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The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERs) organized a daylong symposium at the 2024 annual meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research as well as debates on the mechanisms and management of eosinophilic gastrointestinal diseases. Updates on recent clinical trials and consensus guidelines were also presented. We summarize the updates on eosinophilic gastrointestinal diseases presented at the symposium. [ABSTRACT FROM AUTHOR]

BackgroundAfrican American subjects have a greater burden from asthma compared with white subjects. Whether the pattern of airway inflammation differs between African American and white subjects is unclear.ObjectiveWe sought to compare sputum airway inflammatory phenotypes of African American and white subjects treated or not with inhaled corticosteroids (ICSs; ICS+ and ICS-, respectively).MethodsWe performed a secondary analysis of self-identified African American and white subjects with asthma enrolled in clinical trials conducted by the National Heart, Lung, and Blood Institute-sponsored Asthma Clinical Research Network and AsthmaNet. Demographics, clinical characteristics, and sputum cytology after sputum induction were examined. We used a sputum eosinophil 2% cut point to define subjects with either an eosinophilic (≥2%) or noneosinophilic (

The Consortium of Eosinophilic Gastrointestinal Diseases and The International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs. [ABSTRACT FROM AUTHOR]

Background: Esophageal histology is critical for diagnosis and surveillance of disease activity in eosinophilic esophagitis (EoE). A validated noninvasive biomarker has not been identified. We aimed to determine the utility of blood and urine eosinophil‐associated proteins to diagnose EoE and predict esophageal eosinophilia. Methods: Blood and urine were collected from children undergoing endoscopy with biopsy. Absolute eosinophil count (AEC), plasma eosinophil‐derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein‐1 (MBP‐1), galectin‐10 (CLC/GAL‐10), Eotaxin‐2 and Eotaxin‐3, and urine osteopontin (OPN) and matrix metalloproteinase‐9 (MMP‐9) were determined. Differences were assessed between EoE and control, and with treatment response. The capacity to predict EoE diagnosis and esophageal eosinophil counts was assessed. Results: Of 183 specimens were collected from 56 EoE patients and 15 non‐EoE controls with symptoms of esophageal dysfunction; 33 EoE patients had paired pre‐ and post‐treatment specimens. Plasma (CLC/GAL‐10, ECP, EDN, Eotaxin‐3, MBP‐1) and urine (OPN) biomarkers were increased in EoE compared to control. A panel comprising CLC/GAL‐10, Eotaxin‐3, ECP, EDN, MBP‐1, and AEC was superior to AEC alone in distinguishing EoE from control. AEC, CLC/GAL‐10, ECP, and MBP‐1 were significantly decreased in patients with esophageal eosinophil counts <15/hpf in response to treatment. AEC, CLC/GAL‐10, ECP, EDN, OPN, and MBP‐1 each predicted esophageal eosinophil counts utilizing mixed models controlled for age, gender, treatment, and atopy; AEC combined with MBP‐1 best predicted the counts. Conclusions: We identified novel panels of eosinophil‐associated proteins that along with AEC are superior to AEC alone in distinguishing EoE from controls and predicting esophageal eosinophil counts. [ABSTRACT FROM AUTHOR]

CCAAT/enhancer binding protein epsilon (C/EBPε) is required for eosinophil differentiation, lineage-specific gene transcription, and expression of C/EBPε32 and shorter 27kD and 14kD isoforms is developmentally regulated during this process. We previously defined the 27kD isoform (C/EBPε27) as an antagonist of GATA-1 transactivation of the eosinophil's major basic protein-1 (MBP1) P2-promoter, showing C/EBPε27 and GATA-1 physically interact. In the current study, we used a Tat-C/EBPε27 fusion protein for cell/nuclear transduction of an eosinophil myelocyte cell line to demonstrate that C/EBPε27 is a potent repressor of MBP1 transcription. We performed structure-function analyses of C/EBPε27 mapping its repressor domains, comparing it to C/EBPε32 and C/EBPε14, using GATA-1 co-transactivation of the MBP1-P2 promoter. Results show C/EBPε27 repression of GATA-1 is mediated by its unique 68aa N-terminus combined with previously identified RDI domain. This repressor activity does not require, but is enhanced by, DNA binding via the basic region of C/EBPε27 but independent of sumoylation of the RDI core "VKEEP" sumoylation site. These findings identify the N-terminus of C/EBPε27 as the minimum repressor domain required for antagonism of GATA-1 in the eosinophil. C/EBPε27 repression of GATA-1 occurs via a combination of both C/EBPε27-GATA-1 protein–protein interaction and C/EBPε27 binding to a C/EBP site in the MBP1 promoter. The C/EBPε27 isoform may serve to titrate and/or turn off eosinophil granule protein genes like MBP1 during eosinophil differentiation, as these genes are ultimately silenced in the mature cell. Understanding the functionality of C/EBPε27 in eosinophil development may prove promising in developing therapeutics that reduce eosinophil proliferation in allergic diseases. [ABSTRACT FROM AUTHOR]

Background: Surfactant dysfunction is implicated in small airway closure in asthma. Increased activity of secretory phospholipase A2 (sPLA2) in the airways is associated with asthma exacerbations. Phosphatidylcholine, the principal component of pulmonary surfactant that maintains small airway patency, is hydrolyzed by sPLA2. The lysophosphatidylcholine product is the substrate for eosinophil lysophospholipases. Objective: To determine whether surfactant phospholipid hydrolysis by the combined activities of sPLA2s and eosinophil lysophospholipases induces surfactant dysfunction. Methods: The effect of these enzymes on surfactant function was determined by capillary surfactometry. Thin layer chromatography was used to correlate enzyme-induced changes in surfactant phospholipid composition and function. Phosphatidylcholine and its hydrolytic products were measured by using mass spectrometry. Results: Eosinophils express a 25-kd lysophospholipase and group IIA sPLA2. Phospholipase A2 alone induced only a small decrease in surfactant function, and 25-kd lysophospholipase alone degraded lysophosphatidylcholine but had no effect on surfactant function. The combined actions of sPLA2 and lysophospholipase produced dose-dependent and time-dependent losses of surfactant function, concomitant with hydrolysis of phosphatidylcholine and lysophosphatidylcholine. Lysates of AML14.3D10 eosinophils induced surfactant dysfunction, indicating these cells express all the necessary lipolytic activities. In contrast, lysates of blood eosinophils required exogenous phospholipase A2 to induce maximal surfactant dysfunction. Conclusion: The combined activities of sPLA2s and eosinophil lysophospholipases are necessary to degrade surfactant phospholipids sufficiently to induce functional losses in surfactant activity as reported in asthma. Clinical implications: The phospholipases and lysophospholipases expressed by eosinophils or other airway cells may represent novel therapeutic targets for blocking surfactant degradation, dysfunction, and peripheral airway closure in asthma. [Copyright &y& Elsevier]

Background: Eosinophils are frequently associated with tissue remodeling and fibrosis in allergic and other diseases and animal models. Their close physical proximity to fibroblasts at sites of tissue remodeling strongly implicates them in fibrogenesis, including subepithelial fibrosis and airway remodeling characteristic of asthma. Objective: To identify the mediators and characterize the mechanisms underlying the fibrogenic activities of eosinophils. Methods: A coculture system of blood eosinophils or eosinophil cell lines with normal fibroblasts was used to assess their ability to induce a fibrogenic fibroblast phenotype, including IL-6 secretion and mRNA expression, and induction of genes involved in extracellular matrix production and homeostasis. The mediators of these responses were identified by using transwell barrier cocultures, eosinophil-conditioned media, and cytokine-specific antibody neutralization. Results: Eosinophil-fibroblast coculture induced potent fibroblast IL-6 secretion and mRNA expression, responses further enhanced by IL-5. The soluble nature of the eosinophil-derived mediators was demonstrated by using eosinophil-fibroblast coculture in the presence of permeable transwell barriers, and fibroblast culture in eosinophil-conditioned media, indicating that cell contact was not required. Induction of fibroblast IL-6 expression was accompanied by increased expression of fibronectin and the extracellular matrix regulatory genes plasminogen activator inhibitor 1 and tissue inhibitor of metalloproteinase 1. Antibody neutralization identified the principal eosinophil-derived mediator of fibroblast IL-6 expression as IL-1β (>60%), with lesser contributions from IL-1α, IL-4, and TGF-β (10% to 20%). Conclusion: Eosinophils express at least 2 potent mediators (IL-1β and TGF-β) that induce a fibrogenic fibroblast phenotype, strongly supporting a role for the eosinophil in the dysregulation of extracellular matrix homeostasis and consequent tissue remodeling and fibrosis in eosinophil-associated diseases. [Copyright &y& Elsevier]

Background Chemokine signaling through CCR3 is a key regulatory pathway for eosinophil recruitment into tissues associated with allergic inflammation and asthma. To date, none of the CCR3 antagonists have shown efficacy in clinical trials. One reason might be their unbiased mode of inhibition that prevents receptor internalization, leading to drug tolerance. Objective We sought to develop a novel peptide nanoparticle CCR3 inhibitor (R321) with a biased mode of inhibition that would block G protein signaling but enable or promote receptor internalization. Methods Self-assembly of R321 peptide into nanoparticles and peptide binding to CCR3 were analyzed by means of dynamic light scattering and nuclear magnetic resonance. Inhibitory activity on CCR3 signaling was assessed in vitro by using flow cytometry, confocal microscopy, and Western blot analysis in a CCR3+ eosinophil cell line and blood eosinophils. In vivo effects of R321 were assessed by using a triple-allergen mouse asthma model. Results R321 self-assembles into nanoparticles and binds directly to CCR3, altering receptor function. Half-maximal inhibitory concentration values for eotaxin-induced chemotaxis of blood eosinophils are in the low nanomolar range. R321 inhibits only the early phase of extracellular signal-regulated kinase 1/2 activation and not the late phase generally associated with β-arrestin recruitment and receptor endocytosis, promoting CCR3 internalization and degradation. In vivo R321 effectively blocks eosinophil recruitment into the blood, lungs, and airways and prevents airway hyperresponsiveness in a mouse eosinophilic asthma model. Conclusions R321 is a potent and selective antagonist of the CCR3 signaling cascade. Inhibition through a biased mode of antagonism might hold significant therapeutic promise by eluding the formation of drug tolerance. Graphical abstract [ABSTRACT FROM AUTHOR]

Background: Mechanisms underlying esophageal remodeling with subepithelial fibrosis in subjects with eosinophilic esophagitis (EoE) have not been delineated. Objectives: We sought to explore a role for epithelial mesenchymal transition (EMT) in subjects with EoE and determine whether EMT resolves with treatment. Methods: Esophageal biopsy specimens from 60 children were immunostained for epithelial (cytokeratin) and mesenchymal (vimentin) EMT biomarkers, and EMT was quantified. Subjects studied had EoE (n = 17), indeterminate EoE (n = 15), gastroesophageal reflux disease (n = 7), or normal esophagus (n = 21). EMT was analyzed for relationships to diagnosis, eosinophil counts, and indices of subepithelial fibrosis, eosinophil peroxidase, and TGF-β immunostaining. EMT was assessed in pretreatment and posttreatment biopsy specimens from 18 subjects with EoE treated with an elemental diet, 6-food elimination diet, or topical corticosteroids (n = 6 per group). Results: TGF-β1 treatment of esophageal epithelial cells in vitro for 24 hours induced upregulation of mesenchymal genes characteristic of EMT, including N-cadherin (3.3-fold), vimentin (2.1-fold), and fibronectin (7.5-fold). EMT in esophageal biopsy specimens was associated with EoE (or indeterminate EoE) but not gastroesophageal reflux disease or normal esophagus and was correlated to eosinophil counts (r = 0.691), eosinophil peroxidase (r = 0.738), and TGF-β (r = 0.520) immunostaining and fibrosis (r = 0.644) indices. EMT resolved with EoE treatments that induced clinicopathologic remission with reduced eosinophil counts. EMT decreased significantly after treatment by 74.1% overall in the 18 treated subjects with EoE; pretreatment versus posttreatment EMT scores were 3.17 ± 0.82 versus 0.82 ± 0.39 (P < .001), with similar decreases within treatment groups. Pretreatment/posttreatment EMT was strongly correlated with eosinophil counts for combined (r = 0.804, P < .001) and individual treatment groups. Conclusions: EMT likely contributes to subepithelial fibrosis in subjects with EoE and resolves with treatments that decrease esophageal inflammation, and its resolution correlates with decreased numbers of esophageal eosinophils. [Copyright &y& Elsevier]