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.
Background In the skin, eosinophils are found in a broad spectrum of diseases, including infectious diseases. Objective In this study, we investigated whether eosinophil extracellular traps, ...structures containing DNA in association with eosinophil granule proteins able to bind and kill bacteria, are present in the skin under various pathologic conditions. Methods Immunofluorescence staining was performed on sections of paraformaldehyde-fixed and paraffin-embedded skin biopsy tissues of 25 different eosinophilic skin diseases by using propidium iodide and an antibody to eosinophil cationic protein. Slides were evaluated by laser scanning microscopy. Results Eosinophils releasing DNA together with eosinophil cationic protein were detected in infectious skin diseases such as ectoparasitosis and larva migrans. Further, we observed the extracellular DNA structures in allergic/reactive diseases (Wells syndrome, hypereosinophilic syndrome, positive reaction of atopy patch test, allergic contact dermatitis, drug hypersensitivity) and in autoimmune diseases (bullous pemphigoid, pemphigus foliaceus, dermatitis herpetiformis). The average number of eosinophils releasing DNA in the skin was usually below 10%, although in Wells syndrome the proportion was up to 30%. In areas with clusters of eosinophils, up to 50% of the eosinophils were seen to generate eosinophil extracellular traps. Conclusion Eosinophil extracellular traps are seen in both infectious and noninfectious inflammatory skin diseases and are particularly common in Wells syndrome.
Background Atopic eczema (AE) is a chronic inflammatory skin disorder characterized by eczematous skin lesions, pruritus, and typical histopathologic features. Objective We asked whether depletion of ...B cells by monoclonal anti-CD20 antibody therapy (rituximab) would improve severe AE. Methods Six patients (4 women and 2 men) with severe AE received 2 intravenous applications of rituximab, each 1000 mg, 2 weeks apart. To evaluate the efficacy of rituximab, we monitored clinical parameters (eczema area and severity index, pruritus), total and allergen-specific IgE levels, skin histology, and inflammatory cells and cytokine expression in the skin and peripheral blood before and after therapy (ClinicalTrials.gov Identifier: NCT00267826). Results All patients showed an improvement of their skin symptoms within 4 to 8 weeks. The eczema area and severity index significantly decreased (before therapy, 29.4 ± 4.3; week 8, 8.4 ± 3.6; P < .001). Histologic alterations such as spongiosis, acanthosis, and dermal infiltrate, including T and B cell numbers, also dramatically improved. However, whereas blood B cells were below detectable levels as a consequence of rituximab administration, skin B cells were reduced by approximately 50% only. Expression of IL-5 and IL-13 was reduced after therapy. Moreover, whereas allergen-specific IgE levels were not altered, we observed a slight reduction in total IgE concentrations in blood. Conclusions B cells play a major role in AE pathogenesis. Treatment with an anti-CD20 antibody leads to an impressive improvement of AE in patients with severe disease.
Eosinophilic inflammatory responses occur in association with multiple disorders. Although the initial cause and the affected organs vary among the different eosinophilic disorders, there are only 2 ...major pathways that mediate eosinophilia: (1) cytokine-mediated increased differentiation and survival of eosinophils (extrinsic eosinophilic disorders), and (2) mutation-mediated clonal expansion of eosinophils (intrinsic eosinophilic disorders). Independent from the original trigger, the most common cause of eosinophilia is the increased generation of IL-5–producing T cells. In some cases, tumor cells are the source of eosinophil hematopoietins. The intrinsic eosinophilic disorders are characterized by mutations in pluripotent or multipotent hematopoietic stem cells leading to chronic myeloid leukemias with eosinophils as part of the clone. Here, we propose a new classification of eosinophilic disorders on the basis of these obvious pathogenic differences between the 2 groups of patients. We then discuss many known eosinophilic disorders, which can be further subdivided by differences in T-cell activation mechanisms, origin of the cytokine-producing tumor cell, or potency of the mutated stem cell. Interestingly, many subgroups of patients originally thought to have the idiopathic hypereosinophilic syndrome can be integrated in this classification.
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.
Eosinophils are multifunctional leukocytes that increase in various tissues in patients with a variety of disorders. Locally, they can be involved in the initiation and propagation of diverse ...inflammatory responses. In this review the clinical association of eosinophils with diseases of the skin, lung, and gastrointestinal tract is summarized. An approach to determining the causal role of eosinophils in these diseases is presented. Recent findings concerning molecular diagnosis, cause, and treatment are discussed.
Eosinophilia in Dermatologic Disorders de Graauw, Elisabeth; Beltraminelli, Helmut; Simon, Hans-Uwe ...
Immunology and allergy clinics of North America,
08/2015, Letnik:
35, Številka:
3
Journal Article
Recenzirano
Eosinophil infiltration can be observed in skin disorders, such as allergic/immunologic, autoimmune, infectious, and neoplastic diseases. Clinical presentations are variable and include eczematous, ...papular, urticarial, bullous, nodular, and fibrotic lesions; pruritus is a common symptom in all. In this review, we present representative eosinophilic skin diseases according to their clinical pattern, together with histologic findings and diagnostic procedures. We also discuss the potential roles of eosinophils in the pathogenesis of dermatologic disorder. Current pathogenesis-based diagnostic and therapeutic approaches are outlined.
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.
In parallel, the pruritus (patient assessment: 0, no; 1, mild; 2, moderate; and 3, severe) significantly decreased (2.5 ± 0.17 before therapy, 0.85 ± 0.18 at week 12, and 1.05 ±0.19 at week 22; P ...< .001). ...with the improvement of the skin lesions, all patients could drastically reduce the application of concomitant medication. Alefacept therapy had no effect on the spontaneous cytokine production of PBMCs, but on stimulation with anti-CD3 mAb, we observed a significant decrease in the production of IL-4 (P = .009), IL-5 (P = .012), and IL-13 (P = .043), indicating reduced numbers of TH2 effector memory cells in the blood. ...the production of IFN-γ after LPS stimulation decreased with alefacept therapy (P = .027).
Abstract Background Eosinophils are a subset of granulocytes which can be involved in the pathogenesis of different diseases, including allergy. Their effector functions are closely linked to their ...cytotoxic granule proteins. The release takes place by several different mechanisms, one of which is cytolysis, which is associated with the release of intact granules, so-called clusters of free eosinophil granules. The mechanism underlying this activation-induced form of cell death in eosinophils has remained unclear. Objective We aimed to elucidate the molecular mechanism of eosinophil cytolysis. Methods Isolated blood eosinophils were incubated on glass cover slips coated with intravenous immunoglobulin (IVIG) and inactive complement component 3b (iC3b). A morphological characterization of the distinct stages of the proposed cascade was addressed by means of time-lapse automated fluorescence microscopy, electron microscopy, and immunohistochemistry. Experiments with pharmacological inhibitors were performed to elucidate the sequence of events within the cascade. Tissue samples of patients suffering from eosinophilic skin diseases or eosinophilic esophagitis were used for in vivo analyses. Results Following eosinophil adhesion, we observed reactive oxygen species (ROS) production, early degranulation, and granule fusion processes leading to a distinct morphology exhibiting cytoplasmic vacuolization and, finally, to cytolysis. Using a pharmacological approach, we demonstrate the presence of a receptor-interacting protein kinase 3 (RIPK3) – mixed lineage kinase-like (MLKL) signaling pathway in eosinophils, which, following its activation, leads to the production of high levels of reactive oxygen species (ROS) in a p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3’-kinase (PI3K) - dependent manner. All these steps are required for cytoplasmic vacuolization and subsequent cytolysis to occur. Interestingly, triggering cytolysis is associated with an induction of autophagy in eosinophils and additional stimulation of autophagy by pharmacological inhibition of the mechanistic target of rapamycin (mTOR) counter-regulates cell death. Moreover, MLKL phosphorylation, cytoplasmic vacuolization, and cytolysis were observed in eosinophils under in vivo inflammatory conditions. Conclusion We report that adhesion-induced eosinophil cytolysis takes place by a RIPK3-MLKL-dependent necroptosis which can be counter-regulated by autophagy. The receptor-interacting protein kinase 3 (RIPK3) - mixed lineage kinase-like (MLKL) signaling pathway mediates eosinophil cytolysis, a phenomenon often observed in eosinophilic tissues of patients suffering from diseases with eosinophil-mediated immunopathology.
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