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1.  Factors driving the aspirin exacerbated respiratory disease phenotype 
Aspirin-exacerbated respiratory disease (AERD) is explained in part by overexpression of 5-lipoxygenase and leukotriene C4 synthase (LTC4S), resulting in constitutive overproduction of cysteinyl leukotrienes (CysLTs) and driving the surge in CysLT production that occurs with aspirin ingestion. Similarly, AERD is characterized by the overexpression of CysLT receptors. Increased levels of both interleukin (IL)-4 and interferon (IFN)-γ are present in the tissue of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the up-regulation of LTC4S by mast cells.
Literature review.
Our previous studies demonstrated that IFN-γ, but not IL-4, drives this process in eosinophils. These published studies also extend to both IL-4 and IFN-γ the ability to up-regulate CysLT receptors. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD, and our published studies confirm that this reflects diminished expression of cyclooxygenase (COX)-2. A process again that is driven by IL-4. Thus, IL-4 and IFN-γ together play an important pathogenic role in generating the phenotype of AERD. Finally, induction of LTC4S and CysLT1 receptors by IL-4 reflects in part the IL-4-mediated activation of signal transducer and activator of transcription 6 (STAT6). Our previous studies demonstrated that aspirin blocks trafficking of STAT6 into the nucleus and thereby prevents IL-4-mediated induction of these transcripts, thereby suggesting a modality by which aspirin desensitization could provide therapeutic benefit for AERD patients.
This review will examine the evidence supporting this model.
PMCID: PMC4288232  PMID: 25590316
Leukotriene; cyclooxygenase; prostaglandin; aspirin-exacerbated respiratory disease
2.  Sino-nasal Outcome Test (SNOT-22): A predictor of post-surgical improvement in patients with chronic sinusitis 
PMCID: PMC3977600  PMID: 24054358
Chronic Rhinosinusitis; Sino-nasal Outcome Test-22; Functional Endoscopic Sinus Surgery; Predictive factors; Asthma; Allergy; Smoking; Depression
3.  Prominent Role of Interferon-γ in Aspirin-Exacerbated Respiratory Disease 
Aspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their over-expression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs).
We defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of interferon (IFN)-γ in the differentiation of eosinophils.
qPCR was performed for Th1 and Th2 signature cytokines on control, chronic hyperplastic eosinophilic sinusitis (CHES), and AERD tissue and their cellular source was determined. The influence of interferon (IFN)-γ on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined.
Gene expression analysis revealed that both aspirin tolerant and AERD tissue display a Th2 cytokine signature, however AERD was distinguished from CHES by the prominent expression of IFN-γ. Intracellular and immunohistochemical cytokine staining revealed that the major source of these cytokines were the eosinophils themselves. IFN-γ promoted the maturation of eosinophil progenitors as measured by increased mRNA and surface expression of CCR3 and Siglec-8. Additionally, IFN-γ increased expression of genes involved in leukotriene synthesis that led to increased secretion of cysteinyl leukotrienes. IFN-γ-matured eosinophil progenitors were also primed as demonstrated by their enhanced degranulation.
High IFN-γ levels distinguish AERD from aspirin tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.
PMCID: PMC3788084  PMID: 23806637
aspirin exacerbated respiratory disease; aspirin tolerant asthma; chronic sinusitis; cytokines; eosinophils; interferon-γ; nasal polyps
4.  Epidemiological analysis of chronic rhinitis in pediatric patients 
Nonallergic rhinitis is a poorly understood entity, especially among pediatric patients. Objective: This study identifies clinical features that may distinguish phenotypes of allergic and nonallergic patients and to evaluate the usefulness of current diagnostic modalities.
We reviewed medical records for 151 pediatric patients with perennial rhinitis, evaluated in a multidisciplinary allergy and otolaryngology clinic. Results obtained by standard history, validated questionnaire (SN-5), epicutaneous allergy testing, acoustic rhinometry, and sinus CT were compared.
Nasal congestion was the most frequent primary presenting complaint (62%). Among subjects having a positive allergy test, associated eye symptoms were more frequent (p = 0.01) and responses to the SN-5 allergic domain were higher (p = 0.02). Sinus CT scores were similar among allergic and nonallergic subjects (median 7 and 8, respectively) and did not correlate with symptom scores (p = 0.6). Among nonallergic subjects, quality of life ratings weakly correlated with sinus CT scores (r = 0.4; p = 0.05). By rhinometry, absolute mean cross-sectional area was similar among allergic (0.32 cm2) and nonallergic (0.36 cm2) subjects and did not correlate with symptom scores (p = 0.8 for allergic and p = 0.6 for nonallergic subjects). Distinct groups of nonallergic patients including those with prominent conjunctival pruritus (n = 24), frequent cold symptoms (n = 3), and chronic sinus disease (n = 2) were observed.
It is difficult to distinguish allergic and nonallergic rhinitis in patients with perennial disease, but associated eye symptoms and questionnaire responses are predictive of allergy. Acoustic rhinometry and sinus CT suggest that physical obstruction and sinus disease are not related to nasal symptoms including, surprisingly, the sensation of congestion.
PMCID: PMC4152912  PMID: 22186247
5.  Fifty-five-year-old man with chronic yeast infections 
Allergy and Asthma Proceedings  2014;35(5):415-422.
As immunologists, we are frequently asked to evaluate patients with recurrent infections. These infections can provide us with clues regarding what pathways might be aberrant in a given patient, e.g., specific pyogenic bacteria with Toll-like receptor problems, atypical mycobacteria with interferon gamma receptor autoantibodies, and Candida/staphylococcal infections with cellular immune abnormalities. We present a 55-year-old man who presented to our immunology clinic with onychodystrophy of the toenails and fingernails and recurrent oral–esophageal candidiasis. The differential diagnosis for recurrent yeast infections is complex and includes usual suspects as well as some that are not as straightforward.
PMCID: PMC4147028  PMID: 25295810
Antibody deficiency; autoantibodies; chronic mucocutaneous candidiasis; Good's syndrome; IL-12; interferon alpha; thymoma
7.  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.
PMCID: PMC3662023  PMID: 23235830
8.  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.
PMCID: PMC3894600  PMID: 22370536
9.  Decision-making analysis for allergen immunotherapy versus nasal steroids in the treatment of nasal steroid–responsive allergic rhinitis 
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.
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.
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.
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.
PMCID: PMC3899446  PMID: 24717886
10.  Chronic rhinosinusitis and antibiotics: The good, the bad, and the ugly 
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.
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.
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.
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.
PMCID: PMC3836217  PMID: 24274221
Antibiotic resistance; aspirin exacerbated respiratory disease; biofilms; chronic hyperplastic eosinophilic sinusitis; inflammatory sinusitis; local antibiotic therapy; planktonic
11.  Autoimmune Mechanisms in Chronic Idiopathic Urticaria 
PMCID: PMC3432140  PMID: 22694931
Chronic idiopathic urticaria; anti-FcεRIα antibodies; mast cells; prostaglandin D2, calcium flux
12.  Etiology of Nasal Polyps in Cystic Fibrosis: Not a Unimodal Disease 
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.
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.
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.
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
13.  Chronic sinusitis pathophysiology: The role of allergy 
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.
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.
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.
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.
PMCID: PMC3781389  PMID: 23601202
Allergy; chronic hyperplastic eosinophilic sinusitis; chronic sinusitis; eosinophil; nasal polyposis; omalizumab; Staphylococcus; superantigen; systemic humoral recirculation
14.  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.
PMCID: PMC3622643  PMID: 22694932
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
15.  Pathogenesis of Rhinovirus Infection 
Current Opinion in Virology  2012;2(3):287-293.
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.
PMCID: PMC3378761  PMID: 22542099
Rhinovirus; asthma; pathogenesis; viral-induced asthma exacerbations
17.  Evidence for distinct histological profile of nasal polyps: with and without eosinophilia 
The Laryngoscope  2011;121(10):2262-2267.
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
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.
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.
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.
PMCID: PMC3183261  PMID: 21898422
fibrosis; chronic sinusitis; mast cells; growth factors; nasal polyps
18.  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.
PMCID: PMC3485530  PMID: 23136642
Severe asthma; Difficult-to-treat asthma; Asthma control; Exacerbation
19.  Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose 
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.
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.
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.
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.
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.
PMCID: PMC3324851  PMID: 19070355
Anaphylaxis; urticaria; food allergy; galactose-α-1; 3-galactose; cross-reactive carbohydrate determinant
20.  Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcεRI 
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.
We derived and characterized a human mast cell line that arose spontaneously from a culture of non-transformed hematopoietic progenitor cells.
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.
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.
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.
PMCID: PMC3052637  PMID: 21281958
Mast cell; SCF; FcεRI; c-Kit; Tryptase; CPA3
21.  Common Variable Immunodeficiency Presenting as Herpes Simplex Encephalitis 
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.
PMCID: PMC3032019  PMID: 21167568
Common variable immunodeficiency; Herpes simplex encephalitis; anti-viral antibodies
22.  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.
PMCID: PMC3068600  PMID: 20931364
Asthma; Interleukin-33; ST2; Interleukin-1 family
23.  Interleukin-4 in the Generation of the AERD Phenotype: Implications for Molecular Mechanisms Driving Therapeutic Benefit of Aspirin Desensitization 
Journal of Allergy  2012;2012:182090.
Aspirin-exacerbated respiratory disease (AERD) is explained in part by over-expression of 5-lipoxygenase, leukotriene C4 synthase (LTC4S) and the cysteinyl leukotriene (CysLT) receptors (CysLT1 and 2), resulting in constitutive over-production of CysLTs and the hyperresponsiveness to CysLTs that occurs with aspirin ingestion. Increased levels of IL-4 have been found in the sinus mucosa and nasal polyps of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the upregulation of LTC4S by mast cells and the upregulation of CysLT1 and 2 receptors on many immune cell types. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD reflecting diminished expression of cyclooxygenase (COX)-2. IL-4 can inhibit basal and stimulated expression of COX-2 and microsomal PGE synthase 1 leading to decreased capacity for PGE2 secretion. Thus, IL-4 plays an important pathogenic role in generating the phenotype of AERD. This review will examine the evidence supporting this hypothesis and describe a model of how aspirin desensitization provides therapeutic benefit for AERD patients.
PMCID: PMC3259477  PMID: 22262978
24.  Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children 
PLoS ONE  2011;6(2):e16522.
Candidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs) that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma. Our aim was to compare association patterns of asthma candidate genes between children of European and African ancestry.
Methodology/Principal Findings
Using a custom-designed Illumina SNP array, we genotyped 1,485 children within the Greater Cincinnati Pediatric Clinic Repository and Cincinnati Genomic Control Cohort for 259 SNPs in 28 genes and evaluated their associations with asthma. We identified 14 SNPs located in 6 genes that were significantly associated (p-values <0.05) with childhood asthma in African Americans. Among Caucasians, 13 SNPs in 5 genes were associated with childhood asthma. Two SNPs in IL4 were associated with asthma in both races (p-values <0.05). Gene-gene interaction studies identified race specific sets of genes that best discriminate between asthmatic children and non-allergic controls.
We identified IL4 as having a role in asthma susceptibility in both African American and Caucasian children. However, while IL4 SNPs were associated with asthma in asthmatic children with European and African ancestry, the relative contributions of the most replicated asthma-associated SNPs varied by ancestry. These data provides valuable insights into the pathways that may predispose to asthma in individuals with European vs. African ancestry.
PMCID: PMC3046166  PMID: 21387019
25.  Assessment of the lung microstructure in patients with asthma using hyperpolarized 3He diffusion MRI at two time scales: Comparison with healthy subjects and patients with COPD 
To investigate short- and long-time-scale 3He diffusion in asthma.
Materials and methods
A hybrid MRI sequence was developed to obtain co-registered short- and long-time-scale ADC maps during a single breath-hold. Study groups: asthma (n=14); healthy (n=14); COPD (n=9). Correlations were made between mean-ADC and %ADC-abn (%pixels with ADC>mean+2SD of healthy) at both time-scales, and spirometry. Sensitivities were determined using ROC analysis.
For asthmatics, the short- and long-time-scale group-mean ADC were 0.254±0.032 cm2/s and 0.0237±0.0055 cm2/s, respectively, representing a 9% and 27% (p=0.038 and p=0.005) increase compared to healthy group. The group-mean %ADC-abn were 6.4%±3.7% and 17.5%±14.2%, representing a 107% and 272% (p=0.004 and p=0.006) increase. For COPD much greater elevations were observed. %ADC-abn provided better discrimination than mean-ADC between asthmatic and healthy subjects. In asthmatics ADC did not correlate with spirometry.
With long-time-scale 3He diffusion magnetic resonance imaging (MRI) changes in lung microstructure were detected in asthma that were more conspicuous regionally than at the short time scale. The hybrid diffusion method is a novel means of identifying small airway disease.
PMCID: PMC2833091  PMID: 18581381
Asthma; small airways; hyperpolarized gas; hyperpolarized helium-3; MRI; diffusion MRI

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