Background Omalizumab treatment suppresses FcϵRI expression faster on blood basophils than skin mast cells. Objective We used omalizumab to elucidate the relative contributions of basophil versus ...mast cell FcϵRI activation in a nasal allergen challenge (NAC) model. Methods Eighteen subjects with cat allergy were enrolled in a 3.5-month, double-blind, randomized (3.5:1), placebo-controlled trial of omalizumab using standard dosing. At baseline, subjects underwent NAC with lavage for prostaglandin D2 measurement, skin prick test titration (SPTT), and blood sampling for basophil histamine release (BHR) and basophil IgE/FcϵRI measurements. Basophil studies were repeated at day 3 and then weekly until cat allergen–induced BHR was <20% of baseline or until day 45. Baseline visit procedures were repeated after the BHR reduction (midstudy NAC) and at the treatment period's completion (final NAC). Results Subjects treated with omalizumab who completed all NACs (n = 12) demonstrated significant mean reduction in BHR to an optimal dose of cat allergen by midstudy NAC compared with baseline (74% decrease; P = .001). In addition, these subjects demonstrated significant decreases in mean combined nasal symptom scores (50% decrease; P = .007) and total sneeze counts (59% decrease; P = .01) by midstudy NAC relative to baseline NAC. In contrast, measures of mast cell response (SPTT and nasal lavage prostaglandin D2 ) were only significantly reduced by the final NAC. Subjects on placebo (n = 4) did not experience a shift in basophil, NAC symptom, or mast cell measures. Conclusion Reduction in nasal symptom scores occurred when the basophil, but not mast cell, response was reduced on omalizumab, implicating a role for basophils in the acute NAC response.
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.
Virtually all cells and extracellular material are heavily decorated by various glycans, yet our understanding of the structure and function of these moieties lags behind the understanding of nucleic ...acids, lipids, and proteins. Recent years have seen a tremendous acceleration of knowledge in the field of glycobiology, revealing many intricacies and functional contributions that were previously poorly appreciated or even unrecognized. This review highlights several topics relevant to glycoimmunology in which mammalian and pathogen-derived glycans displayed on glycoproteins and other scaffolds are recognized by specific glycan-binding proteins (GBPs), leading to a variety of proinflammatory and anti-inflammatory cellular responses. The focus for this review is mainly on 2 families of GBPs, sialic acid–binding immunoglobulin-like lectins (siglecs) and selectins, that are involved in multiple steps of the immune response, including distinguishing pathogens from self, cell trafficking to sites of inflammation, fine-tuning of immune responses leading to activation or tolerance, and regulation of cell survival. Importantly for the clinician, accelerated rates of discovery in the field of glycoimmunology are being translated into innovative medical approaches that harness the interaction of glycans and GBPs to the benefit of the host and might soon lead to novel diagnostics and therapeutics.
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.
Background Sialic acid–binding immunoglobulin-like lectin (Siglec)-8 is expressed on human eosinophils, where its ligation induces cell death. Paradoxically, Siglec-8–mediated cell death is markedly ...enhanced by the presence of the activation and survival factor IL-5 and becomes independent of caspase activity. Objective In this report we investigate the mechanism of Siglec-8–mediated cell death in activated eosinophils. Methods Human peripheral blood eosinophils were treated with agonistic anti–Siglec-8 antibody and IL-5, and cell death was determined by using flow cytometry and morphology. Phosphorylation of mitogen-activated protein kinase (MAPK) was determined by using phosphoLuminex, flow cytometry, and Western blotting. Reactive oxygen species (ROS) accumulation was determined by using dihydrorhodamine fluorescence. Results Costimulation with anti–Siglec-8 and IL-5 significantly increased the rate and proportion of cell death by means of necrosis accompanied by granule release compared with that seen after stimulation with anti–Siglec-8 alone, in which apoptosis predominated. Together with the caspase-independent mode of cell death in costimulated cells, these findings suggest the activation of a specific and distinct biochemical pathway of cell death during anti–Siglec-8/IL-5 costimulation. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and MAPK-ERK kinase (MEK) 1 was significantly enhanced and sustained in costimulated cells compared with that seen in cells stimulated with IL-5 alone; anti–Siglec-8 alone did not cause ERK1/2 phosphorylation. MEK1 inhibitors blocked anti–Siglec-8/IL-5–induced cell death. ROS accumulation was induced by Siglec-8 ligation in a MEK-independent manner. In contrast, an ROS inhibitor prevented the anti–Siglec-8/IL-5–induced enhancement of ERK phosphorylation and cell death. Exogenous ROS mimicked stimulation by anti–Siglec-8 and was sufficient to induce enhanced cell death in IL-5–treated cells. Collectively, these data suggest that the enhancement of ERK phosphorylation is downstream of ROS generation. Conclusions In activated eosinophils ligation of Siglec-8 leads to ROS-dependent enhancement of IL-5–induced ERK phosphorylation, which results in a novel mode of biochemically regulated eosinophil cell death.
Conclusions These results demonstrate an elevation of epithelial, endothelial and eosinophil MPs, along with a trend toward increased levels of mast cell MP, in CRS patients, and support previous ...findings of activation of these cells in CRS.
Background Microparticles (MPs) are submicron-sized shed membrane vesicles released from activated or injured cells and are detectable by flow cytometry. MP levels have been used as biomarkers to ...evaluate cell injury or activation in patients with pathological conditions. Objective We sought to compare MP types and levels in nasal lavage fluids (NLFs) from controls and patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). Methods We collected NLFs from patients with CRSsNP (n = 33), CRSwNP (n = 45), and AERD (n = 31) and control (n = 24) subjects. Standardized flow cytometry methods were used to characterize the following MP types: endothelial MPs, epithelial MPs (epithelial cell adhesion molecule EpCAM(+)MPs, E-cadherin(+)MPs), platelet MPs (CD31(+)CD41(+)MPs), eosinophil MPs (EGF-like module-containing mucin-like hormone receptor-like 1EMR1(+)MPs), mast cell MPs (high-affinity IgE receptor FcεRI(+)c-kit(+)MPs), and basophil MPs (CD203c(+)c-kit(−)MPs). Basophil activation was evaluated by the mean fluorescence intensity of CD203c on basophil MPs. Results Activated mast cell MPs (CD137(+) FcεRI(+)c-kit(+)MPs) were significantly increased in NLFs of controls compared with NLFs of patients with CRSsNP (2.3-fold; P < .02), CRSwNP (2.3-fold; P < .03), and AERD (7.4-fold; P < .0001). Platelet MPs (3.5-fold; P < .01) and basophil MPs (2.5-fold; P < .05) were increased only in patients with AERD. Mean fluorescence intensity of CD203c on MPs was increased in patients with CRSwNP ( P < .002) and AERD ( P < .0001), but not in patients with CRSsNP. EpCAM(+)MPs in patients with CRSwNP were no different from control ( P = .91) and lower than those in patients with CRSsNP ( P < .02) and AERD ( P < .002). Conclusions Based on released MPs, mast cells, platelets, and basophils were more highly activated in patients with AERD than in patients with CRS. Epithelial injury was lower in patients with CRSwNP than in patients with CRSsNP and AERD. MP analysis may help identify phenotypes of CRS, and in distinguishing AERD from CRSwNP.
Background The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that ...harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. Objective We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. Methods We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. Results A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium–adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 × 10−5 ; odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. Conclusion These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting TH 2 responses.
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.
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