RobertP Schleimer | Northwestern University (original) (raw)

Papers by RobertP Schleimer

Research paper thumbnail of Epithelial genes in chronic rhinosinusitis with and without nasal polyps

American Journal of Rhinology, 2008

Background-Genetic studies on chronic inflammatory diseases have resulted in an emphasis on the e... more Background-Genetic studies on chronic inflammatory diseases have resulted in an emphasis on the epithelial interface with the environment and the genes that influence this interaction. This study examines the expression of key epithelial genes implicated in the pathogenesis of other inflammatory disorders for their role in chronic rhinosinusitis (CRS).

Research paper thumbnail of Enhancement of Host Defense Gene Expression by Glucocorticoids (GC) is Mediated by CCAAT-Enhancer Binding Protein (C/EBP)

Journal of Allergy and Clinical Immunology, 2006

Research paper thumbnail of A sensitive high throughput ELISA for human eosinophil peroxidase: A specific assay to quantify eosinophil degranulation from patient-derived sources

Journal of Immunological Methods, 2012

Quantitative high throughput assays of eosinophil-mediated activities in fluid samples from patie... more Quantitative high throughput assays of eosinophil-mediated activities in fluid samples from patients in a clinical setting have been limited to ELISA assessments for the presence of the prominent granule ribonucleases, ECP and EDN. However, the demonstration that these

Research paper thumbnail of Complement Activation in Nasal Tissue of Patients with Chronic Rhinosinusitis

Journal of Allergy and Clinical Immunology, 2015

Research paper thumbnail of Elevated presence of myeloid dendritic cells in nasal polyps of patients with chronic rhinosinusitis

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2015

Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, ... more Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the mechanism underlying the onset and amplification of this inflammation has not been fully elucidated. Dendritic cells (DCs) are major antigen-presenting cells, central inducers of adaptive immunity and critical regulators of many inflammatory diseases. However, the presence of DCs in CRS, especially in nasal polyps (NPs), has not been extensively studied. The objective of this study was to characterize DC subsets in CRS. We used real-time PCR to assess the expression of mRNA for markers of myeloid DCs (mDCs; CD1c), plasmacytoid DCs (pDCs; CD303) and Langerhans cells (LCs; CD1a, CD207) in uncinate tissue (UT) from controls and patients with CRS as well as in NP. We assayed the presence of DCs by immunohistochemistry and flow cytometry. Compared to UT from control subjects (n = 15) and patients with CRS without NP (CRSsNP) (n = 16) and CRSwNP (n = 17), mRNAs for CD1a and CD1c were signi...

Research paper thumbnail of Decreased Production of Antimicrobial Peptides in Chronic Rhinosinusitis Associated with Age and Elevated Soluble gp130

Journal of Allergy and Clinical Immunology, 2013

T U E S D A Y 842 Decreased Production of Antimicrobial Peptides in Chronic Rhinosinusitis Associ... more T U E S D A Y 842 Decreased Production of Antimicrobial Peptides in Chronic Rhinosinusitis Associated with Age and Elevated Soluble gp130 Sun Hye Lee, PhD, Seong Ho Cho, MD, Kathryn E. Hulse, PhD, James Norton, MS, Jason Siebert, David Conley, MD, Rakesh Chandra, MD, Anju Peters, MD, Robert Kern, MD, Leslie C. Grammer, MD, FAAAAI, Robert P. Schleimer, PhD, FAAAAI; Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: S100 proteins play an important role in epithelial innate immune function.We previously reported that levels of epithelium-derived S100A8/A9 (calprotectin) in patients with CRS (chronic rhinosinusitis) were significantly diminished and inversely correlated with aging. In this study, we further investigated the mechanism of this age-related reduction of S100A8/A9 in patients with CRS. METHODS: IL-6 signaling is known to be important in the production of S100 proteins. We first examined age-related expression of IL-6, soluble IL-6 receptor (sIL-6R), and its natural inhibitor, soluble gp130 (sgp130) in nasal lavage fluids from patients of various ages with CRS using ELISA. In vitro, we treated normal human bronchial epithelial cells (NHBE) with IL6 or oncostatin M (OSM), a gp130-dependent cytokine, and measured mRNA of S100A8 and S100A9 by real time PCR and levels of S100A8/A9 and S100A8/A8 homodimer (calgranulin A) by ELISA. RESULTS: Levels of sgp130, not IL-6 or sIL-6R, were increased significantly with age in patients with CRS (r 5 0.76, p < 0.02). The gene expression of S100A8 and S100A9 was induced up-to 3-fold by IL-6 or OSM in submerged NHBE in vitro (p< 0.05 vs control). The production of S100A8/9 and S100A8/8 was also enhanced 3-fold or 20-fold by OSM, respectively in air-liquid interface cultured NHBE cells (p < 0.01 vs control). CONCLUSIONS: This study suggests that age-related reduction of S100A8/A9 expression in patients with CRSmay bemediated by increased sgp130, an inhibitor of IL-6 trans-signaling in epithelial cells.

Research paper thumbnail of Increased Expression of the Epithelial Anion Transporter Pendrin in Nasal Polyp Tissues of Patients with Chronic Rhinosinusitis

Journal of Allergy and Clinical Immunology, 2013

Research paper thumbnail of Evidence for Expansion of Sinonasal B-Lineage Cells in Chronic Rhinosinusitis

Journal of Allergy and Clinical Immunology, 2013

Research paper thumbnail of Evidence for Elevated IL-6 and its Signaling Components in Chronic Rhinosinusitis with Nasal Polyps

Journal of Allergy and Clinical Immunology, 2007

Research paper thumbnail of High Plasma Levels of Plasminogen Activator Inhibitor-1 are Associated with Decreased Lung Function in Asthmatic Patients

Journal of Allergy and Clinical Immunology, 2010

RATIONALE: Angiogenesis is considered to be important for both development of airway inflammation... more RATIONALE: Angiogenesis is considered to be important for both development of airway inflammation and airway remodeling in asthma and serum levels of proangiogenic factors (PFs) may reflect local activity of angiogenesis in asthmatic airways. The aim of the study was to compare PFs concentrations in sera of asthmatic patients and in healthy subjects, and to refer PFs concentration to the disease severity. METHODS: Serum was collected from 26 patients with severe/difficult (S/D) asthma and 28 patients with non-severe (NS) asthma. The control group included 10 healthy subjects (HS). Serum concentrations of Angiopoietin-1, Angiopoietin-2, Vascular Endothelial Growth Factor (VEGF) and osteopontin were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the whole asthma group (n5 54), as compared to HS, significantly higher serum concentrations was found for angiopoietin-1 (57,8 +/-3,2 ng/ml vs 10,3 +/-4,8 ng/ml; p<0,001), angiopoietin-2 (6,65 +/-1,7 vs 1,4 +/-0,13 ng/ml; p<0,001) and VEGF (307,1 +/-27 pg/ml vs 33,8 +/-13,5 pg/ml; p<0,001). The mean concentration of angiopoietin-2 was significantly increased in S/D asthmatics as compared to NS asthmatics (6,04+/-0,45 ng/ml vs 3,8+/0,44ng/ml, p<0,001). FEV1% of predicted value correlated inversely with serum concentrations of angiopoietin-2 (r 5-0,39; p <0,05) and osteopontin (r5-0,29, p<0,05). The dose of inhaled glucocorticosteroids correlated with serum levels of angiopoetin-2 (r 5 0,46; p<0,05) and oesteopontin (r50,27, p<0,05). CONCLUSION: Increased serum levels of proangiogenic factors in asthmatics and relation to asthma severity may reflect ongoing airway remodeling.

Research paper thumbnail of Analysis of the TLR2 Signaling Pathway in Nasal Epithelial Cells from Patients with Chronic Rhinosinusitis (CRS)

Journal of Allergy and Clinical Immunology, 2007

RATIONALE: Phosphorylation commonly regulates protein function, and GR has several phosphorylatio... more RATIONALE: Phosphorylation commonly regulates protein function, and GR has several phosphorylation sites. Phosphorylation may then modulate its activity. In steroid insensitive asthma, impaired GR responsiveness has been attributed to cytokines, particularly a combination of IL-2 and IL-4, which also increases phosphorylation of GR. However, the exact residues involved are not known. The objective of this study is to identify the phosphorylation of serine residues 203, 211 and 226 in GR in response to cytokine treatment. METHODS: Human lung fibroblasts (CCL-211) were grown to near confluence, and cultured with or without ED50 concentrations of IL-2, IL-4, IL-2 plus IL-4, IFN-g, TNF-a and GM-CSF for 24 hrs. 20 mg of total cellular protein was subjected to western blotting using specific antibodies to GR-a, GR-b, and phosphoserine 203, 211 and 226. RESULTS: A combination of IL-2 and IL-4 hyper-phosphorylated all three serine residues, whereas IL-2, IFN-g, and GM-CSF hyper-phosphorylated serine 226 only. Treatment with IL-2, IL-4, IFN-g, TNF-a and GM-CSF significantly decreased phosphorylation of serine 203 compared to control cells. Decreased phosphorylation of serine 211 was observed in response to IL-4, IFN-g and TNF-a. CONCLUSIONS: These results indicate that phosphorylation may be a key factor in regulating GR function. Structural modification may regulate GR function by altering binding affinity to glucocorticoids. The functional consequences of these modifications require further study. Funding: HL-69130 (US SARP)

Research paper thumbnail of Levels of the Cytokines IL-5, IL-13 and Rantes in Nasal Lavage Fluids Parallel the Cytokine Content of Nasal Polyps in Patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

Journal of Allergy and Clinical Immunology, 2013

Research paper thumbnail of A retrospective, cross‐sectional study reveals that women with CRSwNP have more severe disease than men

Immunity, Inflammation and Disease, 2015

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reporte... more Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen-specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex-specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n ¼ 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin-exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Research paper thumbnail of A retrospective, cross‐sectional study reveals that women with CRSwNP have more severe disease than men

Immunity, Inflammation and Disease, 2015

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reporte... more Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen-specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex-specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n ¼ 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin-exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Research paper thumbnail of Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease

The Journal of allergy and clinical immunology, 2015

Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asth... more Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis. The objective of this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease. OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate-dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells. Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue (P < .05). OSM levels were also in...

Research paper thumbnail of Association of common filaggrin null mutations with atopy but not chronic rhinosinusitis

Annals of Allergy, Asthma & Immunology, 2015

Mutations in the filaggrin gene (FLG) are strongly associated with atopic dermatitis (AD) and ski... more Mutations in the filaggrin gene (FLG) are strongly associated with atopic dermatitis (AD) and skin barrier dysfunction (1, 2). FLG has been linked to asthma and asthma severity in subjects with and without atopic dermatitis (1, 3-5), and individuals with FLG null mutations are at increased risk of allergic sensitization and allergic rhinitis (5). However, despite evidence indicating a link between FLG, barrier dysfunction, and respiratory diseases (1), the importance of FLG in the pathogenesis of chronic rhinosinusitis (CRS) has never been evaluated. We hypothesized that FLG mutations might cause mucosal barrier dysfunction and thereby be associated with CRS (6, 7). To test this hypothesis, we investigated the frequency of the two most common FLG null mutations (R501X and 2282del4 (3, 5)) that have been implicated in asthma and allergic rhinitis in a group of European American CRS and control subjects. Patients with CRS (determined using Sinus and Allergy Health Partnership

Research paper thumbnail of Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

Journal of Allergy and Clinical Immunology, 2015

Background-Balanced activation and inhibition of the immune system ensures pathogen clearance whi... more Background-Balanced activation and inhibition of the immune system ensures pathogen clearance while avoiding hyperinflammation. Siglecs, sialic acid binding proteins found on subsets of immune cells, often inhibit inflammation: Siglec-8 on eosinophils and Siglec-9 on neutrophils engage sialoglycan ligands on airways to diminish ongoing inflammation. The identities of human siglec ligands and their expression during inflammation are largely unknown. Objective-The histological distribution, expression and molecular characteristics of siglec ligands were explored in healthy and inflamed human upper airways and in a cellular model of airway inflammation. Methods-Normal and chronically inflamed upper airway tissues were stained for siglec ligands. The ligands were extracted from normal and inflamed tissues and from human Calu-3 cells for quantitative analysis by siglec blotting and isolation by siglec capture. Results-Siglec-8 ligands were expressed on a subpopulation of submucosal gland cells of human inferior turbinate, whereas Siglec-9 ligands were expressed more broadly (submucosal glands, epithelium, connective tissue); both were significantly upregulated in chronic rhinosinusitis patients. Human airway (Calu-3) cells expressed Siglec-9 ligands on mucin 5B

Research paper thumbnail of Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Nature communications, Jan 24, 2015

Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health probl... more Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 × 10(-8)) and rs9275596 (P=6.8 × 10(-10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites…

Research paper thumbnail of Epithelium, inflammation, and immunity in the upper airways of humans: studies in chronic rhinosinusitis

Proceedings of the American Thoracic Society, 2009

The purpose of this review is to discuss recent findings made during studies of the upper airways... more The purpose of this review is to discuss recent findings made during studies of the upper airways and sinuses of people with chronic rhinosinusitis (CRS) in the context of the literature. CRS is a chronic inflammatory disorder affecting nearly 30 million Americans and is generally resistant to therapy with antibiotics and glucocorticoids (Meltzer EO and coworkers, J Allergy Clin Immunol 2004;114:155-212). We have formed a collaboration that consists of otolaryngologists, allergists, and basic scientists to address the underlying immunologic and inflammatory processes that are occurring in, and possibly responsible for, this disease. The main emphasis of our work has been to focus on the roles that epithelium, in the sinuses and upper airways, plays as both a mediator and regulator of immune and inflammatory responses. It is not our intention here to provide a comprehensive review of the literature in this area, but we will try to put our work in the context of the findings of others...

Research paper thumbnail of Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia

The Journal of allergy and clinical immunology, Jan 10, 2014

In this study we found a significantly lower eosinophilia in nasal polyps surgically removed from... more In this study we found a significantly lower eosinophilia in nasal polyps surgically removed from second-generation Asian patients, similar to studies of native-born patients in Asian countries, suggesting the hypothesis that there may be genetic regulation of eosinophilia.

Research paper thumbnail of Epithelial genes in chronic rhinosinusitis with and without nasal polyps

American Journal of Rhinology, 2008

Background-Genetic studies on chronic inflammatory diseases have resulted in an emphasis on the e... more Background-Genetic studies on chronic inflammatory diseases have resulted in an emphasis on the epithelial interface with the environment and the genes that influence this interaction. This study examines the expression of key epithelial genes implicated in the pathogenesis of other inflammatory disorders for their role in chronic rhinosinusitis (CRS).

Research paper thumbnail of Enhancement of Host Defense Gene Expression by Glucocorticoids (GC) is Mediated by CCAAT-Enhancer Binding Protein (C/EBP)

Journal of Allergy and Clinical Immunology, 2006

Research paper thumbnail of A sensitive high throughput ELISA for human eosinophil peroxidase: A specific assay to quantify eosinophil degranulation from patient-derived sources

Journal of Immunological Methods, 2012

Quantitative high throughput assays of eosinophil-mediated activities in fluid samples from patie... more Quantitative high throughput assays of eosinophil-mediated activities in fluid samples from patients in a clinical setting have been limited to ELISA assessments for the presence of the prominent granule ribonucleases, ECP and EDN. However, the demonstration that these

Research paper thumbnail of Complement Activation in Nasal Tissue of Patients with Chronic Rhinosinusitis

Journal of Allergy and Clinical Immunology, 2015

Research paper thumbnail of Elevated presence of myeloid dendritic cells in nasal polyps of patients with chronic rhinosinusitis

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2015

Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, ... more Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the mechanism underlying the onset and amplification of this inflammation has not been fully elucidated. Dendritic cells (DCs) are major antigen-presenting cells, central inducers of adaptive immunity and critical regulators of many inflammatory diseases. However, the presence of DCs in CRS, especially in nasal polyps (NPs), has not been extensively studied. The objective of this study was to characterize DC subsets in CRS. We used real-time PCR to assess the expression of mRNA for markers of myeloid DCs (mDCs; CD1c), plasmacytoid DCs (pDCs; CD303) and Langerhans cells (LCs; CD1a, CD207) in uncinate tissue (UT) from controls and patients with CRS as well as in NP. We assayed the presence of DCs by immunohistochemistry and flow cytometry. Compared to UT from control subjects (n = 15) and patients with CRS without NP (CRSsNP) (n = 16) and CRSwNP (n = 17), mRNAs for CD1a and CD1c were signi...

Research paper thumbnail of Decreased Production of Antimicrobial Peptides in Chronic Rhinosinusitis Associated with Age and Elevated Soluble gp130

Journal of Allergy and Clinical Immunology, 2013

T U E S D A Y 842 Decreased Production of Antimicrobial Peptides in Chronic Rhinosinusitis Associ... more T U E S D A Y 842 Decreased Production of Antimicrobial Peptides in Chronic Rhinosinusitis Associated with Age and Elevated Soluble gp130 Sun Hye Lee, PhD, Seong Ho Cho, MD, Kathryn E. Hulse, PhD, James Norton, MS, Jason Siebert, David Conley, MD, Rakesh Chandra, MD, Anju Peters, MD, Robert Kern, MD, Leslie C. Grammer, MD, FAAAAI, Robert P. Schleimer, PhD, FAAAAI; Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: S100 proteins play an important role in epithelial innate immune function.We previously reported that levels of epithelium-derived S100A8/A9 (calprotectin) in patients with CRS (chronic rhinosinusitis) were significantly diminished and inversely correlated with aging. In this study, we further investigated the mechanism of this age-related reduction of S100A8/A9 in patients with CRS. METHODS: IL-6 signaling is known to be important in the production of S100 proteins. We first examined age-related expression of IL-6, soluble IL-6 receptor (sIL-6R), and its natural inhibitor, soluble gp130 (sgp130) in nasal lavage fluids from patients of various ages with CRS using ELISA. In vitro, we treated normal human bronchial epithelial cells (NHBE) with IL6 or oncostatin M (OSM), a gp130-dependent cytokine, and measured mRNA of S100A8 and S100A9 by real time PCR and levels of S100A8/A9 and S100A8/A8 homodimer (calgranulin A) by ELISA. RESULTS: Levels of sgp130, not IL-6 or sIL-6R, were increased significantly with age in patients with CRS (r 5 0.76, p < 0.02). The gene expression of S100A8 and S100A9 was induced up-to 3-fold by IL-6 or OSM in submerged NHBE in vitro (p< 0.05 vs control). The production of S100A8/9 and S100A8/8 was also enhanced 3-fold or 20-fold by OSM, respectively in air-liquid interface cultured NHBE cells (p < 0.01 vs control). CONCLUSIONS: This study suggests that age-related reduction of S100A8/A9 expression in patients with CRSmay bemediated by increased sgp130, an inhibitor of IL-6 trans-signaling in epithelial cells.

Research paper thumbnail of Increased Expression of the Epithelial Anion Transporter Pendrin in Nasal Polyp Tissues of Patients with Chronic Rhinosinusitis

Journal of Allergy and Clinical Immunology, 2013

Research paper thumbnail of Evidence for Expansion of Sinonasal B-Lineage Cells in Chronic Rhinosinusitis

Journal of Allergy and Clinical Immunology, 2013

Research paper thumbnail of Evidence for Elevated IL-6 and its Signaling Components in Chronic Rhinosinusitis with Nasal Polyps

Journal of Allergy and Clinical Immunology, 2007

Research paper thumbnail of High Plasma Levels of Plasminogen Activator Inhibitor-1 are Associated with Decreased Lung Function in Asthmatic Patients

Journal of Allergy and Clinical Immunology, 2010

RATIONALE: Angiogenesis is considered to be important for both development of airway inflammation... more RATIONALE: Angiogenesis is considered to be important for both development of airway inflammation and airway remodeling in asthma and serum levels of proangiogenic factors (PFs) may reflect local activity of angiogenesis in asthmatic airways. The aim of the study was to compare PFs concentrations in sera of asthmatic patients and in healthy subjects, and to refer PFs concentration to the disease severity. METHODS: Serum was collected from 26 patients with severe/difficult (S/D) asthma and 28 patients with non-severe (NS) asthma. The control group included 10 healthy subjects (HS). Serum concentrations of Angiopoietin-1, Angiopoietin-2, Vascular Endothelial Growth Factor (VEGF) and osteopontin were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the whole asthma group (n5 54), as compared to HS, significantly higher serum concentrations was found for angiopoietin-1 (57,8 +/-3,2 ng/ml vs 10,3 +/-4,8 ng/ml; p<0,001), angiopoietin-2 (6,65 +/-1,7 vs 1,4 +/-0,13 ng/ml; p<0,001) and VEGF (307,1 +/-27 pg/ml vs 33,8 +/-13,5 pg/ml; p<0,001). The mean concentration of angiopoietin-2 was significantly increased in S/D asthmatics as compared to NS asthmatics (6,04+/-0,45 ng/ml vs 3,8+/0,44ng/ml, p<0,001). FEV1% of predicted value correlated inversely with serum concentrations of angiopoietin-2 (r 5-0,39; p <0,05) and osteopontin (r5-0,29, p<0,05). The dose of inhaled glucocorticosteroids correlated with serum levels of angiopoetin-2 (r 5 0,46; p<0,05) and oesteopontin (r50,27, p<0,05). CONCLUSION: Increased serum levels of proangiogenic factors in asthmatics and relation to asthma severity may reflect ongoing airway remodeling.

Research paper thumbnail of Analysis of the TLR2 Signaling Pathway in Nasal Epithelial Cells from Patients with Chronic Rhinosinusitis (CRS)

Journal of Allergy and Clinical Immunology, 2007

RATIONALE: Phosphorylation commonly regulates protein function, and GR has several phosphorylatio... more RATIONALE: Phosphorylation commonly regulates protein function, and GR has several phosphorylation sites. Phosphorylation may then modulate its activity. In steroid insensitive asthma, impaired GR responsiveness has been attributed to cytokines, particularly a combination of IL-2 and IL-4, which also increases phosphorylation of GR. However, the exact residues involved are not known. The objective of this study is to identify the phosphorylation of serine residues 203, 211 and 226 in GR in response to cytokine treatment. METHODS: Human lung fibroblasts (CCL-211) were grown to near confluence, and cultured with or without ED50 concentrations of IL-2, IL-4, IL-2 plus IL-4, IFN-g, TNF-a and GM-CSF for 24 hrs. 20 mg of total cellular protein was subjected to western blotting using specific antibodies to GR-a, GR-b, and phosphoserine 203, 211 and 226. RESULTS: A combination of IL-2 and IL-4 hyper-phosphorylated all three serine residues, whereas IL-2, IFN-g, and GM-CSF hyper-phosphorylated serine 226 only. Treatment with IL-2, IL-4, IFN-g, TNF-a and GM-CSF significantly decreased phosphorylation of serine 203 compared to control cells. Decreased phosphorylation of serine 211 was observed in response to IL-4, IFN-g and TNF-a. CONCLUSIONS: These results indicate that phosphorylation may be a key factor in regulating GR function. Structural modification may regulate GR function by altering binding affinity to glucocorticoids. The functional consequences of these modifications require further study. Funding: HL-69130 (US SARP)

Research paper thumbnail of Levels of the Cytokines IL-5, IL-13 and Rantes in Nasal Lavage Fluids Parallel the Cytokine Content of Nasal Polyps in Patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

Journal of Allergy and Clinical Immunology, 2013

Research paper thumbnail of A retrospective, cross‐sectional study reveals that women with CRSwNP have more severe disease than men

Immunity, Inflammation and Disease, 2015

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reporte... more Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen-specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex-specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n ¼ 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin-exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Research paper thumbnail of A retrospective, cross‐sectional study reveals that women with CRSwNP have more severe disease than men

Immunity, Inflammation and Disease, 2015

Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reporte... more Up to 50% of patients with chronic rhinosinusitis (CRS) have comorbid asthma, and we have reported that a subset of CRS patients who have nasal polyps (CRSwNP) have elevated autoantigen-specific antibodies within their nasal polyps (NP). While increases in the prevalence and/or severity of both asthma and autoimmunity in women are well characterized, it is not known whether CRSwNP is more severe or frequent in women than men. We sought to determine whether CRSwNP demonstrated sex-specific differences in frequency and/or severity. Using a retrospectively collected database of tertiary care patients (n ¼ 1393), we evaluated the distribution of sex in patients with CRSwNP with or without comorbid asthma or aspirin hypersensitivity. We further compared the severity of sinus disease between men and women with CRSwNP. Although women comprised 55% of CRS patients without NP (CRSsNP), a significantly smaller proportion of CRSwNP patients were female (38%, P < 0.001). Interestingly, women with CRSwNP were significantly more likely than men to have comorbid asthma (P < 0.001), and 61% of patients with the most severe form of disease (aspirin-exacerbated respiratory disease (CRSwNP plus asthma plus aspirin sensitivity)) were women (P < 0.05). Women with CRSwNP were significantly more likely to have taken oral steroids, and were more likely to have a history of revision surgeries (P < 0.05) compared to men. These data suggest that women with CRSwNP have more severe disease than men in a tertiary care setting. Future studies are needed to elucidate the mechanisms that drive disease severity in men and women, paving the way for the development of personalized treatment strategies for CRSwNP based on sex.

Research paper thumbnail of Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease

The Journal of allergy and clinical immunology, 2015

Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asth... more Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis. The objective of this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease. OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate-dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells. Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue (P < .05). OSM levels were also in...

Research paper thumbnail of Association of common filaggrin null mutations with atopy but not chronic rhinosinusitis

Annals of Allergy, Asthma & Immunology, 2015

Mutations in the filaggrin gene (FLG) are strongly associated with atopic dermatitis (AD) and ski... more Mutations in the filaggrin gene (FLG) are strongly associated with atopic dermatitis (AD) and skin barrier dysfunction (1, 2). FLG has been linked to asthma and asthma severity in subjects with and without atopic dermatitis (1, 3-5), and individuals with FLG null mutations are at increased risk of allergic sensitization and allergic rhinitis (5). However, despite evidence indicating a link between FLG, barrier dysfunction, and respiratory diseases (1), the importance of FLG in the pathogenesis of chronic rhinosinusitis (CRS) has never been evaluated. We hypothesized that FLG mutations might cause mucosal barrier dysfunction and thereby be associated with CRS (6, 7). To test this hypothesis, we investigated the frequency of the two most common FLG null mutations (R501X and 2282del4 (3, 5)) that have been implicated in asthma and allergic rhinitis in a group of European American CRS and control subjects. Patients with CRS (determined using Sinus and Allergy Health Partnership

Research paper thumbnail of Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells

Journal of Allergy and Clinical Immunology, 2015

Background-Balanced activation and inhibition of the immune system ensures pathogen clearance whi... more Background-Balanced activation and inhibition of the immune system ensures pathogen clearance while avoiding hyperinflammation. Siglecs, sialic acid binding proteins found on subsets of immune cells, often inhibit inflammation: Siglec-8 on eosinophils and Siglec-9 on neutrophils engage sialoglycan ligands on airways to diminish ongoing inflammation. The identities of human siglec ligands and their expression during inflammation are largely unknown. Objective-The histological distribution, expression and molecular characteristics of siglec ligands were explored in healthy and inflamed human upper airways and in a cellular model of airway inflammation. Methods-Normal and chronically inflamed upper airway tissues were stained for siglec ligands. The ligands were extracted from normal and inflamed tissues and from human Calu-3 cells for quantitative analysis by siglec blotting and isolation by siglec capture. Results-Siglec-8 ligands were expressed on a subpopulation of submucosal gland cells of human inferior turbinate, whereas Siglec-9 ligands were expressed more broadly (submucosal glands, epithelium, connective tissue); both were significantly upregulated in chronic rhinosinusitis patients. Human airway (Calu-3) cells expressed Siglec-9 ligands on mucin 5B

Research paper thumbnail of Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Nature communications, Jan 24, 2015

Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health probl... more Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 × 10(-8)) and rs9275596 (P=6.8 × 10(-10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites…

Research paper thumbnail of Epithelium, inflammation, and immunity in the upper airways of humans: studies in chronic rhinosinusitis

Proceedings of the American Thoracic Society, 2009

The purpose of this review is to discuss recent findings made during studies of the upper airways... more The purpose of this review is to discuss recent findings made during studies of the upper airways and sinuses of people with chronic rhinosinusitis (CRS) in the context of the literature. CRS is a chronic inflammatory disorder affecting nearly 30 million Americans and is generally resistant to therapy with antibiotics and glucocorticoids (Meltzer EO and coworkers, J Allergy Clin Immunol 2004;114:155-212). We have formed a collaboration that consists of otolaryngologists, allergists, and basic scientists to address the underlying immunologic and inflammatory processes that are occurring in, and possibly responsible for, this disease. The main emphasis of our work has been to focus on the roles that epithelium, in the sinuses and upper airways, plays as both a mediator and regulator of immune and inflammatory responses. It is not our intention here to provide a comprehensive review of the literature in this area, but we will try to put our work in the context of the findings of others...

Research paper thumbnail of Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia

The Journal of allergy and clinical immunology, Jan 10, 2014

In this study we found a significantly lower eosinophilia in nasal polyps surgically removed from... more In this study we found a significantly lower eosinophilia in nasal polyps surgically removed from second-generation Asian patients, similar to studies of native-born patients in Asian countries, suggesting the hypothesis that there may be genetic regulation of eosinophilia.