• Humans
• Basophils/immunology
• Basophils/metabolism
• Immunoglobulin E/immunology
• Immunoglobulin E/metabolism
• Mast Cells/immunology
• Mast Cells/metabolism
• Animals
• Receptors, IgE/metabolism
• Hypersensitivity/immunology
• Cytokines/metabolism
• Allergens/immunology
• Th2 Cells/immunology

• EQU201903007794 Fondation pour la Recherche Médicale (FRM)
• ANR-19-CE15-0016 IDEA Agence Nationale de la Recherche (ANR)
• ANR-19-CE17-0029 BALUMET Agence Nationale de la Recherche (ANR)
• ANRPIA-10-LABX-0017 INFLAMEX Agence Nationale de la Recherche (ANR)

• Humans
• Eosinophilic Esophagitis/blood
• Tandem Mass Spectrometry/methods
• Tyrosine/analogs & derivatives
• Tyrosine/blood
• Chromatography, High Pressure Liquid/methods
• Biomarkers/blood
• Reproducibility of Results
• Limit of Detection
• Eosinophils
• Liquid Chromatography-Mass Spectrometry

• EETosis
• eosinophil activation
• eosinophilic diseases
• extracellular vesicles
• inflammation
• sombrero vesicles

• Pulmonary Disease, Chronic Obstructive/immunology
• Humans
• Inflammation/immunology
• Th2 Cells/immunology
• Asthma/immunology

• Animals
• Chiroptera/immunology
• Hendra Virus
• Leukocytes
• Queensland

• Defense Advanced Research Projects Agency
• National Science Foundation
• Montana State University
• Australian Research Council
• USDA National Institute of Food and Agriculture

Eosinophils act as a secondary antigen-presenting cell (APC) to stimulate Th cell responses against antigens. IL-25 plays a significant role in eosinophil activation in allergic asthma. The role of IL-25 on the classic APC functions of dendritic cells has been elucidated. However, whether IL-25 facilitates eosinophils for antigen presentation is unknown.

To elucidate the role of IL-25 on eosinophils antigen presenting function during allergic asthma and its related mechanism.

Eosinophils from allergic asthma subjects were cultured with IL-25 and HDM to identify the co-stimulator molecules expression. Co-cultures of patient eosinophils and autologous naïve CD4⁺ T cells in the same culture system were to explore whether eosinophils had the capacity to promote Th cell differentiation in response to IL-25 engagement. In asthma mouse model, IL-25^-/- mice were exposed to HDM to investigate the effect of IL-25 on eosinophils during the sensitization phase. The impact of IL-25 on the capacity for eosinophils taking up antigens was evaluated. Mouse bone marrow derived eosinophils (BmEOS) were co-cultured with naïve CD4⁺T cells sorted from spleens under HDM and IL-25 stimulation to identify T cell differentiation.

IL-25 upregulated HLA-DR, PD-L1, and OX-40L expression on eosinophils from allergic asthma patients. IL-25 and HDM co-sensitized eosinophils promoted Th2 differentiation. In mouse model, IL-25^-/- mice experienced restrained allergic pulmonary inflammation and reduced eosinophils recruitment and antigen uptake capacity during the early sensitization phase. In vitro, IL-25 promoted antigen uptake by eosinophils. In BmEOS and naïve CD4⁺T cells co-culture, IL-25 accreted the proportion of CD4⁺Th2 cells, which was absent in CD4⁺T cells culture alone.

Our data identify a novel role of IL-25 in enhancing eosinophils antigen uptake and co-stimulator molecules expression to induce Th2 priming in the context of allergic inflammation.

• Animals
• Asthma
• Cytokines/metabolism
• Eosinophils
• Humans
• Mice
• Pulmonary Eosinophilia
• Th2 Cells

• Bot
• nictitating membrane
• oestrid
• ophthalmomyiasis
• orbit
• third eyelid

• Animals
• Cat Diseases/diagnosis
• Cat Diseases/parasitology
• Cats
• Diptera
• Eye Infections, Parasitic/diagnosis
• Eye Infections, Parasitic/veterinary
• Larva
• Myiasis/diagnosis
• Myiasis/veterinary
• Retrospective Studies

Sézary syndrome is an aggressive leukemic variant of cutaneous T-cell lymphomas, characterized by erythroderma, lymphadenopathy, and peripheral blood involvement by CD4+ malignant T-cells. The pathogenesis of Sézary syndrome is not fully understood. However, the course of the disease is strongly influenced by the tumor microenvironment, which is altered by a combination of cytokines, chemokines, and growth factors. The crosstalk between malignant and reactive cells affects the immunologic response against tumor cells causing immune dysregulation. This review focuses on the interaction of malignant Sézary cells and the tumor microenvironment.

• Sézary syndrome
• chemokines
• cutaneous T-cell lymphoma
• cytokines
• tumor microenvironment

• Antibacterial
• Antihelminthic
• Antiprotozoan
• Antiviral
• Eosinophil granule protein

• allometry
• birds
• immunology
• leucocyte
• life history
• scaling

Background: Eosinophils develop from CD34⁺ progenitor cells in the bone marrow under the influence of interleukin (IL)-5. Several cell types produce IL-5, including type 2 innate lymphoid cells (ILC2s). The alarmin cytokine IL-33 is known to activate ILC2s in mucosal tissues, but little is known about IL-33-responsive ILC2s in the bone marrow in allergen-induced airway inflammation.

Methods: Wild type (WT) and Rag1 deficient (Rag1^−/−) mice, which lack mature T and B cells, received intranasal doses of papain to induce acute allergic inflammation. In some experiments, mice were pre-treated with anti-IL-5 prior to the papain challenge. Furthermore, recombinant IL-33 was administered to WT mice, Rag1^−/− mice, lymphocyte deficient mice (Rag2^−/−Il2rg^−/−) and to ex vivo whole bone marrow cultures. Bone marrow eosinophils and ILC2s were analyzed by flow cytometry. Eosinophil count was assessed by differential cell count and secreted IL-5 from bone marrow cells by ELISA.

Results: Intranasal administration of papain or IL-33 increased the number of mature eosinophils in the bone marrow despite the absence of adaptive immune cells in Rag1^−/− mice. In parallel, an increased number of eosinophils was observed in the airways together with elevated levels of Eotaxin-2/CCL24. Bone marrow ILC2s were increased after papain or IL-33 administration, whereas ILC2s was found to be increased at baseline in Rag1^−/− mice compared to WT mice. An upregulation of the IL-33 receptor (ST2) expression on bone marrow ILC2s was observed after papain challenge in both Rag1^−/− and WT mice which correlated to increased number of bone marrow eosinophilia. Furthermore, an increased number of ST2⁺ mature eosinophils in the bone marrow was observed after papain challenge, which was further dependent on IL-5. In addition, bone marrow-derived ILC2s from both mouse strains produced large amounts of IL-5 ex vivo after IL-33 stimulation of whole bone marrow cultures. In contrast, IL-33-induced bone marrow and airway eosinophilia were abolished in the absence of ILC2s in Rag2^−/−Il2rg^−/− mice and no production of IL-5 was detected in IL-33-stimulated bone marrow cultures.

Conclusion: These findings establish bone marrow ILC2s and the IL-33/ST2 axis as promising targets for modulation of uncontrolled IL-5-dependent eosinophilic diseases including asthma.

• ILC2
• allergy
• asthma
• bone marrow
• eosinophilia
• interleukin-33
• interleukin-5
• papain

• IL-33
• IL-5
• ST2
• T helper cells
• adaptive immunity
• allergy
• asthma
• eosinophilia
• innate lymphoid cells
• type 2 inflammation

• Animals
• Antigens, Dermatophagoides/immunology
• Bone Marrow Cells/cytology
• Bone Marrow Cells/immunology
• Cell Differentiation
• Cells, Cultured
• Eosinophils/cytology
• Eosinophils/immunology
• Interleukin-33/immunology
• Interleukin-5 Receptor alpha Subunit/genetics
• Interleukin-5 Receptor alpha Subunit/metabolism
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred C57BL
• Th2 Cells/cytology
• Th2 Cells/immunology

• 2017-02302 Vetenskapsrådet
• 20170392 Swedish Heart and Lung Foundation

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease that encompasses esophageal symptoms along with eosinophilic infiltration of the esophageal epithelium. EoE is an evolving disease that has been a subject of interest to many researchers since the first studies recognized this condition as a new and distinct clinicopathological entity 25 years ago. Clinical presentation in adult patients may include dysphagia, food impaction, vomiting, and reflux symptoms. The diagnosis of EoE is based on the combination of clinical history suggestive of esophageal dysfunction, endoscopic features indicative of the disease, and histology revealing eosinophilic infiltration of the esophageal epithelium that persists after a trial of proton pump inhibitor therapy along with the exclusion of other disorders that may be associated with esophageal tissue eosinophilia. The interplay between EoE and gastroesophageal reflux disease (GERD) is complex, and differentiating these two conditions continues to be difficult and challenging in clinical practice. The mainstay treatment includes dietary modification, topical steroids, and/or endoscopic dilation. The primary care physician (PCP) plays an important role in improving patient care and quality of life by ensuring early referral and participating in management and follow-up. This article provides an overview of the current knowledge base regarding the disease including epidemiology, genetics, pathogenesis, common clinical presentations, the interplay between EoE and GERD, diagnostic approaches, and therapeutic options available to the PCP.

• Diagnosis
• Eosinophilic Esophagitis
• Management
• Primary Care Physicians

Dectin-2, which is a C-type lectin, interacts with the house dust mite (HDM) Dermatophagoides pteronyssinus allergen. This study aimed to investigate whether Dectin-2 blockade by antagonistic monoclonal antibodies (MoAbs) attenuates HDM-induced allergic responses.

Two anti-Dectin-2 MoAbs were generated and validated for specific binding to Dectin-2 Fc fusion protein (Dectin-2.Fc) and inhibition of Dectin-2.Fc/HDM interaction. Patients with asthma exhibiting high titers of anti-D. pteronyssinus IgE were enrolled. Peripheral blood mononuclear cells with depleted CD14⁺ monocytes were obtained from these patients and co-cultured with autologous monocyte-derived conventional dendritic cells in the presence of D. pteronyssinus or its group 2 allergens (Der p 2). Interleukin (IL)-5 and IL-13 levels in the culture supernatants were determined using ELISA in the presence or absence of anti-Dectin-2 MoAbs.

Two MoAbs, 6A4G7 and 17A1D10, showed specific binding to recombinant Dectin-2.Fc and inhibited HDM binding to Dectin-2.Fc. Both anti-Dectin-2 MoAbs inhibited IL-5 and IL-13 production in co-cultures with Der p 2 stimulation in a dose-dependent manner. 6A4G7 and 17A1D10 (3 μg/mL) significantly inhibited Der p 2-induced (3 μg/mL) IL-5 production by 69.7 and 86.4% and IL-13 production by 84.0 and 81.4%, respectively. Moreover, this inhibitory effect of the two MoAbs remained significant in the presence of D. pteronyssinus.

Anti-Dectin-2 MoAbs significantly inhibited HDM-induced allergic responses in vitro and therefore have the potential to become therapeutic agents in mite-induced allergic diseases.

• Asthma
• Dectin-2
• Dermatophagoides pteronyssinus
• House dust mite

• Eosinophilic infiltration
• Etiology
• Hypereosinophilic syndrome
• Liver
• Parasite

• Eosinophilia
• Eosinophilic colitis

Hypereosinophilia (HE) is currently defined by a peripheral blood absolute eosinophil count (AEC) of ≥1,500 cells/microL. Although mild blood eosinophilia (AEC 500–1,500 cells/microL) is observed relatively frequently within the pediatric population, persistent HE is uncommon and should prompt additional clinical evaluation. While the clinical manifestations and underlying etiologies of HE in adults have been well-characterized, there is a paucity of data on HE in children. Limited evidence suggests that many similarities between adult and pediatric HE likely exist, but some important differences remain between these populations. The evaluation of HE in children can be challenging given the broad differential diagnosis, which includes primary hematologic disorders and secondary eosinophilia in which the increased eosinophil levels are propagated by disease states that promote eosinophil production and survival. On the basis of the underlying etiology, clinical manifestations can range from benign, self-resolving elevations in the AEC to life-threatening disorders with the potential for significant end-organ damage. Given the broad differential diagnosis of HE, it remains essential to systematically approach the evaluation of unexplained HE in children. This review will discuss the differential diagnosis for pediatric HE, highlighting etiologies that are more prevalent within the pediatric population. Additionally, a summary of the epidemiology of pediatric HE will be presented, with focus on some of the differences that exist between pediatric and adult HE. Finally, a directed approach to the diagnostic evaluation of children with HE will be discussed.

• children
• diagnostic testing
• differential diagnosis
• eosinophil
• epidemiology
• hypereosinophilia

• Strongyloides stercoralis
• eosinophils
• granular proteins
• helminths
• mast cells
• neutrophils

• Eosinophilic diseases
• collaborations
• multicenter consortium
• rare diseases

• U01 TR001263 NCATS NIH HHS
• U54 AI117804 NIAID NIH HHS

The liver is one of the main organs in the body, performing several metabolic and immunological functions that are indispensable to the organism. The liver is strategically positioned in the abdominal cavity between the intestine and the systemic circulation. Due to its location, the liver is continually exposed to nutritional insults, microbiota products from the intestinal tract, and to toxic substances. Hepatocytes are the major functional constituents of the hepatic lobes, and perform most of the liver’s secretory and synthesizing functions, although another important cell population sustains the vitality of the organ: the hepatic immune cells. Liver immune cells play a fundamental role in host immune responses and exquisite mechanisms are necessary to govern the density and the location of the different hepatic leukocytes. Here we discuss the location of these pivotal cells within the different liver compartments, and how their frequency and tissular location can dictate the fate of liver immune responses.

• hepatic leukocytes
• hepatocytes
• immune response
• liver

Mepolizumab (Nucala^®) is an effective and specific anti-eosinophil molecular therapy that has recently been approved as add-on therapy for the management of severe eosinophilic asthma by the US Food and Drug Administration (FDA), European Medicines Agency (EMA; European Union) and more recently National Institute for Health and Care Excellence (NICE; UK). It is one of several molecular therapies in development for this indication and is illustrative of the strategic trajectory for pharmaceutical drug development taken over the past decade in several disease areas. Molecular therapies offer the prospect of improved specificity and effectiveness of biological effect. However, this necessitates a clear understanding of the underlying mechanistic pathways underpinning pathological processes, to inform drug development that yields novel more efficacious treatment options with a better clinical profile than existing agents. For the first time, utilization of molecular therapies in clinical trials is providing a novel in vivo model to characterize the association between specific pathways and clinical disease expression. It is increasingly recognized that asthma exhibits both clinical and pathological heterogeneity. It follows that a one-size-fits-all approach will not be appropriate and cost-effectiveness may only be achieved by identifying responder subgroups. This so-called personalized approach to therapy is being supported by the parallel development of companion biomarkers for clinical application. In this review, the author summarizes the clinical studies, their interpretation and the lessons learnt with mepolizumab that have informed our understanding of the approach to personalized molecular therapy in asthma.

• IL-5
• Nucala
• exacerbations

• Airway inflammation
• Anthocyanins
• Blackcurrant
• CCL11
• Polyphenolics

• children
• eosinophilic colitis

RNA interference has been considered as an effective gene silencing method in basic and preclinical investigations. The aims of the present study were to construct a lentiviral vector expressing a short hairpin RNA (shRNA) targeting the murine CC chemokine receptor 3 (mCCR3), and to investigate its effects on the proliferation and apoptosis of mouse eosinophils. A recombinant lentiviral vector expressing four fragments of mouse CCR3 shRNA (pLVX-mCCR3-1+2+3+4-shRNA) was constructed using subcloning techniques. This novel lentivirus was then packaged into 293T cells by co-transduction with plasmids, including Baculo p35, pCMV R8.2 and VSV. The interference effects of the vector were verified using polymerase chain reaction (PCR) and western blot analyses. The effects of the interference on the proliferation and apoptosis of mouse eosinophils were investigated using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and terminal deoxynucleotidyl transferase dUTP nick end labeling methods, respectively. The results of the PCR and western blot analyses confirmed that the novel recombinant vector, pLVX-mCCR3-1+2+3+4-shRNA, had high efficiency in inhibiting the mRNA and protein expression levels of mCCR3 in mouse eosinophils. The downregulation of mCCR3 significantly inhibited proliferation of the eosinophils. Furthermore, the present study found that the downregulation of mCCR3 significantly promoted apoptosis of the eosinophils. Therefore, the downregulation of mCCR3 led to the inhibition of proliferation and induction of apoptosis in mouse eosinophils. The predominant characteristics of allergic rhinitis are eosinophil infiltration and release of inflammatory mediators, which appear in a variety of clinical manifestations. The results of the present study indicate that mCCR3 silencing may serve as a putative approach for the treatment of allergic rhinitis.

• Chronic eosinophilic leukemia
• Myeloid proliferative neoplasm with eosinophilia
• NOS
• Novel ETV6-ACSL6 gene fusion

Interleukin-5, an important cytokine in the pathophysiology of asthma, participates in terminal maturation and increases chemotaxis, endothelial adhesion, and activation of eosinophils. Blockade of interleukin-5 activity with monoclonal antibodies have been successful in decreasing eosinophil counts. Reslizumab, a monoclonal antibody that targets interleukin-5, has been studied for the treatment of severe asthma. Several studies have shown that reslizumab can effectively treat severe asthma with an eosinophilic phenotype. Compared to placebo, patients treated with reslizumab had a reduction in the rates of asthma exacerbations and experienced improvement in FEV₁ and asthma control questionnaires scores as early as 4 weeks after the therapy was initiated. Reslizumab was not effective in various asthma outcomes in patients without eosinophilia. The adverse events reported were similar in both treatment and placebo groups. Patients should be observed immediately after treatment because anaphylaxis may occur rarely (0.3%) after exposure to reslizumab. Future surveillance studies are still needed to establish the risks of malignancy and safety during pregnancy.

• IL-5 antibody
• IL-5 blockage
• Sch 55700
• anti-IL-5
• eosinophilic asthma
• reslizumab
• severe asthma

• Allergic broncho-pulmonary aspergillosis
• Asthma
• Eosinophilic granulomatosis with polyangiitis
• IgG4

• Case series
• IL-5
• dialysis membrane
• eosinophilia
• hemodialysis

• IL-5
• asthma
• eosinophil
• eosinophil cationic protein
• inflammation
• markers

• Churg–Strauss syndrome
• Löffler’s syndrome
• chronic eosinophilic pneumonia
• eosinophilic granulomatosis with polyangiitis

• Aedes aegypti
• Inflammatory bowel disease
• Saliva
• Therapy

• innate immunity
• commensal flora
• natural antibiotics
• neutropenia
• humoral immunity
• cellular immunity
• host defenses
• mucosal barrier injury
• mucositis
• infectious complications

• Animals
• Host-Pathogen Interactions/immunology
• Humans
• Immunity, Cellular/physiology
• Neoplasms/immunology
• Neoplasms/pathology

• Animals
• Anti-Infective Agents/pharmacology
• Bacteria/drug effects
• Eosinophil Granule Proteins/pharmacology
• Helminths/drug effects
• Humans
• Viruses/drug effects

Shigellosis is a worldwide disease, characterized by abdominal pain, fever, vomiting, and the passage of blood- and mucus-streaked stools. Rhesus monkeys and other primates are the only animals that are naturally susceptible to shigellosis. A suitable animal model is required for the pre-clinical evaluation of vaccines candidates. In this study, the minimal dose of Shigella dysenteriae1 1617 strain required to produce dysentery in four of five (80% attack rate) monkeys using an escalating dose range for three groups [2 × 10⁸, 2 × 10⁹ and 2 × 10¹⁰ colony forming unit (CFU)] was determined. In addition, the monkeys were re-infected. The identified optimal challenge dose was 2 × 10⁹ CFU; this dose elicited 60% protection in monkeys when they were re-challenged with a one log higher dose (2 × 10¹⁰ CFU). The challenge dose, 2 × 10¹⁰ CFU, produced severe dysentery in all monkeys, with one monkey dying within 24 h, elicited 100% protection when re-challenged with the same dose. All monkeys exhibited immune responses. This study concludes that the rhesus monkey model closely mimics the disease and immune response seen in humans and is a suitable animal model for the pre-clinical evaluation of Shigella vaccine candidates. Prior infection with the 1617 strain can protect monkeys against subsequent re-challenges with homologous strains.

• Shigellosis
• challenge model
• rhesus monkey (Macaca mulatta)

Leukocyte adhesion molecules are involved in cell recruitment in an allergic airway response and therefore provide a target for pharmaceutical intervention. Neutrophil inhibitory factor (NIF), derived from canine hookworm (Ancylostoma caninum), binds selectively and competes with the A-domain of CD11b for binding to ICAM-1. The effect of recombinant NIF was investigated. Intranasal administration of rNIF reduced pulmonary eosinophilic infiltration, goblet cell hyperplasia, and Th₂ cytokine production in OVA-sensitized mice. In vitro, transendothelial migration of human blood eosinophils across IL-4-activated umbilical vein endothelial cell (HUVEC) monolayers was inhibited by rNIF (IC₅₀: 4.6 ± 2.6 nM; mean ± SEM), but not across TNF or IL-1-activated HUVEC monolayers. Treatment of eosinophils with rNIF together with mAb 60.1 directed against CD11b or mAb 107 directed against the metal ion-dependent adhesion site (MIDAS) of the CD11b A-domain resulted in no further inhibition of transendothelial migration suggesting shared functional epitopes. In contrast, rNIF increased the inhibitory effect of blocking mAbs against CD18, CD11a, and VLA-4. Together, we show that rNIF, a selective antagonist of the A-domain of CD11b, has a prominent inhibitory effect on eosinophil transendothelial migration in vitro, which is congruent to the in vivo inhibition of OVA-induced allergic lung inflammation.