Publications by authors named "Carine Blanchard"

51 Publications

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

J Allergy Clin Immunol 2021 Jul 6. Epub 2021 Jul 6.

Inform Diagnostics, Irving, Tex; Department of Pathology, Baylor College of Medicine, Houston, Tex.

Background: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments.

Objective: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE.

Methods: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists.

Results: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life.

Conclusions: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.001DOI Listing
July 2021

Novel approach to visualize the inter-dependencies between maternal sensitization, breast milk immune components and human milk oligosaccharides in the LIFE Child cohort.

PLoS One 2020 21;15(4):e0230472. Epub 2020 Apr 21.

Nestlé Research, Vers-chez-les-Blanc, Lausanne, Switzerland.

Background: Numerous studies have shown that specific components of breast milk, considered separately, are associated with disease status in the mother or the child using univariate analyses. However, very few studies have considered multivariate analysis approaches to evaluate the relationship between multiple breast milk components simultaneously.

Aim: Here we aimed at visualizing breast milk component complex interactions in the context of the allergy status of the mother or the child.

Methods: Milk samples were collected from lactating mothers participating in the Leipziger Forschungszentrum für Zivilisationskrankheiten (LIFE) Child cohort in Leipzig, Germany. A total of 156 breast milk samples, collected at 3 months after birth from mother/infant pairs, were analyzed for 51 breast milk components. Correlation, principal component analysis (PCA) and graphical discovery analysis were used.

Result: Correlations ranging from 0.40 to 0.96 were observed between breast milk fatty acid and breast milk phospholipids levels and correlations ranging from 0 to 0.76 between specific human milk oligosaccharides (HMO) were observed. No separation of the data based on the risk of allergy in the infants was identified using PCA. When graphical discovery analysis was used, dependencies between maternal plasma immunoglobulin E (IgE) level and the breast milk immune marker transforming growth factor-beta 2 (TGF-ß2), between TGF-ß2, breast milk immunoglobulin A (IgA) and TGF-ß1 as well as between breast milk total protein and birth weight were observed. Graphical discovery analysis also exemplifies a possible competition for the fucosyl group between 2'FL, LNFP-I and 3'FL in the HMO group. Additionally, dependencies between immune component IgA and specific HMO (6'SL and blood group A antigen tetraose type 5 or PI-HMO) were identified.

Conclusion: Graphical discovery analysis applied to complex matrices such as breast milk composition can aid in understanding the complexity of interactions between breast milk components and possible relations to health parameters in the mother or the infant. This approach can lead to novel discoveries in the context of health and diseases such as allergy. Our study thus represents the first attempt to visualize the complexity and the inter-dependency of breast milk components.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230472PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173766PMC
July 2020

Transcriptomic Analysis Links Eosinophilic Esophagitis and Atopic Dermatitis.

Front Pediatr 2019 20;7:467. Epub 2019 Nov 20.

Nestlé Institute of Health Sciences, Nestlé Research, Lausanne, Switzerland.

Eosinophilic esophagitis (EoE) is commonly associated with concomitant atopic diseases including atopic dermatitis (AD) and allergic airway (AA) diseases including asthma. Despite this link and the shared pathologic features across these three disorders, detailed analyses of the unifying molecular pathways are lacking. We sought to investigate the mRNA expression profile overlap between EoE, AA, and AD and to identify the involvement of interleukin 13 (IL-13) in modulating gene expression. Whole-genome mRNA expression analyses were performed on tissue specimens (biopsies or nasal brushes) from patients with EoE, AD, and AA, and IL-13-stimulated primary human epithelial cells from the esophagus, the skin, and the airways. By human disease expression profiles, EoE evidenced a significantly higher overlap ( = 0.0006) with AD (181 transcripts; 10%) than with AA (124 transcripts, 7%). Only 18 genes were found to be commonly dysregulated among the three diseases; these included filaggrin, histamine receptor H1, claudin 1, cathepsin C, plasminogen activator urokinase receptor, and suppressor of cytokine signaling 3. Ontogenetic analysis revealed a common immune/inflammatory response among the three diseases and a different epithelial response (epidermal cell differentiation) between EoE and AA. The overlap between the IL-13-stimulated epithelial cell transcriptome and the respective disease transcriptome was 22, 9, and 5% in EoE, AD, and AA, respectively, indicating a greater involvement of the IL-13 pathway in EoE than AA ( = 0.0007) or AD ( = 0.02). EoE, AD, and AA share a common set of disease-specific transcripts, highlighting common molecular etiology. Their comparative analysis indicates relatively closer relationships between EoE and AD, particularly centered around IL-13-driven pathways. Therefore, these findings provide an increased rationale for shared therapeutic strategies.
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http://dx.doi.org/10.3389/fped.2019.00467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879454PMC
November 2019

Overview of in vivo and ex vivo endpoints in murine food allergy models: Suitable for evaluation of the sensitizing capacity of novel proteins?

Allergy 2020 02 9;75(2):289-301. Epub 2019 Jul 9.

Wageningen Food and Biobased Research, Wageningen, The Netherlands.

Significant efforts are necessary to introduce new dietary protein sources to feed a growing world population while maintaining food supply chain sustainability. Such a sustainable protein transition includes the use of highly modified proteins from side streams or the introduction of new protein sources that may lead to increased clinically relevant allergic sensitization. With food allergy being a major health problem of increasing concern, understanding the potential allergenicity of new or modified proteins is crucial to ensure public health protection. The best predictive risk assessment methods currently relied on are in vivo models, making the choice of endpoint parameters a key element in evaluating the sensitizing capacity of novel proteins. Here, we provide a comprehensive overview of the most frequently used in vivo and ex vivo endpoints in murine food allergy models, addressing their strengths and limitations for assessing sensitization risks. For optimal laboratory-to-laboratory reproducibility and reliable use of predictive tests for protein risk assessment, it is important that researchers maintain and apply the same relevant parameters and procedures. Thus, there is an urgent need for a consensus on key food allergy parameters to be applied in future food allergy research in synergy between both knowledge institutes and clinicians.
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http://dx.doi.org/10.1111/all.13943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065134PMC
February 2020

A Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Oral Administration of a Heat-Treated Lactobacillus paracasei  Supplement in Infants with Atopic Dermatitis Receiving Topical Corticosteroid Therapy.

Skin Pharmacol Physiol 2019 22;32(4):201-211. Epub 2019 May 22.

Nestlé Research, Lausanne, Switzerland,

Background/aims: Atopic dermatitis (AD) is a common disease in infancy, for which topical steroids are the first-line therapy but have side effects. Innovative approaches are needed to reduce the burden of AD and corticosteroid usage in infants.

Methods: The once-daily consumption of heat-treated probiotic Lactobacillus paracasei GM-080 or placebo for 16 weeks as supplementary approach to topical treatment with fluticasone propionate cream was compared in AD infants aged 4-30 months. Outcomes were SCORAD and its subscores, TEWL, Infants' Dermatitis Quality of Life Index (IDQOL), corticoid "sparing effect," CCL17/TARC, and IgE status.

Results: SCORAD, objective SCORAD, itching, and IDQOL decreased significantly (p < 0.001) over the treatment period in both treatment groups. Slight decreases (ns) were noted in TEWL in lesional and unaffected skin and CCL17 levels. There were no differences between the treatment groups. Total IgE increased over the treatment period in both groups, with significantly higher increase in the heat-treated probiotic group (p = 0.038). There was no evidence of a corticoid "sparing effect" by the probiotic.

Conclusions: In this design, the probiotic L. paracasei was not beneficial as a complementary approach to topical corticosteroids in infants with AD. However, slight beneficial effects may have been masked by the moderate potency corticoid.
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http://dx.doi.org/10.1159/000499436DOI Listing
January 2020

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference.

Gastroenterology 2018 10 6;155(4):1022-1033.e10. Epub 2018 Sep 6.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Illinois, University of Illinois, Peoria, Illinois.

Background & Aims: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis.

Methods: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences.

Results: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement.

Conclusions: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.
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http://dx.doi.org/10.1053/j.gastro.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174113PMC
October 2018

Partially Hydrolyzed Whey Infant Formula: Literature Review on Effects on Growth and the Risk of Developing Atopic Dermatitis in Infants from the General Population.

Int Arch Allergy Immunol 2018;177(2):123-134. Epub 2018 Jul 12.

Institute of Nutritional Science, Nestlé Research Center, Lausanne, Switzerland.

Limited evidence is available regarding the effect of partially hydrolyzed whey-based formula (pHF-W) on growth and atopic dermatitis (AD) risk reduction in infants within the general infant population, and without a familial history of allergy as an inclusion or exclusion criterion. We reviewed the current evidence available from studies using pHF-W in the general population and summarized the data on safety (growth) and efficacy outcomes (reduction of AD), comparing the studies side by side. A total of 8 clinical trials were identified from the literature search, 7 of which used the same pHF-W. Six out of 8 studies indicated a reduction of atopic manifestations using a specific pHF-W versus cow's milk formula (CMF) in the first years of life. Data were summarized and compared side by side for growth (3 studies) and efficacy (5 studies). In these diverse general populations, the results on growth and AD were consistent with the previous findings reported on infants with a family history of allergy, but numerous limitations to these studies were identified. This literature review confirms that pHF-W supports normal growth in infants, and suggests that the risk of AD may be reduced in not-fully breastfed infants from the general population when supplemented with a specific pHF-W when compared to CMF during the first 4-6 months of life. Further studies are warranted to confirm these results.
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http://dx.doi.org/10.1159/000489861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191881PMC
November 2018

Eosinophilic esophagitis: latest insights from diagnosis to therapy.

Ann N Y Acad Sci 2018 12 15;1434(1):84-93. Epub 2018 May 15.

Division of Gastroenterology, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi of Milan, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milan, Italy.

Eosinophilic esophagitis (EoE) represents a chronic, local immune-mediated esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Other systemic and local causes of esophageal eosinophilia should be excluded. Clinical manifestations or pathologic data should not be interpreted in isolation. EoE was first described as a distinct disease entity in 1993. Most patients are diagnosed with underlying food allergies. The first diagnostic and therapeutic guidelines were published in 2007 with a first update in 2011. In 2017, new international guidelines were published based on the GRADE methodology. These guidelines provide, among many other topics, insights on the role of proton pump inhibitor-responsive esophageal eosinophilia. Over the last two decades, considerable progress was made by stakeholders regarding the understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization of assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. This brief review provides further insights into latest diagnostic and therapeutic advances.
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http://dx.doi.org/10.1111/nyas.13731DOI Listing
December 2018

Eosinophilic Esophagitis: Relationship of Subepithelial Eosinophilic Inflammation With Epithelial Histology, Endoscopy, Blood Eosinophils, and Symptoms.

Am J Gastroenterol 2018 03 16;113(3):348-357. Epub 2018 Jan 16.

Swiss EoE Clinic, Praxis Römerhof, Olten, Switzerland.

Objectives: For technical reasons, the histologic characterization of eosinophilic esophagitis (EoE)-specific alterations is almost exclusively based on those found in the esophageal epithelium, whereas little is known about subepithelial abnormalities. In this study, we aimed to systematically assess the nature of subepithelial histologic alterations, and analyze their relationship with epithelial histologic findings, endoscopic features, and symptoms.

Methods: Adult patients with established EoE diagnosis were prospectively included during a yearly follow-up visit. Patients underwent assessment of clinical, endoscopic, and histologic disease activity using EoE-specific scores.

Results: We included 200 EoE patients (mean age 43.5±15.7 years, 74% males) with a median peak count of 36 intraepithelial eosinophils/hpf (IQR 14-84). The following histologic features were identified in the subepithelial layer: eosinophilic infiltration (median peak count of 20 eosinophils/hpf (IQR 10-51)), eosinophil degranulation (43%), fibrosis (82%), and lymphoid follicles (56%). Peak intraepithelial eosinophil counts were higher, identical, and lower when compared to the subepithelial layer in 62.5%, 7%, and 30.5% of patients, respectively. Anti-eosinophilic treatment at inclusion did not influence the relation between subepithelial and epithelial peak eosinophil counts. Subepithelial histologic activity correlated with epithelial histologic activity (rho 0.331, P<0.001), endoscopic severity (rho 0.208, P=0.003), and symptom severity (rho 0.179, P=0.011). Forty percent (21/52) of patients with <15 intraepithelial eosinophils/hpf had subepithelial peak counts of ≥15/hpf.

Conclusions: There is a significant but modest correlation between subepithelial histologic activity and epithelial histologic activity, endoscopic severity, and symptom severity. The long-term clinical impact of assessing subepithelial alterations in EoE needs to be further elucidated.
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http://dx.doi.org/10.1038/ajg.2017.493DOI Listing
March 2018

A history into genetic and epigenetic evolution of food tolerance: how humanity rapidly evolved by drinking milk and eating wheat.

Authors:
Carine Blanchard

Curr Opin Allergy Clin Immunol 2017 Dec;17(6):460-464

Immunology group, Gut Ecosystem Department, Nestlé Research Center, Lausanne, Switzerland.

Purpose Of Review: Human exposure to wheat and milk is almost global worldwide. Yet the introduction of milk and wheat is very recent (5000-10 000 years) when compared to the human evolution. The last 4 decades have seen a rise in food allergy and food intolerance to milk and wheat. Often described as plurifactorial, the cause of allergic diseases is the result from an interplay between genetic predisposition and epigenetic in the context of environmental changes.

Recent Findings: Genetic and epigenetic understanding and their contribution to allergy or other antigen-driven diseases have considerably advanced in the last few years. Yet, environmental factors are also quite difficult to identify and associate with disease risk. Can we rethink our old findings and learn from human history and recent genetic studies?

Summary: More than one million years separate Homo habilis to today's mankind, more than 1 million years to develop abilities to obtain food by foraging in diverse environments. One million year to adjust and fine-tune our genetic code and adapt; and only 1% of this time, 10 000 years, to face the three biggest revolutions of the human kind: the agricultural revolution, the industrial revolution and the postindustrial revolution. With big and rapid environmental changes come adaptation but with no time for fine-tuning. Today tolerance and adverse reactions to food may be a testimony of adaptation successes and mistakes.
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http://dx.doi.org/10.1097/ACI.0000000000000397DOI Listing
December 2017

Bifidobacterium longum extract exerts pro-differentiating effects on human epidermal keratinocytes, in vitro.

Exp Dermatol 2017 01 2;26(1):92-94. Epub 2016 Dec 2.

DE-MTA "Lendület" Cellular Physiology Research Group, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

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http://dx.doi.org/10.1111/exd.13130DOI Listing
January 2017

Current challenges facing the assessment of the allergenic capacity of food allergens in animal models.

Clin Transl Allergy 2016 16;6:21. Epub 2016 Jun 16.

Swiss Institute of Allergy and Asthma Research, University of Zürich, Obere Strasse 22, 7270 Davos Platz, Switzerland.

Food allergy is a major health problem of increasing concern. The insufficiency of protein sources for human nutrition in a world with a growing population is also a significant problem. The introduction of new protein sources into the diet, such as newly developed innovative foods or foods produced using new technologies and production processes, insects, algae, duckweed, or agricultural products from third countries, creates the opportunity for development of new food allergies, and this in turn has driven the need to develop test methods capable of characterizing the allergenic potential of novel food proteins. There is no doubt that robust and reliable animal models for the identification and characterization of food allergens would be valuable tools for safety assessment. However, although various animal models have been proposed for this purpose, to date, none have been formally validated as predictive and none are currently suitable to test the allergenic potential of new foods. Here, the design of various animal models are reviewed, including among others considerations of species and strain, diet, route of administration, dose and formulation of the test protein, relevant controls and endpoints measured.
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http://dx.doi.org/10.1186/s13601-016-0110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910256PMC
June 2016

Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression.

J Allergy Clin Immunol 2016 Apr 21;137(4):1264-1267.e10. Epub 2015 Oct 21.

Nutrition and Health Research, Nestlé Research Center, Lausanne, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2015.08.033DOI Listing
April 2016

Molecular pathogenesis of eosinophilic esophagitis.

Authors:
Carine Blanchard

Curr Opin Gastroenterol 2015 Jul;31(4):321-7

Nutrition and Health Research, Nestec Ltd, Nestlé Research Center, Lausanne, canton of Vaud, Switzerland.

Purpose Of Review: Eosinophilic esophagitis (EoE) is an esophageal disease characterized by an accumulation of eosinophils in the esophagus, which is normally devoid of eosinophils. The interest of the scientific community in EoE has grown considerably over the past two decades, and understanding of the molecular mechanisms involved in this disease has increased greatly in the last 2 years.

Recent Findings: Important new insights into the pathogenesis of EoE recently have been achieved. Recent evaluations considering genetic and the environmental risk factors have led to the concept that some still-unknown environmental factors influence the risk of developing EoE more than the genetic predisposition. New molecules (in addition to interleukin-13, eotaxin-3, transforming growth factor-β1, thymic stromal lymphopoietin, filaggrin, or interleukin-5) also have been shown to be involved in the disease pathogenesis.

Summary: The present review describes recent advances in the understanding of the molecular mechanisms underlying EoE, and how these new findings have enhanced understanding of the pathogenesis of this new esophageal disorder.
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http://dx.doi.org/10.1097/MOG.0000000000000186DOI Listing
July 2015

How do gastroenterologists assess overall activity of eosinophilic esophagitis in adult patients?

Am J Gastroenterol 2015 Mar 3;110(3):402-14. Epub 2015 Mar 3.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Objectives: There is no "gold standard" for assessing disease activity in patients with eosinophilic esophagitis (EoE). We aimed to compare physicians' judgment of EoE activity with patients' judgment of symptom severity. We also aimed to examine the relative contribution of symptoms as well as endoscopic and histologic findings in shaping physicians' judgment of EoE activity.

Methods: Six gastroenterologists (all EoE experts) assessed EoE-associated symptoms in adult patients. Patients completed a symptom instrument and provided global assessment of EoE symptom severity (PatGA) (Likert scale: 0 (inactive) to 10 (most active)). Following esophagogastroduodenoscopy with biopsy sampling, gastroenterologists provided a global assessment of EoE activity (PhysGA) (Likert scale from 0 to 10) based on patient history and endoscopic and histologic findings. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms and endoscopic and histologic findings explain variations in PhysGA.

Results: A total of 149 EoE patients were prospectively included (71.8% male, median age at inclusion 38 years, 71.8% with concomitant allergies). A moderate positive correlation between PhysGA and PatGA (rho=0.442, P<0.001) was observed and the mean difference in the Bland-Altman plot was 1.77. Variations in severity of endoscopic findings, symptoms, and histologic findings alone explained 53%, 49%, and 30%, of the variability in PhysGA, respectively. Together, these findings explained 75% of variability in PhysGA.

Conclusions: Gastroenterologists rate EoE activity mainly on the basis of endoscopic findings and symptoms and, to a lesser extent, on histologic findings.
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http://dx.doi.org/10.1038/ajg.2015.32DOI Listing
March 2015

Low-allergenic hydrolyzed egg induces oral tolerance in mice.

Int Arch Allergy Immunol 2014 27;164(1):64-73. Epub 2014 May 27.

Allergy Group, Nutrition and Health Research, Nestlé Research Center, Lausanne, Switzerland.

Background: Egg allergy is one of the most common food allergies in children. The standard therapy for egg allergy is strict avoidance. Yet, there is considerable clinical and scientific interest in primary or secondary prevention. A major drawback of oral tolerance (OT) induction protocols, however, is the possibility of severe side effects; thus, we have formulated a hypoallergenic egg product and demonstrate its in vivo capacity to modulate the immune system in the current study.

Methods: Hydrolyzed egg (HE) was produced using a combination of moderate heat treatment and enzymatic hydrolysis. The capacity of HE to induce OT was tested in experimental models and compared to whole egg (WE). Delayed-type hypersensitivity (DTH) responses, immune markers and potential early markers of OT were analyzed.

Results: Allergic responses, assessed by both DTH responses upon OVA challenge and serum OVA-specific IgE and IgG1, were decreased after treatment with HE and WE compared to the control group. Additionally, feeding WE and HE significantly decreased Th2 cytokine induction and cell proliferation, induced the activation of effector CD4+ T cells and increased numbers and percentages of ICOS+CD4+CD25+Foxp3+ cells. Furthermore, DO11.10 mouse experiments showed that HE contains other peptides than the OVA323-339 peptide that are able to induce tolerance to OVA.

Conclusions: Altogether, results showed that HE induces OT in mice in a dose-dependent manner. Due to its low allergenicity compared to WE, it may represent a safer alternative for OT induction in at-risk subjects or oral immunotherapy in allergic patients.
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http://dx.doi.org/10.1159/000363110DOI Listing
August 2014

Genetics of eosinophilic esophagitis.

Dig Dis 2014 28;32(1-2):22-9. Epub 2014 Feb 28.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Eosinophilic esophagitis (EoE) is a complex genetic disorder characterized by eosinophilic inflammation within the esophagus. Multiple epidemiological studies estimate the prevalence of EoE is 4 in 10,000, with a higher disease prevalence in individuals of European ancestry and in males, highlighting a genetic etiology of the disease. EoE has often been noted to occur in multiple family members, particularly siblings, in a non-Mendelian pattern, indicating the heritable component of EoE is likely complex in nature. Although EoE is a newly diagnosed disorder involving a complex polygenic etiology, much progress has been made towards identifying the molecular pathways contributing to the disease pathogenesis and the genetic variants associated with disease susceptibility using a variety of approaches (genome-wide and candidate gene) as well as study designs (case-control and family-based cohorts). Here, we discuss the major scientific findings that have shaped the current molecular and genetic landscape of EoE as well as the major obstacles in the discovery of disease causal variants in complex disorders.
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http://dx.doi.org/10.1159/000357005DOI Listing
November 2014

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.

Nat Med 2014 Feb 5;20(2):159-66. Epub 2014 Jan 5.

Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, BH19.206 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.
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http://dx.doi.org/10.1038/nm.3444DOI Listing
February 2014

Intragastric and Intranasal Administration of Lactobacillus paracasei NCC2461 Modulates Allergic Airway Inflammation in Mice.

Int J Inflam 2012 21;2012:686739. Epub 2012 Mar 21.

R&D Laboratory of the Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.

Introduction. Preclinical and clinical evidences for a role of oral probiotics in the management of allergic diseases are emerging. Aim. We aimed at testing the immunomodulatory effects of intranasal versus intragastric administration of Lactobacillus paracasei NCC2461 in a mouse model of allergic airway inflammation and the specificity of different probiotics by comparing L. paracasei NCC2461 to Lactobacillus plantarum NCC1107. Methods. L. paracasei NCC2461 or L. plantarum NCC1107 strains were administered either intragastrically (NCC2461) or intranasally (NCC2461 or NCC1107) to OVA-sensitized mice challenged with OVA aerosols. Inflammatory cell recruitment into BALF, eotaxin and IL-5 production in the lungs were measured. Results. Intranasal L. paracasei NCC2461 efficiently protected sensitized mice upon exposure to OVA aerosols in a dose-dependent manner as compared to control mice. Inflammatory cell number, eotaxin and IL-5 were significantly reduced in BALF. Intranasal supplementation of L. paracasei NCC2461 was more potent than intragastric application in limiting the allergic response and possibly linked to an increase in T regulatory cells in the lungs. Finally, intranasal L. plantarum NCC1107 reduced total and eosinophilic lung inflammation, but increased neutrophilia and macrophages infiltration. Conclusion. A concerted selection of intervention schedule, doses, and administration routes (intranasal versus intragastric) may markedly contribute to modulate airway inflammation in a probiotic strain-specific manner.
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http://dx.doi.org/10.1155/2012/686739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382844PMC
August 2012

The pan-B cell marker CD22 is expressed on gastrointestinal eosinophils and negatively regulates tissue eosinophilia.

J Immunol 2012 Feb 21;188(3):1075-82. Epub 2011 Dec 21.

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

CD22 is currently recognized as a B cell-specific Siglec and has been exploited therapeutically with humanized anti-CD22 mAb having been used against B cell leukemia. In this study, tissue-specific eosinophil mRNA microarray analysis identified that CD22 transcript levels of murine gastrointestinal (GI) eosinophils are 10-fold higher than those of lung eosinophils. To confirm the mRNA data at the protein level, we developed a FACS-based protocol designed to phenotype live GI eosinophils isolated from the murine lamina propria. Indeed, we found that jejunum eosinophils expressed remarkably high levels of surface CD22, similar to levels found in B cells across multiple mouse strains. In contrast, CD22 was undetectable on eosinophils from the colon, blood, thymus, spleen, uterus, peritoneal cavity, and allergen-challenged lung. Eosinophils isolated from newborn mice did not express CD22 but subsequently upregulated CD22 expression to adult levels within the first 10 d after birth. The GI lamina propria from CD22 gene-targeted mice harbored more eosinophils than wild type control mice, whereas the GI eosinophil turnover rate was unaltered in the absence of CD22. Our findings identify a novel expression pattern and tissue eosinophilia-regulating function for the "B cell-specific" inhibitory molecule CD22 on GI eosinophils.
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http://dx.doi.org/10.4049/jimmunol.1102222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262961PMC
February 2012

Epigenetic regulation of the IL-13-induced human eotaxin-3 gene by CREB-binding protein-mediated histone 3 acetylation.

J Biol Chem 2011 Apr 16;286(15):13193-204. Epub 2011 Feb 16.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

The etiology of a variety of chronic inflammatory disorders has been attributed to the interaction of genetic and environmental factors. Herein, we identified a link between epigenetic regulation and IL-13-driven eotaxin-3 in the pathogenesis of chronic allergic inflammation. We first demonstrated that the cAMP-responsive element (CRE) site in the eotaxin-3 promoter affects IL-13-induced eotaxin-3 promoter activity. Furthermore, the CRE-binding protein-binding protein (CBP), a histone acetyltransferase, induced base-line and IL-13-induced eotaxin-3 promoter activity. Additionally, IL-13 treatment promoted global histone 3 acetylation as well as the formation of a complex containing CBP and STAT6 and the subsequent acetylation of histone 3 at the eotaxin-3 promoter. CBP gene silencing decreased IL-13-induced transcription of eotaxin-3. Conversely, inhibition of histone deacetylation increased IL-13-induced eotaxin-3 production. Clinical studies demonstrated markedly increased global acetylation of histone 3 in the inflamed tissue of patients with allergic inflammation. Collectively, these results identify an epigenetic mechanism involving CBP and chromatin remodeling in regulating IL-13-induced chemokine transcription.
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http://dx.doi.org/10.1074/jbc.M110.210724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075666PMC
April 2011

A striking local esophageal cytokine expression profile in eosinophilic esophagitis.

J Allergy Clin Immunol 2011 Jan;127(1):208-17, 217.e1-7

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

Background: Eosinophilic esophagitis (EE) is an emerging worldwide disease that mimics gastroesophageal reflux disease.

Objective: Early studies have suggested that esophageal eosinophilia occurs in association with T(H)2 allergic responses, yet the local and systemic expression of relevant cytokines has not been well characterized.

Methods: A human inflammatory cytokine and receptor PCR array containing 84 genes followed by PCR validation and multiplex arrays were used to quantify cytokine mRNA in esophageal biopsies and blood samples.

Results: Esophageal transcripts of numerous chemokines (eg, chemokine [C-C motif] ligand [CCL] 1, CCL1, CCL23, CCL26 [eotaxin-3], chemokine [C-X-C motif] ligand [CXCL] 1, and CXCL2), cytokines (eg, IL13 and ATP-binding cassette, subfamily F, member 1), and cytokine receptors (eg, IL5 receptor, alpha) were induced at least 4-fold in individuals with EE. Analysis of esophageal biopsies (n = 288) revealed that eotaxin-3 mRNA level alone had 89% sensitivity for distinguishing individuals with and without EE. The presence of allergy was associated with significantly increased esophageal expression of IL4 and IL5 mRNA in patients with active EE. We identified 8 cytokines (IL-4, IL-13, IL-5, IL-6, IL-12p70, CD40 ligand, IL-1α, and IL-17) whose blood levels retrospectively distinguished 12 patients without EE from 13 patients with EE with 100% specificity and 100% sensitivity. When applied to a blind, prospectively recruited group of 36 patients, the cytokine panel scoring system had a 79% positive predictive value, 68% negative predictive value, 61% sensitivity, and 83% specificity for identifying EE.

Conclusion: Evidence is presented that IL13 and IL5 associate with eosinophil and eotaxin-3 levels, indicating the key role of adaptive T(H)2 immunity in regulating eotaxin-3-driven esophageal eosinophilia in the absence of a consistent systemic change in cytokines.
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http://dx.doi.org/10.1016/j.jaci.2010.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027004PMC
January 2011

Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis.

J Allergy Clin Immunol 2010 Jul;126(1):160-5.e3

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 45229, USA.

Background: The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored.

Objective: We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy.

Methods: We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells.

Results: A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation.

Conclusion: These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.
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http://dx.doi.org/10.1016/j.jaci.2010.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904342PMC
July 2010

IL-13 induces esophageal remodeling and gene expression by an eosinophil-independent, IL-13R alpha 2-inhibited pathway.

J Immunol 2010 Jul 11;185(1):660-9. Epub 2010 Jun 11.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Eosinophilic esophagitis (EE) is an emerging disease associated with both food and respiratory allergy characterized by extensive esophageal tissue remodeling and abnormal esophageal gene expression, including increased IL-13. We investigated the ability of increased airway IL-13 to induce EE-like changes. Mice with pulmonary (but not esophageal) overexpression of IL-13 evidenced esophageal IL-13 accumulation and developed prominent esophageal remodeling with epithelial hyperplasia, angiogenesis, collagen deposition, and increased circumference. IL-13 induced notable changes in esophageal transcripts that overlapped with the human EE esophageal transcriptome. IL-13-induced esophageal eosinophilia was dependent on eotaxin-1 (but not eotaxin-2). However, remodeling occurred independent of eosinophils as demonstrated by eosinophil lineage-deficient, IL-13 transgenic mice. IL-13-induced remodeling was significantly enhanced by IL-13Ralpha2 deletion, indicating an inhibitory effect of IL-13Ralpha2. In the murine system, there was partial overlap between IL-13-induced genes in the lung and esophagus, yet the transcriptomes were divergent at the tissue level. In human esophagus, IL-13 levels correlated with the magnitude of the EE transcriptome. In conclusion, inducible airway expression of IL-13 results in a pattern of esophageal gene expression and extensive tissue remodeling that resembles human EE. Notably, we identified a pathway that induces EE-like changes and is IL-13-driven, eosinophil-independent, and suppressed by IL-13Ralpha2.
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http://dx.doi.org/10.4049/jimmunol.1000471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746758PMC
July 2010

Involvement of mast cells in eosinophilic esophagitis.

J Allergy Clin Immunol 2010 Jul 9;126(1):140-9. Epub 2010 Jun 9.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Background: Eosinophilic esophagitis (EE) is an emerging disorder with poorly understood pathogenesis.

Objective: Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Methods: Total and degranulated mast cell counts were correlated to microarray and RT-PCR data to generate transcriptome expression profiles related to mast cell number and degranulation in patients with EE and healthy control subjects.

Results: Esophageal mastocytosis and mast cell degranulation were readily apparent in patients with EE compared with control subjects (P < .01), as assessed by staining for total mast cells and the presence of extracellular mast cell tryptase (P < .01). Microarray analysis revealed that mast cell levels correlated with the dysregulation of 0.8% (301 genes) of the genome, which was partially distinct from the genes that correlated with tissue eosinophilia. The expression of transcripts for the mast cell proteases carboxypeptidase A3 and tryptase, but not chymase, correlated with mast cell levels and distinguished patients with EE from control subjects. Suprabasilar mast cell counts (P < .01) and degranulation (P < .01) were proportional with KIT ligand mRNA expression. Treatment of patients with EE with swallowed fluticasone propionate normalized levels of mast cells and the mast cell-related transcriptome in responder patients.

Conclusion: Herein we have identified local mastocytosis and mast cell degranulation in the esophagi of patients with EE; identified an esophageal mast cell-associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome, with carboxypeptidase A3 mRNA levels serving as the best mast cell surrogate marker; and provided evidence for the involvement of KIT ligand in the pathogenesis of EE.
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http://dx.doi.org/10.1016/j.jaci.2010.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902643PMC
July 2010

Glucocorticoid-regulated genes in eosinophilic esophagitis: a role for FKBP51.

J Allergy Clin Immunol 2010 Apr;125(4):879-888.e8

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

Background: Eosinophilic esophagitis (EE) involves marked accumulation of eosinophils in the esophageal mucosa that responds to swallowed fluticasone propionate (FP) in a subset of patients.

Objectives: We aimed to uncover the mechanism of action of swallowed FP in patients with EE by providing evidence for a topical effect in the esophagus by identifying a molecular signature for FP exposure in vivo.

Methods: Global microarray expression profiles, immunofluorescence microscopy, and cell signaling in esophageal tissue and cell lines were analyzed.

Results: Thirty-two transcripts exhibited altered expression in patients who responded to swallowed FP treatment. Esophageal FK506-binding protein 5 (FKBP51) mRNA levels were increased (P < .05) in FP responders compared with those seen in control subjects and patients with untreated active EE. After FP treatment of esophageal epithelial cells, FKBP51 mRNA and protein levels were increased in a dose- and time-dependent manner by FP treatment in vitro. FP-induced FKBP51 was steroid receptor dependent because RU486 completely inhibited gene and protein induction. The half-life of FKBP51 mRNA was 16 to 18 hours independent of FP treatment. FKBP51 overexpression reduced FP action as assessed by FP inhibition of IL-13-induced eotaxin-3 promoter activity.

Conclusions: Our results suggest that swallowed glucocorticoid treatment directly affects esophageal gene expression in patients with EE. In particular, increased FKBP51 transcript levels identify glucocorticoid exposure in vivo and distinguish FP responders from untreated patients with active EE and patients without EE. In addition, FKBP51 reduces glucocorticoid-mediated inhibition of IL-13 signaling in epithelial cells in vitro, suggesting that FKBP51 might influence FP responsiveness. We propose that esophageal FKBP51 levels have diagnostic and prognostic significance in patients with EE.
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http://dx.doi.org/10.1016/j.jaci.2010.01.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865682PMC
April 2010

Common variants at 5q22 associate with pediatric eosinophilic esophagitis.

Nat Genet 2010 Apr 7;42(4):289-91. Epub 2010 Mar 7.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 x 10(-9)). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.
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http://dx.doi.org/10.1038/ng.547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740732PMC
April 2010

Coordinate interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis.

J Immunol 2010 Apr 5;184(7):4033-41. Epub 2010 Mar 5.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13-driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. In this study, we compared epithelial responses between healthy patients and those with EE, aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained for up to five passages, with 67% and 62% of cell lines reaching confluence in healthy controls and EE cases, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 +/- 1.98 ng/ml versus 12.46 +/- 2.90 ng/ml at pH 7.4 and 4, respectively; p < 0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin and SPRR3, were downregulated both in IL-13-stimulated esophageal epithelial cells and in EE biopsies specimens compared with healthy controls. Whereas the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared with control individuals (6.1% versus 1.3% respectively; p = 0.0172), the decreased filaggrin expression was uniformly seen in all EE cases in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.
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http://dx.doi.org/10.4049/jimmunol.0903069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807813PMC
April 2010

Biology of the eosinophil.

Adv Immunol 2009 ;101:81-121

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.

In this review, we aim to put in perspective the biology of a multifunctional leukocyte, the eosinophil, by placing it in the context of innate and adaptive immune responses. Eosinophils have a unique contribution in initiating inflammatory and adaptive responses, due to their bidirectional interactions with dendritic cells and T cells, as well as their large panel of secreted cytokines and soluble mediators. The mechanisms and consequences of eosinophil responses in experimental inflammatory models and human diseases are discussed.
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http://dx.doi.org/10.1016/S0065-2776(08)01003-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109275PMC
April 2009

Chemotactic factors associated with eosinophilic gastrointestinal diseases.

Immunol Allergy Clin North Am 2009 Feb;29(1):141-8, xi

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7028, Cincinnati, OH 45229-3039, USA.

The gastrointestinal (GI) tract is in constant negotiation with the microbial flora present in the lumen. Resident hematopoietic cells (ie, lymphocytes, mast cells, and eosinophils) are part of this ongoing and silent homeostatic battle. Eosinophilic GI diseases are characterized by an increased number of eosinophil infiltrates with no identified cause. This article describes the past and present knowledge regarding the chemotactic factors involved in GI eosinophilia.
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http://dx.doi.org/10.1016/j.iac.2008.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122321PMC
February 2009
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