Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other ...comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti–IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.
Background Chronic rhinosinusitis with nasal polyps is characterized by TH 2-biased eosinophilic inflammation. Eosinophils have been shown to generate so-called extracellular eosinophilic traps ...(EETs) under similar pathologic conditions. Objective Our aim was to investigate a possible link between EET formation and the presence of Staphylococcus aureus , an organism frequently colonizing the upper airways, at the human mucosal site of the disease. Methods Tissue slides were investigated for the presence of EETs and S aureus by using immunofluorescent staining and the PNA-Fish assay, respectively. An ex vivo human mucosal disease tissue model was used for artificial infection with S aureus . Cell markers were analyzed by using immunohistochemistry, the Luminex Multiplex assay, ELISA, PCR, and immunoblotting and linked to the presence of EETs. Results About 8.8% ± 4.8% of the infiltrating eosinophils exhibited EETs in patients' nasal polyp tissues. Formation of EETs was associated with increased IL-5 ( P < .05) and periostin ( P < .05) tissue levels and colonization with S aureus ( P < .05). By using an ex vivo human mucosal disease tissue model, EET formation was induced (4.2 ± 0.9–fold) on exposure to S aureus but not Staphylococcus epidermidis . Eosinophils were shown to migrate ( P < .01) toward S aureus and entrap the bacteria both inside and outside the mucosal tissue. Blocking NAPDH oxidase activity led to a complete inhibition ( P < .05) of EET formation by S aureus. Conclusion Eosinophils are likely to be specifically recruited to S aureus and possibly other microorganisms and form EETs at sites of airway epithelial damage to protect the host from infections in patients with chronic rhinosinusitis with nasal polyps.
Refining the definition of hypereosinophilic syndrome Simon, Hans-Uwe, MD, PhD; Rothenberg, Marc E., MD, PhD; Bochner, Bruce S., MD ...
Journal of allergy and clinical immunology,
07/2010, Letnik:
126, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Because of advances in our understanding of the hypereosinophilic syndrome (HES) and the availability of novel therapeutic agents, the original criteria defining these disorders are becoming ...increasingly problematic. Here, we discuss shortcomings with the current definition of HES and recent developments in the classification of these disorders. Despite significant progress in our understanding of the pathogenesis of some forms of HES, the current state of knowledge is still insufficient to formulate a new comprehensive etiologic definition of HESs. Nevertheless, we suggest a new working definition that overcomes some of the most obvious limitations with the original definition.
Novel targeted therapies for eosinophilic disorders Wechsler, Michael E., MD, MMSc; Fulkerson, Patricia C., MD, PhD; Bochner, Bruce S., MD ...
Journal of allergy and clinical immunology,
09/2012, Letnik:
130, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic ...disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders.
Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, ...clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.
Two gastroenterologists (A. S. and P. H.) and 1 pathology center serve this area. Since 1989, adult and pediatric patients with EoE from Olten County were consecutively entered into the Swiss EoE ...database (SEED) if they fulfilled the following criteria: (1) proton pump inhibitor (PPI)-refractory esophagus-attributed symptoms (high-dose PPI trial of >4 weeks or gastroesophageal reflux disease (GERD) exclusion by pH-metry before the EoE diagnosis), (2) eosinophilic esophageal peak infiltration of 24 or more eosinophils per hpf, and (3) exclusion of other diseases associated with esophageal eosinophilia. ...EoE diagnosis was based on both clinical and histopathologic features and biopsy specimens were processed and examined in a single pathology center by pathologists with an extensive experience in examining EoE biopsies.
Background Asthma is a heterogeneous inflammatory airway disorder that involves eosinophilic and noneosinophilic phenotypes. Unlike in healthy lungs, eosinophils are often present in atopic asthmatic ...airways, although a subpopulation of asthmatic subjects predominantly experience neutrophilic inflammation. Recently, it has been demonstrated that eosinophils and neutrophils generate bactericidal extracellular traps consisting of DNA and cytotoxic granule proteins. Objective We sought to explore whether living eosinophils and neutrophils infiltrating human atopic asthmatic airways actively form extracellular DNA traps in vivo. Methods Quantitative analysis of eosinophils releasing DNA was performed in endobronchial biopsy specimens from 20 human subjects with mild atopic asthma at baseline and after local allergen challenge and 10 healthy subjects. DNA was stained with propidium iodine and major basic protein with specific antibody. Differential cell counts and cytokines/chemokines were assessed in bronchoalveolar lavage fluid. Results Asthmatic airways were infiltrated with a significantly higher number of eosinophils than healthy airways (39.3 ± 4.6 vs 0.4 ± 0.9, P < .0001). All asthmatic subjects but only 1 control subject expressed eosinophils releasing DNA that colocalized with major basic protein (33.65 ± 20.33 vs 0.3 ± 0.9 per high-power field, P < .0001). Four asthmatic subjects mostly expressed neutrophilic inflammation and neutrophil DNA traps. Allergen challenge had no significant quantitative effect on eosinophil or neutrophil DNA traps. Airway eosinophils or DNA traps did not correlate with either bronchoalveolar lavage levels of IL-5, IFN-γ, or eotaxin or the provoking doses of methacholine or allergen in asthmatic subjects. Conclusions Extracellular DNA traps are generated by eosinophils and neutrophils in human atopic asthmatic airways in vivo . The mechanism and role of this new finding will necessitate further investigation.
Background Eosinophils are blood cells that are often found in high numbers in the tissues of allergic conditions and helminthic parasite infections. The pathophysiologic roles that eosinophils may ...serve in other human “eosinophil-associated” diseases remain obscure. Objective National Institutes of Health (NIH) Institutes and the Office of Disease Prevention assembled an international taskforce of clinical and basic scientists with the charge to propose and prioritize unmet research needs in eosinophil-associated diseases. Methods The taskforce used an organ system approach to identify the different and common themes of eosinophil cell involvement in these diseases. In early 2012, a draft document was circulated for review. The document was amended and the prioritizations were set at a NIH-organized workshop in June 2012. Results The taskforce identified significant research needs. These needs cross disease entities but some are disease specific. There are substantial shortcomings to the various preclinical animal models, as well as significant gaps in our epidemiologic, pathophysiologic, diagnostic, prognostic, and therapeutic knowledge. The taskforce recognized that recent efforts by patient advocacy groups have played instrumental roles in improving the identification and characterization of these disorders. However, communications among the eosinophil-interested communities, for example, governmental funding and regulatory agencies, and industry and clinician scientists need to be more comprehensive. Conclusions Significant efforts are required to address our knowledge gaps to improve the outcomes of eosinophil-associated diseases. NIH Institutes, other federal agencies, lay organizations, and the pharmaceutical industry should consider the taskforce's recommendations in their future research activities.
Background Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia ≥1.5 × 109 /L, absence of a secondary cause, and evidence of ...eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti–IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. Objective The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. Methods Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. Results Eighteen of 161 patients (11%) tested were Fip1-like 1–platelet-derived growth factor receptor α ( FIP1L1-PDGFRA ) mutation—positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-α (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). Conclusion This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.
Abstract Biodegradable nanoparticles have been employed for vaccine delivery, frequently admixed with adjuvants. Surprisingly, there is little information on their modulation of immune responses, ...speculated to be negligible. We analyzed the immunomodulatory capacity of alginate-coated chitosan nanogels (Ng), on porcine and human blood dendritic cells (DCs), when applied with defined adjuvants targeting different DC subpopulations. DC maturation, cytokine production and cell migration were assessed. Ng differentially influenced the immunomodulatory characteristics of individual Toll-like receptor (TLR) ligands: Pam3 Cys-SK4-induced IL-1β was enhanced; CpG-oligodeoxynucleotides (CpG-ODN)-induced IFN-α, IL-6 and TNFα were impaired; CpG-ODN-induced CD86 and CCR7, and cell migration, were diminished—plasmacytoid DCs (pDCs) were particularly sensitive. Therein, the Ng influence on DC endocytosis of the TLR ligands was apparently a major contributory element. This demonstrates the importance of predefining the interplay between delivery vehicles and admixed immunostimulatory moieties, for ensuring appropriate immune activation and efficacious combinations. From the Clinical Editor Biodegradable nanoparticles have been utilized in vaccine delivery; however, there is little information available on their immunomodulatory properties, which are thought to be negligible. This study clearly demonstrates that nanogels do influence the developing immune response, which needs to be taken into consideration when utilizing these otherwise very efficacious vaccine delivery approaches.
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