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Papers by Gurjit Khurana Hershey

Journal of Allergy and Clinical Immunology, 2022

Journal of Allergy and Clinical Immunology, 2022

Journal of Allergy and Clinical Immunology, 2022

Annals of Allergy, Asthma & Immunology, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Journal of Allergy and Clinical Immunology, 2021

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current par... more BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE To define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, food allergy, allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in the Black children. Collectively, our findings provide a new paradigm for the atopic march that is inclusive of Black children.

Journal of Allergy and Clinical Immunology, 2021

Journal of Allergy and Clinical Immunology, 2020

Local anaesthetics (LA) are often suspected as possible causes of allergic reactions but the inci... more Local anaesthetics (LA) are often suspected as possible causes of allergic reactions but the incidence of adverse events (including allergy) is low. The incidence of immediate reactions to LA in patients with clonal mast cell disorders (MCD) is unknown. The purpose of this study was to investigate the true incidence of LA allergy in patients with (MCD). METHODS: In the period 2012-2018, a total of 432 patients (186 women/ 246 men; median age 53 years, range 17-86 years) were underwent to bone marrow biopsy (BMB) with LA in suspicious of MCD. In case of positive history of LA allergy , an allergological work-up was made (skin prick test, intradermal test and subcutaneous provocation). All 432 patients were underwent to BMB in association with LA, chosen based on clinical history and allergological test. MCD was diagnosed in 180 patients (41.7%). 5 patients of them suffered from important mediator symptoms and for reasons were premedicated before BMB with steroids and antiH1. RESULTS: 5 of 180 (2%) patients with MCD and 7 of 252 (3.9%) patients without MCD had history of allergy to LA. All these patients had negative allergological tests for LA. All patients with MCD tolerated BMB with LA as well as all the patients without MCD. Only 1 patients with MCD had vagal hypotension during BMB. CONCLUSIONS: MCD is not a risk factor for allergy to LA. Therefore the use of LA in patients with MCD is safe. Premedication is not necessary exept in patients with history of important mediator symptoms.

Journal of Allergy and Clinical Immunology, 2020

Journal of Allergy and Clinical Immunology, 2020

Journal of Allergy and Clinical Immunology, 2020

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Skin prick testing (SPT) better correlates with clinical allergy, however, many atopic... more RATIONALE: Skin prick testing (SPT) better correlates with clinical allergy, however, many atopic dermatitis (AD) cohorts use IgE to detect sensitization. Longitudinal food and aeroallergen sensitization patterns via SPT have not been evaluated in a large pediatric AD cohort. METHODS: The Mechanisms of Progression of AD to Asthma in Children (MPAACH) cohort followed children with AD annually from age 1-2 years. SPT data for six food and eleven aeroallergens from 203 subjects who completed visits 1 (V1) and 2 (V2) were analyzed. Sensitization patterns were defined as: non-sensitized (no sensitization in V1 or V2), acquired (sensitized in V2 only), transient (sensitized in V1 only) and persistent (sensitized in V1 and V2). RESULTS: At V1 and V2, 51.5% and 49.5% of children were sensitized overall, respectively. Aeroallergen sensitization increased from 37.6% to 43.9% from V1 to V2 while food sensitization decreased from 38.1% to 30.3%. The most common sensitizations at V1 were egg (28.2%), peanut (22.8%), and dog (14.9%). Over one-third (35.0%) of the cohort had persistent sensitization, 12.8% were acquired, 16.3% were transient and 33.0% were non-sensitized. The top persistent allergens were peanut (16.3%), egg (12.8%) and dog (11.3%), the top transient allergens were egg (14.8%), trees (9.4%), and mold (8.4%). The top acquired allergens were trees (13.8%), dog (9.9%), and cat (8.4%). CONCLUSIONS: Predominance of aeroallergen sensitization occurred in V2 of MPAACH which was younger than observed in existing AD cohorts. Peanut was one of the most frequent and persistent sensitizations, supporting early food allergy assessment in children with AD.

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Genetic factors might play a role in the development of asthma combined with sensitiza... more RATIONALE: Genetic factors might play a role in the development of asthma combined with sensitization. Studies on the interaction effects between sensitization and genetic factors on asthma are scarce. The aim of the present study was to identify the associations between sensitization to house dust mite (HDM), genetic polymorphisms of TNF-a, and asthma. METHODS: This study included 2,929 children aged 7 years old from the Children's HEalth and Environmental Research study. International Study of Asthma and Allergies in Childhood questionnaire was used to identify the presence of allergic diseases. Skin prick test and bronchial provocation tests were performed. Genetic polymorphisms of TNF-a (rs1800629) were determined with TaqMan methods. RESULTS: When children with GG genotypes of TNF-a (rs1800629) were sensitization to HDM, the risk of asthma diagnosis ever was increased (aOR, 3.43; 95% CI, 2.19-5.38; interaction P 5 0.021). GG genotype of TNF-a (rs1800629) increased the risk of current asthma by interacting with HDM sensitization (aOR, 6.52; 95% CI, 3.65-11.65; P for interaction 5 0.044). In addition, GG genotype of TNF-a (rs1800629) increased the risk of BHR in children with HDM sensitization, where AG+AA genotype of TNF-a (rs1800629) increased the risk of BHR in children with HDM sensitization (aOR 3.34, 95% CI 2.21-5.07; aOR 1.88; 95% CI 1.09-3.24, respectively) (P for interaction 5 0.002). CONCLUSIONS: The results of the present study suggest that the association between HDM sensitization and asthma might be affected by TNF-a (rs1800629) polymorphism. This study suggests that prevention strategies of asthma need targeting for children with increased susceptibility.

World Allergy Organization Journal, 2017

patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genet... more patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genetic studies revealed epistasis between genetic variants in SPINK7 and PLAU (gene product, uPA) with atopy risk variants in ST2 and thymic stromal lymphopoietin (TSLP), respectively. Conclusions We propose that SPINK7 deficiency and uncontrolled protease activity serve a causative role in compromising the esophageal barrier. We suggest that SPINK7 represents a novel checkpoint in regulating innate immunity, and its deficiency, as occurs in EoE, induces proinflammatory and pro-allergic responses characterized by excessive cytokine production and epithelial barrier impairment, likely via a KLK-and uPA-dependent mechanism. Additionally, EoE disease susceptibility is influenced by genetic interactions between variants in this pathway (SPINK7 and PLAU) and cardinal atopy pathways (ST2 and TSLP).

The Journal of Immunology, Apr 1, 2010

PLOS ONE, 2015

Several studies have identified genes that are differentially expressed in atopic dermatitis (AD)... more Several studies have identified genes that are differentially expressed in atopic dermatitis (AD) compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs) reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures '89ADGES', including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the '89ADGES' discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein), keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16), inflammation (e.g., IL37, IL27RA, CCL18) and lipid metabolism (e.g., AKR1B10, FAD7, FAR2). Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P = <0.0006) among the 89 signature genes. Keratinocytes are known to play a major role in barrier function due to their location in the epidermis. Our result suggests that besides immune-mediated pathway, skin barrier pathways such as the keratinocyte differentiation pathway play a key role in AD pathogenesis. A better understanding of the role of keratinocytes in AD will be important for developing novel "barrier therapy" for this disease.

The Journal of Immunology, May 1, 2013

Journal of Allergy and Clinical Immunology, 2015

Background-There is considerable heterogeneity in asthma treatment response. Objective-To identif... more Background-There is considerable heterogeneity in asthma treatment response. Objective-To identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers. Methods-Children (5-18 years) presenting to the Emergency Department (ED) with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected upon presentation to the ED (T 0) and 18-24 hours later (T 1) and T 1 /T 0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (VNN1) that consistently distinguished good versus poor response phenotypes

Journal of Allergy and Clinical Immunology, 2015

Background: Exposure to traffic pollution particulate matter, predominantly diesel exhaust partic... more Background: Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood. Objective: We sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children. Methods: The effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes. Results: DEP coexposure with HDM resulted in persistent T H 2/T H 17 CD127 1 effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased T H 2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children. Conclusion: These findings suggest that DEP exposure results in accumulation of allergen-specific T H 2/T H 17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.

The Journal of allergy and clinical immunology, 2014

Epithelial genes have previously been associated with asthma but only explain a small fraction of... more Epithelial genes have previously been associated with asthma but only explain a small fraction of heritability. In part, this might be due to epistasis, which is often not considered. We sought to determine independent and epistatic associations between filaggrin (FLG), serine protease inhibitor Kazal-type 5 (SPINK5), and thymic stromal lymphopoietin (TSLP) gene variants and childhood asthma. Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5, and TSLP in asthmatic, allergic, and nonallergic nonasthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository. Associations with asthma were also assessed in 6 replication populations. We observed independent associations of variants in SPINK5 (P = .003) and TSLP (P = .006) with childhood asthma; a SPINK5 single nucleotide polymorphism was replicated. In subjects with 1 or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated ...

The Journal of allergy and clinical immunology, 2014

Journal of Allergy and Clinical Immunology, 2022

Journal of Allergy and Clinical Immunology, 2022

Journal of Allergy and Clinical Immunology, 2022

Annals of Allergy, Asthma & Immunology, 2022

BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin... more BACKGROUND In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE To explore the role of circulating vitamin D levels in allergic sensitization. METHODS Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = -0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

Journal of Allergy and Clinical Immunology, 2021

BACKGROUND The atopic march has been studied mostly in White populations, biasing our current par... more BACKGROUND The atopic march has been studied mostly in White populations, biasing our current paradigms. OBJECTIVE To define the atopic march in Black and White children and explore mechanisms for racial differences. METHODS Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, food allergy, allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. RESULTS White MPAACH children were more likely to be sensitized to aero and food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. CONCLUSIONS Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in the Black children. Collectively, our findings provide a new paradigm for the atopic march that is inclusive of Black children.

Journal of Allergy and Clinical Immunology, 2021

Journal of Allergy and Clinical Immunology, 2020

Local anaesthetics (LA) are often suspected as possible causes of allergic reactions but the inci... more Local anaesthetics (LA) are often suspected as possible causes of allergic reactions but the incidence of adverse events (including allergy) is low. The incidence of immediate reactions to LA in patients with clonal mast cell disorders (MCD) is unknown. The purpose of this study was to investigate the true incidence of LA allergy in patients with (MCD). METHODS: In the period 2012-2018, a total of 432 patients (186 women/ 246 men; median age 53 years, range 17-86 years) were underwent to bone marrow biopsy (BMB) with LA in suspicious of MCD. In case of positive history of LA allergy , an allergological work-up was made (skin prick test, intradermal test and subcutaneous provocation). All 432 patients were underwent to BMB in association with LA, chosen based on clinical history and allergological test. MCD was diagnosed in 180 patients (41.7%). 5 patients of them suffered from important mediator symptoms and for reasons were premedicated before BMB with steroids and antiH1. RESULTS: 5 of 180 (2%) patients with MCD and 7 of 252 (3.9%) patients without MCD had history of allergy to LA. All these patients had negative allergological tests for LA. All patients with MCD tolerated BMB with LA as well as all the patients without MCD. Only 1 patients with MCD had vagal hypotension during BMB. CONCLUSIONS: MCD is not a risk factor for allergy to LA. Therefore the use of LA in patients with MCD is safe. Premedication is not necessary exept in patients with history of important mediator symptoms.

Journal of Allergy and Clinical Immunology, 2020

Journal of Allergy and Clinical Immunology, 2020

Journal of Allergy and Clinical Immunology, 2020

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Skin prick testing (SPT) better correlates with clinical allergy, however, many atopic... more RATIONALE: Skin prick testing (SPT) better correlates with clinical allergy, however, many atopic dermatitis (AD) cohorts use IgE to detect sensitization. Longitudinal food and aeroallergen sensitization patterns via SPT have not been evaluated in a large pediatric AD cohort. METHODS: The Mechanisms of Progression of AD to Asthma in Children (MPAACH) cohort followed children with AD annually from age 1-2 years. SPT data for six food and eleven aeroallergens from 203 subjects who completed visits 1 (V1) and 2 (V2) were analyzed. Sensitization patterns were defined as: non-sensitized (no sensitization in V1 or V2), acquired (sensitized in V2 only), transient (sensitized in V1 only) and persistent (sensitized in V1 and V2). RESULTS: At V1 and V2, 51.5% and 49.5% of children were sensitized overall, respectively. Aeroallergen sensitization increased from 37.6% to 43.9% from V1 to V2 while food sensitization decreased from 38.1% to 30.3%. The most common sensitizations at V1 were egg (28.2%), peanut (22.8%), and dog (14.9%). Over one-third (35.0%) of the cohort had persistent sensitization, 12.8% were acquired, 16.3% were transient and 33.0% were non-sensitized. The top persistent allergens were peanut (16.3%), egg (12.8%) and dog (11.3%), the top transient allergens were egg (14.8%), trees (9.4%), and mold (8.4%). The top acquired allergens were trees (13.8%), dog (9.9%), and cat (8.4%). CONCLUSIONS: Predominance of aeroallergen sensitization occurred in V2 of MPAACH which was younger than observed in existing AD cohorts. Peanut was one of the most frequent and persistent sensitizations, supporting early food allergy assessment in children with AD.

Journal of Allergy and Clinical Immunology, 2020

RATIONALE: Genetic factors might play a role in the development of asthma combined with sensitiza... more RATIONALE: Genetic factors might play a role in the development of asthma combined with sensitization. Studies on the interaction effects between sensitization and genetic factors on asthma are scarce. The aim of the present study was to identify the associations between sensitization to house dust mite (HDM), genetic polymorphisms of TNF-a, and asthma. METHODS: This study included 2,929 children aged 7 years old from the Children's HEalth and Environmental Research study. International Study of Asthma and Allergies in Childhood questionnaire was used to identify the presence of allergic diseases. Skin prick test and bronchial provocation tests were performed. Genetic polymorphisms of TNF-a (rs1800629) were determined with TaqMan methods. RESULTS: When children with GG genotypes of TNF-a (rs1800629) were sensitization to HDM, the risk of asthma diagnosis ever was increased (aOR, 3.43; 95% CI, 2.19-5.38; interaction P 5 0.021). GG genotype of TNF-a (rs1800629) increased the risk of current asthma by interacting with HDM sensitization (aOR, 6.52; 95% CI, 3.65-11.65; P for interaction 5 0.044). In addition, GG genotype of TNF-a (rs1800629) increased the risk of BHR in children with HDM sensitization, where AG+AA genotype of TNF-a (rs1800629) increased the risk of BHR in children with HDM sensitization (aOR 3.34, 95% CI 2.21-5.07; aOR 1.88; 95% CI 1.09-3.24, respectively) (P for interaction 5 0.002). CONCLUSIONS: The results of the present study suggest that the association between HDM sensitization and asthma might be affected by TNF-a (rs1800629) polymorphism. This study suggests that prevention strategies of asthma need targeting for children with increased susceptibility.

World Allergy Organization Journal, 2017

patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genet... more patients and a marked decrease in expression of the uPA receptor by esophageal eosinophils. Genetic studies revealed epistasis between genetic variants in SPINK7 and PLAU (gene product, uPA) with atopy risk variants in ST2 and thymic stromal lymphopoietin (TSLP), respectively. Conclusions We propose that SPINK7 deficiency and uncontrolled protease activity serve a causative role in compromising the esophageal barrier. We suggest that SPINK7 represents a novel checkpoint in regulating innate immunity, and its deficiency, as occurs in EoE, induces proinflammatory and pro-allergic responses characterized by excessive cytokine production and epithelial barrier impairment, likely via a KLK-and uPA-dependent mechanism. Additionally, EoE disease susceptibility is influenced by genetic interactions between variants in this pathway (SPINK7 and PLAU) and cardinal atopy pathways (ST2 and TSLP).

The Journal of Immunology, Apr 1, 2010

PLOS ONE, 2015

Several studies have identified genes that are differentially expressed in atopic dermatitis (AD)... more Several studies have identified genes that are differentially expressed in atopic dermatitis (AD) compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs) reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures '89ADGES', including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the '89ADGES' discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein), keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16), inflammation (e.g., IL37, IL27RA, CCL18) and lipid metabolism (e.g., AKR1B10, FAD7, FAR2). Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P = <0.0006) among the 89 signature genes. Keratinocytes are known to play a major role in barrier function due to their location in the epidermis. Our result suggests that besides immune-mediated pathway, skin barrier pathways such as the keratinocyte differentiation pathway play a key role in AD pathogenesis. A better understanding of the role of keratinocytes in AD will be important for developing novel "barrier therapy" for this disease.

The Journal of Immunology, May 1, 2013

Journal of Allergy and Clinical Immunology, 2015

Background-There is considerable heterogeneity in asthma treatment response. Objective-To identif... more Background-There is considerable heterogeneity in asthma treatment response. Objective-To identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers. Methods-Children (5-18 years) presenting to the Emergency Department (ED) with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected upon presentation to the ED (T 0) and 18-24 hours later (T 1) and T 1 /T 0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (VNN1) that consistently distinguished good versus poor response phenotypes

Journal of Allergy and Clinical Immunology, 2015

Background: Exposure to traffic pollution particulate matter, predominantly diesel exhaust partic... more Background: Exposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood. Objective: We sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children. Methods: The effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes. Results: DEP coexposure with HDM resulted in persistent T H 2/T H 17 CD127 1 effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased T H 2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children. Conclusion: These findings suggest that DEP exposure results in accumulation of allergen-specific T H 2/T H 17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.

The Journal of allergy and clinical immunology, 2014

Epithelial genes have previously been associated with asthma but only explain a small fraction of... more Epithelial genes have previously been associated with asthma but only explain a small fraction of heritability. In part, this might be due to epistasis, which is often not considered. We sought to determine independent and epistatic associations between filaggrin (FLG), serine protease inhibitor Kazal-type 5 (SPINK5), and thymic stromal lymphopoietin (TSLP) gene variants and childhood asthma. Using a candidate gene approach, we genotyped 29 variants in FLG, SPINK5, and TSLP in asthmatic, allergic, and nonallergic nonasthmatic white and black children participating in the well-phenotyped Greater Cincinnati Pediatric Clinic Repository. Associations with asthma were also assessed in 6 replication populations. We observed independent associations of variants in SPINK5 (P = .003) and TSLP (P = .006) with childhood asthma; a SPINK5 single nucleotide polymorphism was replicated. In subjects with 1 or more SPINK5 risk alleles, the absence of the TSLP protective minor alleles was associated ...

The Journal of allergy and clinical immunology, 2014