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author:("boris, Larry")
2.  Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation 
Nature  2012;493(7433):547-551.
Lung epithelial cells can influence immune responses to airway allergens1,2. Airway epithelial cells also undergo apoptosis after encountering environmental allergens3; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1. Inducible deletion of Rac1 expression specifically in airway epithelial cells in a mouse model resulted in defective engulfment by epithelial cells and aberrant anti-inflammatory cytokine production. Intranasal priming and challenge of these mice with house dust mite extract or ovalbumin as allergens led to exacerbated inflammation, augmented Th2 cytokines and airway hyper-responsiveness, with decreased interleukin (IL)-10 in bronchial lavages. Rac1-deficient epithelial cells produced much higher IL-33 upon allergen or apoptotic cell encounter, with increased numbers of nuocyte-like cells1,4,5. Administration of exogenous IL-10 ‘rescued’ the airway inflammation phenotype in Rac1-deficient mice, with decreased IL-33. Collectively, these genetic and functional studies suggest a new role for Rac1-dependent engulfment by airway epithelial cells and in establishing the anti-inflammatory environment, and that defects in cell clearance in the airways could contribute to inflammatory responses towards common allergens.
doi:10.1038/nature11714
PMCID: PMC3662023  PMID: 23235830
3.  A 71-year-old man with anaphylaxis after eating grits 
The allergist is frequently called on to evaluate patients after episodes of anaphylaxis to determine the cause and implement preventive measures that will reduce the patient’s risk from future episodes. The etiology of anaphylaxis can be the result of numerous causes that may go undiagnosed if a thorough evaluation is not performed. We present a 71-year-old man with no history of food allergy or atopy who presented to the emergency room and then our allergy clinic for evaluation after suffering anaphylaxis after a meal of grits and shrimp. The underlying diagnosis, which was subsequently determined, requires a high index of suspicion and should be included in the differential diagnosis of any patient presenting with unexplained anaphylaxis.
doi:10.2500/aap.2012.33.3476
PMCID: PMC3894600  PMID: 22370536
4.  Decision-making analysis for allergen immunotherapy versus nasal steroids in the treatment of nasal steroid–responsive allergic rhinitis 
Background:
The purpose of the study was to determine the age at which initiation of specific subcutaneous immunotherapy (SCIT) becomes more cost-effective than continued lifetime intranasal steroid (NS) therapy in the treatment of allergic rhinitis, with the use of a decision analysis model.
Methods:
A Markov decision analysis model was created for this study. Economic analyses were performed to identify “break-even” points in the treatment of allergic rhinitis with the use of SCIT and NS. Efficacy rates for therapy and cost data were collected from the published literature. Models in which there was only incomplete improvement while receiving SCIT were also evaluated for economic break-even points. The primary perspective of the study was societal.
Results:
Multiple break-even point curves were obtained corresponding to various clinical scenarios. For patients with seasonal allergic rhinitis requiring NS (i.e., fluticasone) 6 months per year, the age at which initiation of SCIT provides long-term direct cost advantage is less than 41 years. For patients with perennial rhinitis symptoms requiring year-round NS, the cut-off age for SCIT cost-effectiveness increases to 60 years. Hypothetical subjects who require continued NS treatment (50% reduction of previous dosage) while receiving SCIT also display break-even points, whereby it is economically advantageous to consider allergy referral and SCIT, dependent on the cost of the NS prescribed.
Conclusion:
The age at which SCIT provides economic advantages over NS in the treatment of allergic rhinitis depends on multiple clinical factors. Decision analysis models can assist the physician in accounting for these factors and customize patient counseling with regard to treatment options.
doi:10.2500/ajra.2014.28.3998
PMCID: PMC3899446  PMID: 24717886
5.  Chronic rhinosinusitis and antibiotics: The good, the bad, and the ugly 
Background:
Despite the recognition that bacteria are universally present in the sinuses of patients with chronic rhinosinusitis (CRS) no compelling role for a primary infectious etiology of CRS has been elucidated. CRS is a constellation of inflammatory diseases that typically involve either noneosinophilic or eosinophilic processes, distinct conditions that must be treated individually.
Methods:
The bacteria that are present in the sinuses may be innocuous bystanders but alternatively may contribute to the presence and severity of the disease through their ability to influence immune responses, function as immune adjuvants, provide antigens or superantigens that contribute to adaptive immune activation, or in forming the basis for the frequent acute superinfections. However, those bacteria that do contribute to the persistence and severity of CRS primarily reside in biofilms, and, as such, are not capable of being eradicated with antibiotics at the doses at which they can be used, even when local irrigation is considered.
Results:
Biofilms create an inhospitable environment for antibiotic potency by down-regulating the metabolic activity of their “core” bacteria, decreasing the oxygen concentration, and altering the pH at the core of the biofilm.
Conclusion:
Ultimately, if topical antibiotics are considered, they should be primarily focused on treating acute exacerbations and choices of antibiotics should optimally be based on endoscopic culture. This should be done with the recognition that while under certain circumstances antibiotics can ameliorate the severity of CRS, even if bacterial eradication were possible, this would not eliminate the underlying primary pathogenic mechanism or the natural history of these conditions.
doi:10.2500/ajra.2013.27.3960
PMCID: PMC3836217  PMID: 24274221
Antibiotic resistance; aspirin exacerbated respiratory disease; biofilms; chronic hyperplastic eosinophilic sinusitis; inflammatory sinusitis; local antibiotic therapy; planktonic
6.  Autoimmune Mechanisms in Chronic Idiopathic Urticaria 
doi:10.1016/j.jaci.2012.04.037
PMCID: PMC3432140  PMID: 22694931
Chronic idiopathic urticaria; anti-FcεRIα antibodies; mast cells; prostaglandin D2, calcium flux
7.  Etiology of Nasal Polyps in Cystic Fibrosis: Not a Unimodal Disease 
Objectives
The objective was to determine whether the polyp subtypes observed in cystic fibrosis (CF)–related sinusitis were similar to those observed in non–CF-related sinusitis.
Methods
Polyp and mucus samples were collected from CF patients who presented for sinus surgery. The polyps underwent histologic and cytochemical evaluation for the presence of lymphocyte cell populations and their respective cytokine markers. The mucus samples were evaluated for DNA content.
Results
Of the polyps, 42% had an eosinophilic infiltrate, of which 80% had an additional mixed neutrophilic infiltrate. Of the remaining polyp samples, 42% did not have a granulocytic infiltrate, consistent with non-eosinophilic polyps. All samples had CD138-positive plasma cells. The mucus samples from the patients with CF showed higher extracellular DNA concentrations than did the mucus samples from patients with non-CF sinus disease.
Conclusions
Cystic fibrosis–related polyps demonstrated an eosinophil-based dichotomy similar to that of idiopathic non–CF-related polyps. Many also demonstrated neutrophilic infiltrate, indicating that chronic mucus stasis and infection complicate the disease. Agents capable of reducing extracellular DNA may help manage sinusitis in CF patients.
PMCID: PMC3616340  PMID: 23012896
cystic fibrosis; DNA; eosinophil; histology; mucolytic; nasal polyp; neutrophil
8.  Chronic sinusitis pathophysiology: The role of allergy 
Background:
Chronic hyperplastic eosinophilic sinusitis (CHES) is an inflammatory disease characterized by eosinophil infiltration of sinus tissue that can present with and without nasal polyps (NPs). Aeroallergen sensitization in CHES occurs regularly, but the causality between allergen sensitivity, exposure, and disease is unclear.
Methods:
Allergen is unlikely to directly enter healthy sinuses either by diffusion or ciliary flow, and, even this is more problematic given the loss of patency of the ostia of diseased sinuses. Inflammation and tissue eosinophilia can develop secondary to allergen exposure in the nares, with systemic humoral recirculation of allergic cells including eosinophils, Th2 lymphocytes, and eosinophil precursors that are nonspecifically recruited back to the diseased sinuses.
Results:
The possibility of an allergic reaction to peptides derived from bacteria (i.e., Staphylococcus or superantigens) or fungi that colonize the diseased sinus also provides a plausible allergic mechanism.
Conclusion:
Treatments of this disease include agents directed at allergic mediators such as leukotriene modifiers and corticosteroids, although this does not necessarily signify that an IgE-dependent mechanism can be ascribed. However, more recently, omalizumab has shown promise, including in patients without obvious aeroallergen sensitization. Although many aspects of the role of allergy in CHES remain a mystery, the mechanisms that are being elucidated allow for improved understanding of this disease, which ultimately will lead to better treatments for our patients who live daily with this disease.
doi:10.2500/ajra.2013.27.3906
PMCID: PMC3781389  PMID: 23601202
Allergy; chronic hyperplastic eosinophilic sinusitis; chronic sinusitis; eosinophil; nasal polyposis; omalizumab; Staphylococcus; superantigen; systemic humoral recirculation
9.  Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study 
Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines’ impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
doi:10.1016/j.jaci.2012.04.014
PMCID: PMC3622643  PMID: 22694932
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
10.  Pathogenesis of Rhinovirus Infection 
Current Opinion in Virology  2012;2(3):287-293.
Summary
Since its discovery in 1956, rhinovirus (RV) has been recognized as the most important virus producing the common cold syndrome. Despite its ubiquity, little is known concerning the pathogenesis of RV infections, and some of the research in this area has led to contradictions regarding the molecular and cellular mechanisms of RV-induced illness. In this article, we discuss the pathogenesis of this virus as it relates to RV-induced illness in the upper and lower airway, an issue of considerable interest in view of the minimal cytopathology associated with RV infection. We endeavor to explain why many infected individuals exhibit minimal symptoms or remain asymptomatic, while others, especially those with asthma, may have severe, even life-threatening, complications (sequelae). Finally, we discuss the immune responses to RV in the normal and asthmatic host focusing on RV infection and epithelial barrier integrity and maintenance as well as the impact of the innate and adaptive immune responses to RV on epithelial function.
doi:10.1016/j.coviro.2012.03.008
PMCID: PMC3378761  PMID: 22542099
Rhinovirus; asthma; pathogenesis; viral-induced asthma exacerbations
12.  Evidence for distinct histological profile of nasal polyps: with and without eosinophilia 
The Laryngoscope  2011;121(10):2262-2267.
Objective/Hypothesis
To evaluate the histology, RNA and protein signatures of nasal polyps in order to demonstrate specific subtypes of disease and differentiate “idiopathic” NPs based on tissue eosinophilia.
Study Design
Prospective laboratory based study
Methods
NP tissue was obtained from patients referred to the University of Virginia Health System for sinus surgery. Histology analyses included hematoxylin-eosin, Gomori's trichrome, toluidine blue, and chloroacetate staining. RNA and protein were extracted from tissue and cytokine transcript or protein concentrations determined.
Results
Idiopathic NPs can be divided into distinct subsets characterized by absence (NE) and presence (E) of prominent eosinophilia. The validity of this distinction is supported by the demonstration that NE polyps are further distinguished by glandular hypertrophy, dense collagen deposition, and mononuclear cellular infiltrate. In contrast, E-NP display edema, rare glandularity, and minimal collagen deposition except within the basement membrane. Total mast cell numbers were reduced in E-NP, whereas connective tissue mast cells were increased in NE-NP. Consistent with the distinctive pattern of increased fibrosis, NE-NP displayed increased transforming growth factor (TGF)-ß and vascular endothelial growth factor transcripts. Similarly, NE-NPs had higher concentrations of TGF-ß, fibroblast growth factor-ß, and platelet-derived growth factor protein.
Conclusion
Idiopathic NPs can be distinguished by their presence or absence of eosinophilia and is supported by the observations that these display distinct histological, gene and protein expression patterns. The findings suggest that as unique diseases, idiopathic NPs will require distinct therapeutic interventions.
doi:10.1002/lary.21969
PMCID: PMC3183261  PMID: 21898422
fibrosis; chronic sinusitis; mast cells; growth factors; nasal polyps
13.  Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort 
Current Respiratory Care Reports  2012;1(4):259-269.
Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.
doi:10.1007/s13665-012-0025-x
PMCID: PMC3485530  PMID: 23136642
Severe asthma; Difficult-to-treat asthma; Asthma control; Exacerbation
14.  Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose 
Background
Carbohydrate moieties are frequently encountered in food and can elicit IgE responses, the clinical significance of which has been unclear. Recent work, however, has shown that IgE antibodies to galactose-α-1,3-galactose (α-gal), a carbohydrate commonly expressed on nonprimate mammalian proteins, are capable of eliciting serious, even fatal, reactions.
Objective
We sought to determine whether IgE antibodies to α-gal are present in sera from patients who report anaphylaxis or urticaria after eating beef, pork, or lamb.
Methods
Detailed histories were taken from patients presenting to the University of Virginia Allergy Clinic. Skin prick tests (SPTs), intradermal skin tests, and serum IgE antibody analysis were performed for common indoor, outdoor, and food allergens.
Results
Twenty-four patients with IgE antibodies to α-gal were identified. These patients described a similar history of anaphylaxis or urticaria 3 to 6 hours after the ingestion of meat and reported fewer or no episodes when following an avoidance diet. SPTs to mammalian meat produced wheals of usually less than 4 mm, whereas intradermal or fresh-food SPTs provided larger and more consistent wheal responses. CAP-RAST testing revealed specific IgE antibodies to beef, pork, lamb, cow’s milk, cat, and dog but not turkey, chicken, or fish. Absorption experiments indicated that this pattern of sensitivity was explained by an IgE antibody specific for α-gal.
Conclusion
We report a novel and severe food allergy related to IgE antibodies to the carbohydrate epitope α-gal. These patients experience delayed symptoms of anaphylaxis, angioedema, or urticaria associated with eating beef, pork, or lamb.
doi:10.1016/j.jaci.2008.10.052
PMCID: PMC3324851  PMID: 19070355
Anaphylaxis; urticaria; food allergy; galactose-α-1; 3-galactose; cross-reactive carbohydrate determinant
15.  Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcεRI 
Background
Studies of human mast cells are constrained by the paucity of functional cell lines, the expense of maintaining mast cells in culture, and technical complexities.
Objective
We derived and characterized a human mast cell line that arose spontaneously from a culture of non-transformed hematopoietic progenitor cells.
Methods
CD34+-enriched mononuclear cells derived from a donor with aspirin exacerbated respiratory disease were cultured for 8 weeks with stem cell factor and interleukin-6 and with interleukin-3 for the first week only. The cells (termed LUVA cells) survived and proliferated without further addition of any growth factors and have been maintained in culture for ~2 years.
Results
LUVA cells possess metachromatic cytoplasmic granules that are immunoreactive for tryptase, cathepsin G, and carboxypeptidase A3. They express transcripts encoding genes for FcεRI, c-kit, chymase, tryptase, histidine decarboxylase, carboxypeptidase A3, and the type 1 receptor for cysteinyl leukotrienes. Flow cytometry confirmed uniform expression of FcεRI, c-kit and FcγRII. FcεRI cross-linkage induced the release of β-hexosaminidase, prostaglandin D2, thromboxane A2, and macrophage inflammatory protein-1β. Immortalization was not associated with either a known genomic mutation of c-kit in the donor or a somatic mutation of c-kit within the cells, and it was not associated with c-kit autophosphorylation.
CONCLUSIONS
LUVA cells are an immortalized human mast cell line that can be maintained without stem cell factor and display high levels of normally signaling c-kit and FcεRI. These cells will prove valuable for functional human mast cell studies.
doi:10.1016/j.jaci.2010.12.1101
PMCID: PMC3052637  PMID: 21281958
Mast cell; SCF; FcεRI; c-Kit; Tryptase; CPA3
16.  Common Variable Immunodeficiency Presenting as Herpes Simplex Encephalitis 
Summary
Common variable immunodeficiency (CVID) is a disorder in which patients are unusually susceptible to infections with encapsulated bacteria. Here we describe three adults with CVID in whom the correct diagnosis was not reached until they had Herpes simplex encephalitis. Failure to identify the underlying immune deficiency likely contributed to these debilitating infections.
doi:10.1016/j.jaci.2010.11.004
PMCID: PMC3032019  PMID: 21167568
Common variable immunodeficiency; Herpes simplex encephalitis; anti-viral antibodies
17.  Interleukin-33 in Asthma: How Big of a Role Does It Play? 
In complex disorders such as asthma and allergic disease, the goal for developing disease-modifying biother-apeutics is to find a target that is a central instigator of immunologic activity. Interleukin (IL)-33 seems to be such a molecule, as it is one of the earliest-released signaling molecules following epithelial damage and can orchestrate the recruitment and activation of the cells responsible for disease. Unregulated IL-33 activity leads to activation of T-helper type 2 cells, mast cells, dendritic cells, eosinophils, and basophils, ultimately leading to increased expression of cytokines and chemokines that define the disease. As such, IL-33 is an attractive candidate for therapeutic intervention with the goal of ameliorating disease. This review focuses on the role of IL-33 in promoting and maintaining the asthma phenotype.
doi:10.1007/s11882-010-0153-8
PMCID: PMC3068600  PMID: 20931364
Asthma; Interleukin-33; ST2; Interleukin-1 family
18.  Microarray analysis of distinct gene transcription profiles in non-eosinophilic chronic sinusitis with nasal polyps 
American journal of rhinology  2008;22(6):568-581.
Background
Recent literature has indicated the feasibility of microarray analysis in the characterization of chronic sinusitis. We hypothesized that previously unexplored inflammatory mechanisms would be involved in the pathophysiology of noneosinophilic chronic rhinosinusitis with nasal polyps (NE-CRSwNP) and that this technology could be used to identify the gene expression of these novel and previously known mediators.
Methods
Patients with CRSwNP failing medical therapy were prospectively enrolled and NP tissue was removed at time of surgery. NE-CRSwNP was diagnosed based on clinical parameters including absence of allergic disease and confirmed with histopathology showing lack of eosinophilic infiltration. Messenger RNA (mRNA) transcripts extracted from study and control patients were then subjected to microarray analysis using Affymatrix based chips. Validation of findings was then confirmed via quantitative reverse transcription polymerase chain reaction (qRT-PCR).
Results
Microarray analysis revealed activation of pathways involved in antigen presentation, cellular movement, hematopoiesis, carcinogenesis, apoptosis, and cell signaling. Previously unexplored genes of interest were identified and their differential regulation was validated via qRT-PCR. Our data showed up-regulation of innate inflammation genes (IL-6, IL-8, and monocyte chemoattractant protein 1), hypoxia-induced inflammation 1α, and fibrosis (tenascin) and lack of up-regulation of genes associated with allergic, eosinophilic inflammation (IL-4 and IL-13). Additionally, the genes for CXCL1 and autocrine motility factor receptor were novelly identified to be up-regulated
Conclusion
This study explores the utility of gene microarray technology in identifying unexplored targets of immune dysregulation in NE-CRSwNP. Furthermore, the data characterize the immunologic profile of NE-CRSwNP as it differs from other forms of CRSwNP, in particular, those known to be associated with eosinophilic inflammation.
doi:10.2500/ajr.2008.22.3233
PMCID: PMC2810097  PMID: 19178793
CRSwNP; CXCL1; gene expression; IL-4; IL-6; IL-8; microarray; noneosinophilic; polyps; RT-PCR
19.  Functional Analysis of -351 Interleukin-9 Promoter Polymorphism Reveals an Activator Controlled by NF-κB 
Genes and immunity  2009;10(4):341-349.
Genetic studies have shown linkages for asthma to the chromosomal region 5q31-q33 in humans that includes the IL-9 gene. An A-to-G base substitution has been identified at bp -351 in the IL-9 promoter. The role of this polymorphism in IL-9 promoter function was assessed utilizing CD4+ T cells purified from individuals with one or two of the G alleles in comparison to those homozygous for the wild type A. The presence of an A at -351 (A allele) increased mitogen-stimulated IL-9 transcription 2-fold in comparison to subjects with one or 2 G alleles at this position. Binding of nuclear extract proteins from IL-9-producing human cell lines to DNA sequences including this base exchange demonstrated specific binding of the transcription factor NF-κB. Binding of NF-κB to the IL-9 promoter was confirmed in vivo using the chromatin immunoprecipitation assay. Recombinant NF-κB bound to a promoter fragment with the A allele with 5 fold higher affinity than it did to a promoter with the G allele. Individuals carrying the A allele of the IL-9 promoter display increased synthesis of IL-9, which may result in strong Th2 immune responses and a modulation of their susceptibility to infectious, neoplastic, parasitic, or atopic disease.
doi:10.1038/gene.2009.28
PMCID: PMC2702712  PMID: 19387455
Interleukin-9; Cytokine; Polymorphism; Functional Genomics; Transcription
20.  Differential Interleukin-10 Production Stratified by -571 Promoter Polymorphism in Purified Human Immune Cells 
Cellular immunology  2008;249(2):101-107.
Summary
A C-to-A base substitution has been identified at bp -571 in the IL-10 promoter and has been linked to numerous diseases. To investigate the role of this polymorphism on IL-10 production, T cells, B cells and monocytes were enriched from peripheral blood from subjects either homozygous for the C or A allele. Treatment of monocytes and B cells with lipopolysaccharide from individuals homozygous for the C allele resulted in higher levels of IL-10 production as compared to monocytes from individuals homozygous for the A allele. Though not statistically significant, when B cells were treated with anti-IgM or T cells with concanavalin A higher levels of IL-10 were produced from individuals homozygous for the A allele. Changes in IL-10 protein production were paralleled by similar changes in IL-10 mRNA production. These results demonstrate that changes in IL-10 production observed due to the -571 genotype depend on both cell type and stimulus.
doi:10.1016/j.cellimm.2007.12.001
PMCID: PMC2274832  PMID: 18191118
Interleukin-10; polymorphism; genetics; lymphocytes
21.  Concordant Modulation of Cysteinyl Leukotriene Receptor Expression by IL-4 and IFN-γ on Peripheral Immune Cells 
Arachidonic acid can be metabolized to form a group of compounds known as the cysteinyl leukotrienes (CysLT) that bind to one of two receptors to mediate their actions. On circulating cells, expression of the leukotriene receptors is low, but in inflamed tissue the receptor number is dramatically increased. We hypothesized that the cytokine milieu present during inflammation can increase receptor expression on infiltrating immune cells. Various cell populations were purified from peripheral blood and stimulated in vitro with cytokines characteristic of allergic inflammatory disorders, and CysLT receptor expression was measured using quantitative PCR analysis, Western blot, and flow cytometry. IL-4, but not IL-13, was able to significantly induce mRNA and protein levels for both CysLT receptor 1 and 2 from T cells and B cells. CysLT2 receptor expression was also significantly increased in monocytes and eosinophils after IL-4 stimulation. Surprisingly, CysLT2 receptor expression was increased in monocytes, T cells, and B cells when IFN-γ was used as the stimulus. Factors involved in eosinophil growth and survival were tested for their ability to alter CysLT receptor expression. These results support the concept that cytokines increase expression of both receptors on lymphocytes and granulocytes, allowing these cells to be more responsive to secreted leukotrienes at sites of inflammation.
doi:10.1165/rcmb.2006-0252OC
PMCID: PMC2720145  PMID: 17272825
cysteinyl leukotriene receptor; T cell; B cell; eosinophil; cytokine
22.  Evaluation of cytokines in nasal secretions after nasal antigen challenge: lack of influence of antihistamines 
Background:
Previous studies of inflammation in allergic rhinitis using nasal irrigation have been unsatisfactory because of 1) poor reproducibility; 2) the tendency of irrigation to overdilute mediators; and 3) the failure of this technique to evaluate interstitial concentrations of relevant mediators. For this study we used filter paper as a matrix to collect nasal secretions in patients undergoing nasal antigen challenge.
Objective:
To evaluate inflammatory mediators of allergen-induced rhinitis during a clinical trial of fexofenadine.
Methods:
Subjects evaluated at a referral medical center were placed on traditional dosing of fexofenadine at 60 mg, twice daily, or placebo in a double-blind, crossover fashion for 1 week before the nasal challenge. Nasal challenge was performed with nasal insufflation of either 1,000 AU timothy or 0.1 mL ragweed (1:100 wt/vol) extract outside the pollen season. Nasal secretions were collected at baseline and then at 2, 4, and 6 hours after nasal challenge. Secretions were evaluated for expression of the cellular adhesion molecule-1, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, macrophage inflammatory protein (MIP)-1α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using commercially available enzyme-linked immunoadsorbent assay kits. Patients’ symptom scores were evaluated during the nasal challenge.
Results:
Significantly (P < 0.05) increased peak levels of TNF-α, IL-4, IL-10, and MIP-1α were detected after antigen challenge as compared with baseline levels. There was a nonsignificant trend toward an increase in GM-CSF after antigen challenge (P = 0.07). There was no difference in the peak levels of TNF-α, IL-4, IL-10, MIP-1α, or GM-CSF measured when patients were on fexofenadine versus placebo. Finally, there were no significant differences in patients’ symptom scores during antigen challenge when subjects were on fexofenadine versus placebo.
Conclusions:
Collection of nasal secretions using a filter paper matrix provides a reproducible model for accurately detecting and evaluating changes in cytokine levels after nasal challenge. Cytokine levels tend to peak 3 to 4 hours after antigen challenge. Standard doses of fexofenadine do not seem to have a mitigating effect on the production of these cytokines. Symptoms of allergic rhinitis using this type of antigen challenge did not differ from treatment with fexofenadine versus placebo.
PMCID: PMC1283081  PMID: 12027065
23.  Sinus computed tomography scan and markers of inflammation in vocal cord dysfunction and asthma 
Background:
The inappropriate closure of the vocal cords is characteristic of vocal cord dysfunction (VCD). These patients present with wheezing and frequently receive a misdiagnosis of asthma.
Objective:
To demonstrate the ability of computed tomography (CT) scored for the presence and extent of sinus disease and markers of inflammation to distinguish patients with VCD from patients with asthma.
Methods:
Comparisons of 13 patients with VCD were made to 77 patients presenting to the emergency room with acute asthma, 31 non-acute asthmatic patients, and 65 nonasthmatic controls. Evaluation consisted of exhaled nitric oxide gas (eNO), circulating eosinophils, and total serum immunoglobulin (Ig)E, as well as the sinus CT scan.
Results:
Extensive sinus CT changes were present in 23 of 74 acute asthmatic patients, 5 of 29 non-acute asthmatic patients, and 2 of 59 nonasthmatic controls. In addition, absolute eosinophil counts, eNO, and total IgE were significantly elevated among the asthmatic patients. Sinus symptoms reported by questionnaire did not predict sinus CT findings. Among the patients with VCD, none had extensive sinus disease. They also had normal eNO, low IgE, and normal eosinophil count. Five of the patients presenting to the emergency room who were identified as acute asthmatic were identified with VCD by laryngoscopy and were all characterized by the absence of significant inflammation on their sinus CT scan, low IgE, and normal eosinophil count.
Conclusions:
Among patients presenting with intermittent or reversible airway obstruction, patients with VCD can be distinguished from asthma by minimum or absence of inflammation in their sinuses as shown by CT scan. Clinical symptom scores are not predictive of presence or extent of sinus disease in most cases.
PMCID: PMC1283080  PMID: 12669895
24.  Th2 cytokines and asthma — Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists 
Respiratory Research  2001;2(2):66-70.
Interleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.
doi:10.1186/rr40
PMCID: PMC59570  PMID: 11686867
asthma; genetics; soluble recombinant human interleukin-4 receptor; T helper lymphocytes

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