Mature Eosinophils Research Articles

Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils.

Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from exvivo studies and targeted therapy invivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation.

Stress-induced eosinophil activation contributes to postoperative morbidity and mortality after lung resection.

Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor-dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration-approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.

Insight into IL-5 as a Potential Target for the Treatment of Allergic Diseases.

Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking. Previous reports raise a potential role for eosinophils in HS, showing a strong association of eosinophil levels with disease severity. To investigate eosinophils in HS, we recruited patients and matched healthy controls and then performed flow-cytometry studies, eosinophil stimulation assays, and lesional skin staining for eosinophils. We found that HS patients reported similar levels of pain and itch. Compared to matched controls, HS blood exhibited decreased mature eosinophils and increased numbers of immature eosinophils, coupled with a significant increase in dermal eosinophilic infiltrates. Additionally, IL-17RA+ eosinophils were highly and significantly correlated with multiple HS-related clinical scores. In both stimulated and unstimulated conditions, HS eosinophils showed an inflammatory phenotype versus controls, including an increase in costimulatory T- and B-cell markers (e.g. CD5 and CD40) following all stimulations (TNFα/IL-17A/IL-17F). These findings highlight the significance of pruritus in HS and suggest a higher turnover of eosinophils in HS blood, potentially due to the consumption of eosinophils in skin lesions. Our data delineate the features and functions of eosinophils in HS and suggest that eosinophils participate in disease pathogenesis, advancing Th17-related inflammation. Further studies are needed to investigate eosinophils' response to current HS treatments and their potential as a therapeutic target in the disease.

Single-cell proteomics and transcriptomics capture eosinophil development and identify the role of IL-5 in their lineage transit amplification

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.

Not just for lymphoid cells: the role of the noncanonical NF-κB signaling pathway in early and late myelopoiesis with a focus on hypereosinophilic disorders.

The noncanonical NF-κB pathway is involved in lymphoid organ development, B-cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis, are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease, including acute and chronic myeloid leukemias, preleukemic processes such as myelodysplastic syndrome, or hyperinflammatory conditions like hypereosinophilic syndrome. In this review, we discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, and how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on hypereosinophilic syndrome. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients with leukemia or idiopathic hypereosinophilic syndrome. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients with such complex and overlapping hematopoietic diseases.

Flow cytometric immunophenotypic differentiation patterns of bone marrow eosinophilopoiesis.

Flow cytometry has been widely used to study immunophenotypic patterns of maturation of most hematopoietic lineages in normal human bone marrow aspirates, thus allowing identification of changes in patterns in many myeloid malignancies. Eosinophils play an important role in a wide variety of disorders, including some myeloid neoplasms. However, changes in flow cytometric immunophenotypic patterns during normal and abnormal bone marrow eosinophilopoiesis have not been well studied. Fresh bone marrow aspirates from 15 healthy donors, 19 patients with hypereosinophilic syndromes (HES), and 11 patients with systemic mastocytosis (SM) were analyzed for candidate markers that included EMR-1, Siglec-8, CCR3, CD9, CD11a, CD11b, CD11c, CD13, CD16, CD29, CD34, CD38, CD45, CD44, CD49d, CD49f, CD54, CD62L, CD69, CD117, CD125 (IL-5Rα), HLA-DR, using 10 parameter flow cytometry. Putative CD34-negative immature and mature normal eosinophil populations were first identified based on changes in expression of the above markers in healthy donors, then confirmed using fluorescence-based cell sorting and morphological evaluation of cytospin preparations. The normal immunophenotypic patterns were then compared to immunophenotypic patterns of eosinophilopoiesis in patients with HES and SM. The eosinophilic lineage was first verified using the human eosinophil-specific antibody EMR-1 in combination with anti-IL-5Rα antibody. Then, a combination of Siglec-8, CD9, CD11b, CCR3, CD49d, and CD49f antibodies was used to delineate normal eosinophilic maturational patterns. Early stages (eosinophilic promyelocytes/myelocytes) were identified as Siglec-8 dim/CD11b dim to moderate/CD9 dim/CCR3 dim/CD49d bright/CD49f dim, intermediate stages (eosinophilic myelocytes/metamyelocytes) as Siglec-8 moderate/CD11b moderate to bright/CD9 moderate/CCR3 moderate/CD49d moderate/CD49f moderate and mature bands/segmented eosinophils as Siglec-8 bright/CD11b bright/CD9 bright/CCR3 bright/CD49d dim/CD49f bright. Overall maturational patterns were also similar in patients with HES and SM; however, the expression levels of several surface markers were altered compared to normal eosinophils. A novel flow cytometric antibody panel was devised to detect alterations in immunophenotypic patterns of bone marrow eosinophil maturation and evaluated in normal, HES and SM samples. This approach will allow us to elucidate changes in immunophenotypic patterns of bone marrow eosinophilopoiesis in other hematological diseases.

Abstract 5339: Establishment of a humanized IL5/IL5RA mouse model to evaluate modulators of eosinophilic inflammation in vivo

Abstract IL-5/IL-5R signaling plays a key role in the maturation, activation, survival, and recruitment of eosinophils to sites of inflammation. Targeting this pathway is an attractive therapeutic strategy for certain inflammatory diseases, such as asthma. Here, we generated a novel humanized IL5/IL5RA model (B-hIL5/hIL5RA) to examine the utility of human IL-5/IL5R-targeting therapeutic candidates. Specifically, the entire murine Il5 coding region was replaced by the corresponding human IL5 sequence, and the human IL5RA sequence coding the extracellular domain was inserted to replace the corresponding murine sequence. Successful generation of the model was confirmed by expression of human IL-5 by ELISA and IL5RA by flow cytometry. Furthermore, the proportion of eosinophils in the blood of B-hIL5/hIL5RA mice increased after stimulation with human IL5 recombinant protein, indicating that the humanized IL5RA protein is functional. Next, the ability of the humanized mice to establish asthma-like disease was tested using ovalbumin: following a 14 day sensitization period, mice were challenged with nebulized OVA daily from day 21 until the endpoint; treatment with mepolizumab or benralizumab analog was performed. Flow cytometric analysis of the bronchioalveolar fluid indicates that treatment with mepolizumab or benralizumab analog significantly lowered the number of eosinophils when compared to the isotype control in homozygous B-hIL5/hIL5RA mice. Blood counts and quantification of lung H&E sections also confirm that the treatments lowered the number of eosinophils in circulation and lung tissue, respectively. Taken together, these data indicate that B-hIL5/hIL5RA mice are a suitable preclinical model to test novel modulators of human IL-5/IL-5RA signaling. Citation Format: Suman Zhao, Shujin Zhang, Zhen Chen, Liya Yang, Mari Kuraguchi, Jiangfeng Yuan, Heiling Shen. Establishment of a humanized IL5/IL5RA mouse model to evaluate modulators of eosinophilic inflammation in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5339.

A162 DEFINING INNATE IMMUNE CELL MECHANISMS UPON HELICOBACTER PYLORI MEDIATED TUMORIGENESIS

Abstract Aims Hypothesis: H. pylori interacts with eosinophils to inhibit degranulation, alter eosinophil gene expression and promote gastric tumorigenesis Aim 1: Elucidate the mechanisms underlying the interactions between eosinophils and H. pylori. Aim 2: Determine the role of eosinophils during H. pylori mediated gastric tumorigenesis. Methods Histological and immunofluorescent staining. Hemotoxilin and eosin staining is important to analyze gastric gland structure and parietal cell loss. Immunofluorescent staining is used to detect and localize specific antigens present in cells and cell membranes. Gastric organoids: Gastric organoids are an important tool for modelling dissease. Gastric organoids generated from adult stem cells from gastric glands depend on growth factors that mimic tissue regeneration. Bone marrow derived eosinophils: Bone marrow progenitor cells isolated from murine femur and tibia are easily converted into maturer eosinophils with the addition of cytokine interleukin-5. Results Addition of mouse derived eosinophils to gastric organoids significantly increases number of organoids. To understand the relationship between eosinophils and gastric epithelial cell (GEC) growth, I designed a co-culture experiment that involved incubating mature eosinophils with gastric glands in an extracellular matrix. These findings revealed a significant increase in the number of gastric organoids per well when eosinophils were present compared to the gastric organoids without eosinophils. This observation supports the hypothesis that eosinophils may play a crucial role in promoting gastric tumorigenesis. Exposure of mouse derived eosinophils to H. pylori significantly increases gastric organoid proliferation. To explore the impact of stimulating eosinophils prior to incubation with GECs I incubated the eosinophils with H. pylori. As expected, there was a significant increase in the number of organoids per well with the addition of uninfected eosinophils. Interestingly, when H. pylori incubated eosinophils were added to the gastric glands, there was a significant increase in the number of gastric organoids per well compared to uninfected eosinophils. Conclusions My preliminary findings have indicated that eosinophils can promote gastric epithelial stem cell proliferation. These results led me to ask how treatment of eosinophils with H. pylori subsequently impacts gastric organoid growth and gastric stem cell proliferation. Interestingly, I found H. pylori treated eosinophils increase growth and gastric stem cell proliferation. These results support my hypothesis as increased proliferation is considered a hallmark of tumorigenesis. There little known about resident and inflammatory GI eosinophils and the role of eosinophils during tumorigenesis in unknown. A better understanding of the role eosinophils play can uncover novel mechanisms to be targeted for therapeutic intervention. Funding Agencies CIHR

Cebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish

Eosinophils are a group of granulocytes well known for their capacity to protect the host from parasites and regulate immune function. Diverse biological roles for eosinophils have been increasingly identified, but the developmental pattern and regulation of the eosinophil lineage remain largely unknown. Herein, we utilize the zebrafish model to analyze eosinophilic cell differentiation, distribution, and regulation. By identifying eslec as an eosinophil lineage-specific marker, we establish a Tg(eslec:eGFP) reporter line, which specifically labeled cells of the eosinophil lineage from early life through adulthood. Spatial-temporal analysis of eslec+ cells demonstrates their organ distribution from larval stage to adulthood. By single-cell RNA-Seq analysis, we decipher the eosinophil lineage cells from lineage-committed progenitors to mature eosinophils. Through further genetic analysis, we demonstrate the role of Cebp1 in balancing neutrophil and eosinophil lineages, and a Cebp1-Cebpβ transcriptional axis that regulates the commitment and differentiation of the eosinophil lineage. Cross-species functional comparisons reveals that zebrafish Cebp1 is the functional orthologue of human C/EBPεP27 in suppressing eosinophilopoiesis. Our study characterizes eosinophil development in multiple dimensions including spatial-temporal patterns, expression profiles, and genetic regulators, providing for a better understanding of eosinophilopoiesis.

Development and characterization of anti-IL-5 monoclonal antibody Fab fragment for blocking IL-5/IL-5Rα binding

Interleukin-5 (IL-5) is a homodimeric cytokine that is a crucial regulator of the proliferation, activation, and maturation of eosinophils. Anti-IL-5 monoclonal antibodies, which block the binding of IL-5 to the IL-5 receptor subunit alpha (IL-5Rα), have been successfully used to treat eosinophilic (EOS) asthma. The currently marketed monoclonal antibody drugs require repeated injections for administration, which seriously affect patient compliance and high systemic exposure for injectable drug delivery. Here we successfully screened and developed the Fab (fragment of antigen binding), which is 1/3rd the molecular weight of IgG, favoring inhalation-mediated delivery to the lungs, making it more effective for asthma treatment. The 20A12-Fab-H12L3 can bind to IL-5 with a binding constant of 1.236E-09 M while significantly inhibiting the IL-5/IL-5Rα complex formation. We found that the light chain amino acids (S46 and F71) significantly affected the antibody expression during humanization. The 20A12-Fab-H12L3 significantly inhibited the proliferation of TF-1 cells and blocked the IL-5 binding to the IL-5Rα-overexpressing human embryonic kidney (HEK)-293 cells in vitro. Therefore, based on the mutant IL-5 binding with Fab, we explained why antibodies blocked IL-5 binding to IL-5Rα. Thus, this study provided a candidate pharmaceutical antibody for inhalation drug delivery.

Anti-IL5 Monoclonal Antibodies Reduce Asthma Exacerbations and Corticosteroids Dose in Three Eosinophilic Granulomatosis with Polyangiitis Case Reports.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare multisystem necrotizing small and medium-sized vessel vasculitis with eosinophilic adult-onset asthma as part of its spectrum. Therapeutic choices include corticosteroids, immunosuppressive agents, and novel immunomodulators. Mepolizumab and benralizumab are monoclonal antibodies targeting Interleukin-5 (IL-5), which plays a leading role in every stage of production and maturation of eosinophils and are recently undergoing evaluation and administered in steroid-dependent, relapsing and/or refractory EGPA. Herein we describe the cases of three patients with a prior EGPA diagnosis, experiencing frequent asthmatic exacerbations despite oral and inhaled corticosteroid treatment (two patients) and adverse effects of corticosteroids (one patient). Two patients are under treatment with mepolizumab and one patient with benralizumab as an add-on supplemental regimen. In our case series anti-IL5 monoclonal antibodies proved efficient asthma-controlling and corticosteroid-sparing agents.

Eosinophils from A to Z.

Eosinophils are bone marrow-derived granulocytes and are found in low numbers in the peripheral blood of healthy subjects. In type 2 inflammatory diseases, eosinopoiesis in the bone marrow is increased, resulting in a rise in the number of mature eosinophils released in the circulation. From the blood, eosinophils can migrate in multiple tissues and organs under both physiological and pathological conditions. Eosinophils exert their various functions through the synthesis and release of a variety of granule proteins and pro-inflammatory mediators. Despite being present in all species of vertebrates, the functional role of eosinophils is still a matter of debate. Eosinophils may play a role in host defense against various pathogens. In addition, eosinophils have been reported to be involved in tissue homeostasis and exhibit immunomodulatory activities. In this review, we aim to provide a broad overview of eosinophil biology and eosinophilic diseases in a lexicon-style format using keywords starting from A until Z with cross-references to other chapters indicated in italics in the text or specified in parentheses.

Ginsenoside Rh1 ameliorates the asthma and allergic inflammation via inhibiting Akt, MAPK, and NF-κB signaling pathways in vitro and in vivo

AimsOverproduction of pro-inflammatory cytokines and its-mediated immune cell infiltration play a crucial role in asthma progression. In this study, we investigated the role of ginsenoside Rh1 (Rh1) in ovalbumin (OVA)/lipopolysaccharide (LPS)-induced allergic asthma both in vitro and in vivo. Materials and main methodsThe phorbol ester (PMA) and LPS were used to induce inflammation in lung airway cells and macrophage activation, respectively. Western blotting, quantitative reverse transcription-PCR, and immunofluorescence (IF) assays were performed to elucidate the underlying molecular mechanisms. To evaluating the effects of Rh1 in vivo, OVA and LPS were used to establish allergic asthma models. Key findingsRh1 significantly suppressed PMA-induced lung inflammation and macrophage activation by suppressing pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1), ICMA-1, and matrix metallopeptidase 9 (MMP9) in A549 cells. Rh1 abolished the PMA-induced inflammation by suppressing MAPK, Akt, and NF-κB p65. Pretreatment with Rh1 blocked PMA-mediated translocation of NF-κB, a key marker of pro-inflammatory cytokine release, into the nucleus. Similar to PMA-induced lung inflammation, Rh1 suppressed LPS-induced macrophage activation by suppressing NF-κB p65 activation and inducible nitric oxide synthase protein and mRNA expression. Consistent with in vitro data, LPS injection enhanced the number of immune cells induced by OVA in bronchoalveolar lavage fluid, whereas 20 mg/kg Rh1 significantly decreased OVA/LPS-mediated immune cell induction. In addition, Rh1 inhibited eosinophil, macrophage, and neutrophil maturation through by IL-4 and OVA-specific IgE production. SignificanceRh1 protects against OVA/LPS-induced allergic asthma by suppressing immune cell infiltration by blocking the activation of MAPK, Akt, and NF-κB signaling pathways.

Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment

The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term "eosinophils" was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. Eosinophils may also be responsible for various possible tissue pathologies in many eosinophil-associated diseases. Since the beginning of the 21st century, the understanding of the nature of this cell population has undergone a fundamental reassessment, and in 2010, J. J. Lee proposed the concept of "LIAR" (Local Immunity And/or Remodeling/Repair), underlining the extensive immunoregulatory functions of eosinophils in the context of health and disease. It soon became apparent that mature eosinophils (in line with previous morphological studies) are not structurally, functionally, or immunologically homogeneous cell populations. On the contrary, these cells form subtypes characterized by their further development, immunophenotype, sensitivity to growth factors, localization, role and fate in tissues, and contribution to the pathogenesis of various diseases, including asthma. The eosinophil subsets were recently characterized as resident (rEos) and inflammatory (iEos) eosinophils. During the last 20 years, the biological therapy of eosinophil diseases, including asthma, has been significantly revolutionized. Treatment management has been improved through the enhancement of treatment effectiveness and a decrease in the adverse events associated with the formerly ultimately used systemic corticosteroids. However, as we observed from real-life data, the global treatment efficacy is still far from optimal. A fundamental condition, "sine qua non", for correct treatment management is a thorough evaluation of the inflammatory phenotype of the disease. We believe that a better understanding of eosinophils would lead to more precise diagnostics and classification of asthma subtypes, which could further improve treatment outcomes. The currently validated asthma biomarkers (eosinophil count, production of NO in exhaled breath, and IgE synthesis) are insufficient to unveil super-responders among all severe asthma patients and thus give only a blurred picture of the adepts for treatment. We propose an emerging approach consisting of a more precise characterization of pathogenic eosinophils in terms of the definition of their functional status or subset affiliation by flow cytometry. We believe that the effort to find new eosinophil-associated biomarkers and their rational use in treatment algorithms may ameliorate the response rate to biological therapy in patients with severe asthma.

The role of biologics in the pathogenesis and treatment of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic immune-mediated disorder characterized by inflammation, and intraepithelial infiltration of eosinophils in the esophageal epithelium. It is associated with unbearable symptoms, such as dysphagia, and bolus impaction which affect the nutritional status, and quality of life of the patients. It is diagnosed from a thorough medical history, and confirmed by endoscopy and esophageal biopsy. Traditionally, it has been treated with elimination diet, proton pump inhibitors, and swallowed topical corticosteroids. However, several of the patients with EoE are refractory to the treatment. Eosinophilic esophagitis like eosinophilic asthma is a T helper type 2 lymphocyte (Th2)-mediated allergic disease. During an allergic inflammation Th2 cells secrete cytokines, such as interleukin-5 (IL-5). IL-4, and IL-13 which play a key role in the pathogenesis of EoE. Th2 cytokines promote eosinophilopoiesis, differentiation, proliferation, maturation and activation of eosinophils. Activated eosinophils liberate several cytotoxic cationic proteins, and reactive oxygen species which cause epithelial injury, inflammation, and remodeling, which later progresses to esophageal fibrosis. Dupilumab (dupixent®)is a monoclonal antibody which target the IL-4 receptor (IL-4Rα) which signals for both IL-4 and IL-13. Dupilumab is the only biologic which is effective, and approved for the treatment of EoE in adults and children 12 years and older. Treatment with dupixent® has been shown to improve dysphagia, dilate and relax the gullet, and allow patients to enjoy their cherished dish. Biologics such as dupilumab should be administered early in patients with EoE in order to prevent the menacing complications of the disease, such as esophageal stricture, and esophageal perforation, which necessitate surgical esophageal dilatation, and repair.

Generation of Functionally Competent Eosinophils and Eosinophil Precursors Using an Induced Pluripotent Stem Cell Model

In vitro studies of normal human eosinophil development are limited by the difficulty in obtaining sufficient numbers of CD34+ stem cells from blood or bone marrow for differentiation into mature eosinophils. Human induced pluripotent stem cells (hiPSCs) have the capacity to generate large numbers of lineage-committed progenitors circumventing this problem.

Long COVID outcomes in an asthmatic cohort and its implications for asthma control

Long COVID outcomes in an asthmatic cohort and its implications for asthma control

Knockdown of CCR3 gene inhibits Proliferation, migration and degranulation of eosinophils in mice by downregulating the PI3K/Akt pathway.

This study aimed to investigate the effects of CCR3 knockdown (CCR3-/-) on the proliferation, migration, and degranulation of the bone marrow eosinophils (EOS) in mice. Bone marrow cells from wild-type mice (WT) were harvested for primary culture and differentiated into mature EOS, which were then randomly divided into the control, 740Y-P, and LY294002 group. The effects of different concentrations of LY294002 (PI3K inhibitor) and 740Y-P (PI3K agonist) on the proliferation viability of EOS, expressions of EPO, Akt, and p-Akt proteins, and migration changes of EOS were detected. CCR3-/- mice were identified. Then, bone marrow cells of WT and CCR3-/- mice were differentiated into mature EOS and grouped into WT EOS, WT EOS+eotaxin (100ng/mL), CCR3-/- EOS, and CCR3-/- EOS+eotaxin (100ng/mL) group. The changes in EOS proliferation, migration, as well as expressions of EPO, Akt, and p-Akt proteins were detected. The number of migrated cells (P<0.01) and expression of EPO (p<0.05) in the 740Y-P group were higher than those in the control group, while opposite trends were observed for the LY294002 group. Expression levels of p-Akt and Akt in the LY294002 group were significantly lower than in the control group (all P<0.01). Also, the expression of p-Akt in the 740Y-P group was significantly higher than that in the control group (p<0.05). The proliferative activity of EOS, expression of EPO and p-Akt, and the number of migrated cells in the WT EOS group were higher than those in CCR3-/- EOS group (all P<0.05). After adding eotaxin, the WT EOS group was higher than the other three groups (all P<0.05). Mechanistically, CCR3-/- inhibited EOS's proliferation, migration, and degranulation by downregulating PI3K/Akt pathway. This data suggests that the knockout of the CCR3 gene in bone marrow cells may inhibit the function of EOS by downregulating the PI3K/Akt pathway, thereby affecting AR; thus, the CCR3 gene may be a target gene for AR therapy.

A CASE OF MYCOBACTERIUM AVIUM COMPLEX PULMONARY INFECTION WITH SEVERE EOSINOPHILIA TREATED WITH MEPOLIZUMAB

A CASE OF MYCOBACTERIUM AVIUM COMPLEX PULMONARY INFECTION WITH SEVERE EOSINOPHILIA TREATED WITH MEPOLIZUMAB