αIIb-Integrin (CD41) associated with blood eosinophils is a potential biomarker for disease activity in eosinophilic esophagitis.
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ABSTRACT:
SUBMITTER: Johansson MW
PROVIDER: S-EPMC7283000 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder characterized by upper gastrointestinal symptoms and the presence of high numbers of eosinophils in the esophagus. Although eosinophils in the esophagus have been found to be activated in subjects with EoE, detailed studies of intracellular signaling pathways involved in the mechanism of activation of eosinophils in EoE have heretofore been limited. The aim of the study was to assess whether any surface molecules or transcription factors are activated in peripheral eosinophils in subjects with EoE.Eosinophils and CD3+ lymphocytes were identified directly from 50 ?L of whole blood of EoE and control subjects. Using Hi-FACS, levels of surface activation markers, including CD66b, and intracellular phosphoepitopes, including phosphorylated forms of signal transducer and activator of transcription (phospho-STAT) 1 and 6, were measured within each cell subset.Levels of surface CD66b as well as levels of intracellular phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were significantly higher for untreated subjects with EoE vs healthy controls (P < 0.05). Levels of phospho-STAT1 and phospho-STAT6 in peripheral blood eosinophils were lower in subjects with EoE on therapy versus untreated subjects with EoE (P < 0.05).Levels of phospho-STAT1 and phospho-STAT6, transcription factors involved in inflammatory processes, were both significantly higher in peripheral eosinophils from untreated (ie, newly diagnosed) subjects with EoE versus subjects with EoE on therapy, healthy controls. Blood-based measurements of CD66b and phospho-STAT levels in peripheral eosinophils may be beneficial for identifying EoE.
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Project description:Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin αIIbβ3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to αIIbβ3 adhesive function that leads to a distinct prothrombotic phenotype in diabetes.
| S-EPMC5852038 | biostudies-literature
Project description:ObjectiveTo review the understanding of the pathogenesis of eosinophilic esophagitis (EoE) and the role of the immune system in the disease process.Data sourcesPeer-reviewed articles on EoE from PubMed searching for "Eosinophilic Esophagitis and fibrosis" in the period of 1995 to 2013.Study selectionsStudies on the clinical and immunologic features, pathogenesis, and management of EoE.ResultsRecent work has revealed that thymic stromal lymphopoietin and basophil have an increased role in the pathogenesis of disease. Additional understanding on the role of fibrosis in EoE is emerging.ConclusionThe incidence of EoE is increasing like most atopic disease. Similar to other allergic diseases, EoE is treated with topical steroids and/or allergen avoidance.
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Project description:Integrin ?IIb?3 is a highly abundant heterodimeric platelet receptor that can transmit information bidirectionally across the plasma membrane, and plays a critical role in hemostasis and thrombosis. Upon platelet activation, inside-out signaling pathways increase the affinity of ?IIb?3 for fibrinogen and other ligands. Ligand binding and integrin clustering subsequently stimulate outside-in signaling, which initiates and amplifies a range of cellular events driving essential platelet processes such as spreading, thrombus consolidation, and clot retraction. Integrin ?IIb?3 has served as an excellent model for the study of integrin biology, and it has become clear that integrin outside-in signaling is highly complex and involves a vast array of enzymes, signaling adaptors, and cytoskeletal components. In this review, we provide a concise but comprehensive overview of ?IIb?3 outside-in signaling, focusing on the key players involved, and how they cooperate to orchestrate this critical aspect of platelet biology. We also discuss gaps in the current understanding of ?IIb?3 outside-in signaling and highlight avenues for future investigation.
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| S-EPMC4725062 | biostudies-literature
Project description:Integrins are transmembrane receptors that play important roles as modulators of cell behaviour through their adhesion properties and the initiation of signaling cascades. The ?IIb integrin subunit (CD41) is one of the first cell surface markers indicative of hematopoietic commitment. ?IIb pairs exclusively with ?3 to form the ?IIb?3 integrin. ?3 (CD61) also pairs with ?v (CD51) to form the ?v?3 integrin. The expression and putative role of these integrins during mouse hematopoietic development is as yet unknown. We show here that hematopoietic stem cells (HSCs) differentially express ?IIb?3 and ?v?3 integrins throughout development. Whereas the first HSCs generated in the aorta at mid-gestation express both integrins, HSCs from the placenta only express ?v?3, and most fetal liver HSCs do not express either integrin. By using ?IIb deficient embryos, we show that ?IIb is not only a reliable HSC marker but it also plays an important and specific function in maintaining the HSC activity in the mouse embryonic aorta.
| S-EPMC3654272 | biostudies-literature
Project description:ObjectivesA minimally invasive biomarker to monitor disease activity is one of the greatest unmet clinical needs of the pediatric eosinophilic esophagitis (EoE) population. We aimed to determine whether circulating eosinophil progenitors (EoPs) could be used as a biomarker to identify pediatric patients with active EoE.MethodsIn a prospective observational study, peripheral blood samples, symptom history, and laboratory data were collected from pediatric patients undergoing endoscopy for evaluation of EoE on dietary therapy at Cincinnati Children's Hospital. Peripheral blood EoP level was determined by flow cytometry.ResultsThirty-four children with active (n = 16) and inactive (n = 18) EoE were included in the analysis. EoP levels in the peripheral blood were 3-fold higher in patients with active EoE than inactive EoE (P < 0.0025). Blood absolute eosinophil count did not distinguish between active and inactive EoE (P = 0.16). A cut-off EoP level ≥17 accurately detected active disease in 79% of patients with 94.4% specificity and 62.5% sensitivity (area under the curve 0.81; P < 0.0024). Antihistamine use lowered the threshold EoP level to detect active EoE.ConclusionsThis study suggests that blood EoP levels may be used as a biomarker to detect active EoE disease in patients undergoing food trials and potentially reduce the need for repeated endoscopies. Larger prospective studies are needed to investigate the effects of antihistamines and swallowed steroids on EoP mobilization into the peripheral blood and longitudinal studies to assess the performance of the assay in individual patients over time.
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Project description:Eosinophilic esophagitis is an emerging disease that is distinguished from gastroesophageal reflux disease by the expression of a unique esophageal transcriptome and the interplay of early life environmental factors with distinct genetic susceptibility elements at 5q22 (TSLP) and 2p23 (CAPN14). Rare genetic syndromes have uncovered the contribution of barrier disruption, mediated in part by defective desmosomes and dysregulated transforming growth factor beta production and signaling, to eosinophilic esophagitis pathophysiology. Experimental modeling has defined a cooperative role of activated eosinophils, mast cells, and the cytokines IL-5 and IL-13, mediated by allergic sensitization to multiple foods. Understanding these processes is opening the way to better treatment based on disrupting allergic inflammatory and type 2 cytokine-mediated responses, including anti-cytokine therapeutics and dietary therapy.
| S-EPMC5787048 | biostudies-literature