epithelial cells, leading to such a proeosinophilic, or "antiparasite," program of gene expres sion.4,20 Dysregulated activity of an epithelial cell-driven, Th2-biased, mucosal innate immune response would be consistent with the characteristic clinico-pathological features of CRSwNP (Fig. 8).

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Figure 8
Role of Th2 cytokines in the characteristic pathophysiology of CRSwNP. The presence of Th2 cytokines in CRSwNP is a prominent feature that relates to the eosinophilic inflammatory histopathology. Evidence presented in this study strongly suggests that Th2 cytokines also suppress innate immune functions of SNECs, which might contribute to microbial colonization in the disease. Whether or not microbial agents in turn stimulate Th2 cytokines and eosinophilic inflammation is a topic for future study.

Maintenance of mucosal homeostasis is a host defense function involving cooperation between multiple integrated immune components. Clearly, studying SNECs in culture imperfectly models the immune function of these cells in vivo. It is important to recognize that the cells lack their normal interactions with other resident cell populations and mediators, which may modulate their function and gene activity. Also, growth in culture, in and of itself, may lead to phenotypic changes that affect innate immune gene expression. We are actively exploring these issues in ongoing studies with acutely isolated brushings of epithelial cells and by developing in vivo animal models of Th2 sinonasal inflammation. Additional research will be needed to better define the precise role by which cytokines modulate TLR9 and other innate immune effector levels at the transcriptional level. A better understanding of the sinonasal mucosal innate immune system and its interaction with microbes and their produc ts has the potential to result in new approaches to the management of recalcitrant CRSwNP.

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Footnotes
Presented at the spring meeting of the American Rhinologic Society, San Diego, California, April 27, 2007

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References
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Review Innate immunity of the sinonasal cavity and its role in chronic rhinosinusitis.
[Otolaryngol Head Neck Surg. 2007]
Review Mucus clearance as a primary innate defense mechanism for mammalian airways.
[J Clin Invest. 2002]
Killing of gram-negative bacteria by lactoferrin and lysozyme.
[J Clin Invest. 1991]
Review New insights into the cellular immunology of the intestine in relation to the pathophysiology of inflammatory bowel diseases.
[Acta Gastroenterol Belg. 2006]
Review Innate immunity in the mucosal immune system.
[Curr Pharm Des. 2006]
Innate immunity of the sinonasal cavity: expression of messenger RNA for complement cascade components and toll-like receptors.
[Arch Otolaryngol Head Neck Surg. 2004]
Altered expression of genes associated with innate immunity and inflammation in recalcitrant rhinosinusitis with polyps.
[Am J Rhinol. 2006]
Activation of airway epithelial cells by toll-like receptor agonists.
[Am J Respir Cell Mol Biol. 2004]
Review Toll-like receptors and immune response in allergic disease.
[Clin Rev Allergy Immunol. 2004]
Review Mammalian Toll-like receptors.
[Curr Opin Immunol. 2003]
Expression of Toll-like receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis.
[Respir Res. 2007]
Sinonasal epithelial cell expression of toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps.
[Am J Rhinol. 2007]
Review Rhinosinusitis: Establishing definitions for clinical research and patient care.
[Otolaryngol Head Neck Surg. 2004]
Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells.
[J Immunol. 2006]
Allergic airway inflammation inhibits pulmonary antibacterial host defense.
[J Immunol. 2006]
Effect of genetic background on the response to bacterial sinusitis in mice.
[Arch Otolaryngol Head Neck Surg. 2006]
Increased expression of acidic mammalian chitinase in chronic rhinosinusitis with nasal polyps.
[Am J Rhinol. 2006]
Review Rhinosinusitis: Establishing definitions for clinical research and patient care.
[Otolaryngol Head Neck Surg. 2004]
mRNA for genes associated with antigen presentation are expressed by human middle meatal epithelial cells in culture.
[Laryngoscope. 2004]
Increased expression of acidic mammalian chitinase in chronic rhinosinusitis with nasal polyps.
[Am J Rhinol. 2006]
Chronic rhinosinusitis: an enhanced immune response to ubiquitous airborne fungi.
[J Allergy Clin Immunol. 2004]
Bacterial biofilms on the sinus mucosa of human subjects with chronic rhinosinusitis.
[Laryngoscope. 2006]
Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells.
[J Immunol. 2006]
Allergic airway inflammation inhibits pulmonary antibacterial host defense.
[J Immunol. 2006]
Effect of genetic background on the response to bacterial sinusitis in mice.
[Arch Otolaryngol Head Neck Surg. 2006]
Review Innate immunity of the sinonasal cavity and its role in chronic rhinosinusitis.
[Otolaryngol Head Neck Surg. 2007]
Increased expression of acidic mammalian chitinase in chronic rhinosinusitis with nasal polyps.
[Am J Rhinol. 2006]
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