Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil‐predominant infiltration, thereby ...conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis (EoE) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that EoE represents a T‐helper (Th)2‐type inflammatory disease. Remodeling of the esophagus is a hallmark of EoE, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single‐nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the EoE population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, EoE seems to be primarily a food antigen–driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for EoE include the 3Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric EoE are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between EoE in adults and children.
Extracellular DNA traps are part of the innate immune response and are seen with many infectious, allergic, and autoimmune diseases. They can be generated by several different leukocytes, including ...neutrophils, eosinophils, and monocytes, as well as mast cells. Here, we review the composition of these extracellular DNA‐containing structures as well as potential mechanisms for their production and function. In general, extracellular DNA traps have been described as binding to and killing pathogens, particularly bacteria, fungi, but also parasites. On the other hand, it is possible that DNA traps contribute to immunopathology in chronic inflammatory diseases, such as bronchial asthma. In addition, it has been demonstrated that they can initiate and/or potentiate autoimmune diseases. Extracellular DNA traps represent a frequently observed phenomenon in inflammatory diseases, and they appear to participate in the cross‐talk between different immune cells. These new insights into the pathogenesis of inflammatory diseases may open new avenues for targeted therapies.
Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil‐predominant inflammation. EoE is frequently ...associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross‐reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE‐mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures.
Background
Eosinophilic esophagitis (EoE) exhibits esophageal dysfunction owing to an eosinophil‐predominant inflammation. Activated eosinophils generate eosinophil extracellular traps (EETs) able to ...kill bacteria. There is evidence of an impaired barrier function in EoE that might allow pathogens to invade the esophagus. This study aimed to investigate the presence and distribution of EETs in esophageal tissues from EoE patients and their association with possible epithelial barrier defects.
Methods
Anonymized tissue samples from 18 patients with active EoE were analyzed. The presence of DNA nets associated with eosinophil granule proteins forming EETs and the expression of filaggrin, the protease inhibitor lympho‐epithelial Kazal‐type‐related inhibitor (LEKTI), antimicrobial peptides, and cytokines were evaluated by confocal microscopy following immune fluorescence staining techniques.
Results
Eosinophil extracellular trap formation occurred frequently and was detected in all EoE samples correlating with the numbers of infiltrating eosinophils. While the expression of both filaggrin and LEKTI was reduced, epithelial antimicrobial peptides (human beta‐defensin‐2, human beta‐defensin‐3, cathelicidin LL‐37, psoriasin) and cytokines (TSLP, IL‐25, IL‐32, IL‐33) were elevated in EoE as compared to normal esophageal tissues. There was a significant correlation between EET formation and TSLP expression (P = 0.02) as well as psoriasin expression (P = 0.016). On the other hand, a significant negative correlation was found between EET formation and LEKTI expression (P = 0.016).
Conclusion
Active EoE exhibits the presence of EETs. Indications of epithelial barrier defects in association with epithelial cytokines are also present which may have contributed to the activation of eosinophils. The formation of EETs could serve as a firewall against the invasion of pathogens.
Background
Eosinophilic esophagitis (EoE) is a chronic, immune/antigen‐mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil‐predominant inflammation. This ...study has aimed to investigate whether the recently observed sensitization to Candida albicans in patients with EoE is owing to pre‐existing disease and its underlying abnormal epithelial barrier or, alternatively, is linked to corticosteroid (CS) therapy.
Methods
Medical histories, as well as serum and tissue samples of 60 patients with EoE (15 CS naive, 45 with current or previous CS therapy) and 20 controls, stored in the Swiss Eosinophilic Esophagitis Database (SEED) and Biobank, were analyzed. We applied ImmunoCAP to measure IgE levels and immunofluorescence techniques to examine epithelial barrier components.
Results
Patients with EoE had higher total IgE levels and were more frequently sensitized to C. albicans than controls. In EoE tissue specimens, increased numbers of eosinophils and mast cells, a higher expression levels of thymic stromal lymphopoietin (TSLP), cathelicidin, proteases, that is, the kallikreins (KLK)‐5 and KLK‐7, were observed as compared with controls, while reduced expression of lympho‐epithelial Kazal‐type‐related inhibitor (LEKTI), filaggrin, E‐cadherin, claudin, occludin, desmoglein‐1 was found, independent of CS therapy. In CS‐treated EoE, significantly lower numbers of CD1a+ cells and cathelicidin expression were noted as compared to CS‐naive EoE.
Conclusion
This study provides further evidence that EoE is associated with an abnormal epithelial barrier and postulates that CS therapy, by reducing innate immune mechanisms, may promote C. albicans colonization and likely subsequent sensitization.
Background
Thymic stromal lymphopoietin (TSLP) that is released by epithelial cells upon certain environmental triggers activates cells of the innate and adaptive immune system resulting in a ...preferential T helper 2 immune response. By releasing eosinophil extracellular traps (EETs), eosinophils achieve an efficient extracellular bacterial killing. Eosinophil extracellular traps release, however, has been observed in both infectious and noninfectious eosinophilic diseases. Here, we aim to investigate whether eosinophils generate functional EETs as a direct response to TSLP, and further to study the extra‐ and intracellular mechanisms involved in this process as well as TSLP receptor (TSLPR) expression by eosinophils in vitro and in vivo.
Methods
Thymic stromal lymphopoietin receptor expression on blood and tissue eosinophils was assessed by immunoblotting, flow cytometry, and immunofluorescence staining. Purified eosinophils were stimulated with recombinant human TSLP. The release of extracellular DNA in association with eosinophilic cationic protein (ECP) was detected by fluorescence staining techniques and confocal microscopy. In addition, cell survival, cell adhesion, production of reactive oxygen species (ROS), and the inhibition of bacterial growth by TSLP‐stimulated eosinophils were measured.
Results
Thymic stromal lymphopoietin receptor was observed on peripheral blood eosinophils as well as on tissue infiltrating eosinophils in skin diseases. TSLP did not affect eosinophil survival, but induced the formation of EETs consisting of mitochondrial DNA in association with ECP in a concentration‐ and time‐dependent manner. Eosinophil extracellular trap release could be inhibited by blocking either cell adhesion or ROS production. While eosinophils prevented the growth of both Staphylococcus aureus and Staphylococcus epidermidis, the latter were unable to elicit EET formation and eosinophils required additional TSLP stimulation to achieve this antibacterial activity.
Conclusions
thymic stromal lymphopoietin directly stimulates eosinophils to produce EETs. Our observations link epithelial TSLP expression triggered by environmental factors with pathogen defense mechanisms involving eosinophils.
Background
Bullous pemphigoid (BP) is an autoimmune bullous disease of the skin characterized by subepidermal blister formation due to tissue‐bound and circulating autoantibodies to the ...hemidesmosomal antigens BP180 and BP230. Although eosinophils and their toxic mediators are found abundantly in BP lesions, their role in blister formation has remained unclear.
Objective
To investigate the role of eosinophils in the pathogenesis of BP with a specific focus on blister formation and to define conditions inducing dermal–epidermal separation (DES).
Methods
In an ex vivo human model of BP, normal human skin cryosections were incubated with purified human peripheral blood eosinophils with or without activation in the presence or absence of BP autoantibodies, brefeldin A, diphenyleneiodonium, DNase or blocking F(ab′)2 fragments to CD16, CD18, CD32 and CD64. Dermal–epidermal separation was assessed by light microscopy studies and quantified using Fiji software.
Results
Following activation with IL‐5 and in the presence of BP autoantibodies, eosinophils induced separation along the dermal–epidermal junction of ex vivo skin. Dermal–epidermal separation was significantly reduced by blocking any of the following: Fcγ receptor binding (P = 0.048), eosinophil adhesion (P = 0.046), reactive oxygen species (ROS) production (P = 0.002), degranulation (P < 0.0001) or eosinophil extracellular trap (EET) formation (P = 0.048).
Conclusions
Our results provide evidence that IL‐5‐activated eosinophils directly contribute to BP blister formation in the presence of BP autoantibodies. Dermal–epidermal separation by IL‐5‐activated eosinophils depends on adhesion and Fcγ receptor activation, requires elevated ROS production and degranulation and involves EET formation. Thus, targeting eosinophils may be a promising therapeutic approach for BP.
This consensus document summarizes the current knowledge on the potential for precision medicine in food allergy, drug allergy, and anaphylaxis under the auspices of the PRACTALL collaboration ...platform. PRACTALL is a joint effort of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology, which aims to synchronize the European and American approaches to allergy care. Precision medicine is an emerging approach for disease treatment based on disease endotypes, which are phenotypic subclasses associated with specific mechanisms underlying the disease. Although significant progress has been made in defining endotypes for asthma, definitions of endotypes for food and drug allergy or for anaphylaxis lag behind. Progress has been made in discovery of biomarkers to guide a precision medicine approach to treatment of food and drug allergy, but further validation and quantification of these biomarkers are needed to allow their translation into practice in the clinical management of allergic disease.
Background
Eosinophilic esophagitis (EoE) is a chronic, Th2‐type inflammatory disease. Chemoattractant receptor‐homologous molecule on Th2 cells (CRTH2) is a prostaglandin D2 (PGD2) receptor, ...expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid‐dependent or corticosteroid‐refractory EoE.
Methods
In this randomized, double‐blind, placebo‐controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22–69 years) with active EoE, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 (n = 14) or placebo (n = 12) twice daily. Pre‐ and post‐treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration.
Results
After an 8‐week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high‐power field (eos/hpf), P = 0.0256, whereas no reduction was observed with placebo (102.80–99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 (P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed.
Conclusions
An 8‐week treatment with the CRTH2‐antagonist, OC000459, exerts modest, but significant, anti‐eosinophil and beneficial clinical effects in adult patients with active, corticosteroid‐dependent or corticosteroid‐refractory EoE and is well tolerated.
Cancer is a heterogeneous disease. Each individual tumor is unique and characterized by structural, cellular, genetic and molecular features. Therefore, patient-derived cancer models are ...indispensable tools in cancer research and have been actively introduced into the healthcare system. For instance, patient-derived models provide a good reproducibility of susceptibility and resistance of cancer cells against drugs, allowing personalized therapy for patients. In this article, we review the advantages and disadvantages of the following patient-derived models of cancer: (1) PDC-patient-derived cell culture, (2) PDS-patient-derived spheroids and PDO-patient-derived organoids, (3) PDTSC-patient-derived tissue slice cultures, (4) PDX-patient-derived xenografts, humanized PDX, as well as PDXC-PDX-derived cell cultures and PDXO-PDX-derived organoids. We also provide an overview of current clinical investigations and new developments in the area of patient-derived cancer models. Moreover, attention is paid to databases of patient-derived cancer models, which are collected in specialized repositories. We believe that the widespread use of patient-derived cancer models will improve our knowledge in cancer cell biology and contribute to the development of more effective personalized cancer treatment strategies.
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