Patients with allergic rhinitis and allergic asthma share the same pattern of eosinophil and neutrophil degranulation after allergen challenge

<p>Abstract</p> <p>Background</p> <p>Patients with allergic rhinitis and allergic asthma demonstrate comparable local and systemic eosinophil inflammation, and yet they present with different clinical pictures. Less is even known about the contribution of neutrophil inflammation in allergic diseases. The aim of the study was to examine the propensity and selectivity of granule release from primed systemic eosinophils and neutrophils in allergic rhinitis and allergic asthma after seasonal and experimental allergen exposure. We hypothesize that the dissimilar clinical manifestations are due to diverse eosinophil and neutrophil degranulation.</p> <p>Methods</p> <p>Nine birch pollen allergic patients with rhinitis, eight with asthma and four controls were studied during pollen season and after nasal and bronchial allergen challenge. Eosinophils and neutrophils were incubated in vitro with assay buffer and opsonized Sephadex particles for spontaneous and C3b-induced granule protein release. The released amount of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) was measured by specific radioimmunoassay.</p> <p>Results</p> <p>C3b-induced degranulation resulted in increased release of ECP and MPO from primed blood eosinophils and neutrophils in both allergic rhinitis and allergic asthma during pollen season and after both nasal and bronchial challenge (p-values 0.008 to 0.043). After bronchial challenge, the ECP release was significantly higher in the rhinitic group compared to the asthmatic group [19.8 vs. 13.2%, (p = 0.010)]. The propensity for EPO release was weak in all challenge models but followed the same pattern in both allergic groups.</p> <p>Conclusions</p> <p>Systemically activated eosinophils and neutrophils have similar patterns of degranulation after allergen exposure in allergic rhinitis and allergic asthma. The released amount of ECP, EPO and MPO was similar in all allergen challenge models in both allergic groups. Our results indicate that other mechanisms than the magnitude of eosinophil and neutrophil inflammation or the degranulation pattern of the inflammatory cells determines whether or not an allergic patient develops asthma.</p

Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis

<p>Abstract</p> <p>Background</p> <p>The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation.</p> <p>Objective</p> <p>To examine whether a dual CCR3 and H₁-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis.</p> <p>Methods</p> <p>Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and α₂-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation.</p> <p>Results</p> <p>Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine.</p> <p>Conclusions</p> <p>AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.</p> <p>Trial registration</p> <p>EudraCT No: 2005-002805-21.</p

In vivo restitution of airway epithelium

Epithelial shedding occurs in health and, extensively, in inflammatory airway diseases. This study describes deepithelialisation, reepithelialisation and associated events in guinea-pig trachea after shedding-like epithelial denudation in vivo. Mechanical deepithelialisation of an 800-microns wide tracheal zone was carried out using an orotracheal steel probe without bleeding or damage to the basement membrane. Reepithelialisation was studied by scanning- and transmission electron microscopy and light microscopy. Nerve fibres were examined by immunostaining. Cell proliferation was analysed by [3H]-thymidine autoradiography. Immediately after epithelial removal secretory and ciliated (and presumably basal) epithelial cells at the wound margin dedifferentiated, flattened and migrated rapidly (2-3 microns/min) over the denuded basement membrane. Within 8-15 h a new, flattened epithelium covered the entire deepithelialised zone. At 30 h a tight epithelial barrier was established and after 5 days the epithelium was fully redifferentiated. After completed migration an increased mitotic activity occurred in the epithelium and in fibroblasts/smooth muscle beneath the restitution zone. Reinnervating intraepithelial calcitonin gene-related peptide-containing nerve fibres appeared within 30 h. We conclude that (1) reproducible shedding-like denudation, without bleeding or damage to the basement membrane, can be produced in vivo; (2) secretory and ciliated cells participate in reepithelialisation by dedifferentiation and migration; (3) the initial migration is very fast in vivo; (4) shedding-like denudation may cause strong secretory and exudative responses as well as proliferation of epithelium, and fibroblasts/smooth muscle. Rapid restitution of airway epithelium may depend on contributions from the microcirculation and innervation

IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive anti-viral immunity

BACKGROUND: Influenza virus triggers severe exacerbations of asthma for which no adequate treatment is available. It is known that IL-33 levels correlate with exacerbation severity, but its role in the immune-pathogenesis of exacerbations has remained elusive. OBJECTIVE: We hypothesized that IL-33 is necessary to drive asthma exacerbations. We intervened with the IL-33 cascade and sought to dissect its role, also in synergy with TSLP, in airway inflammation, anti-viral activity and lung function. We aimed to unveil the major source of IL-33 in the airways and IL-33-dependent mechanisms that underlie severe asthma exacerbation. METHODS: Mild asthmatic patients were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite (HDM) extract and then infected with influenza to resemble key features of exacerbations in humans. Interventions included anti-IL-33-receptor ST2 and/or anti-TSLP. RESULTS: We identified bronchial ciliated cells and Type-II alveolar cells as a major local source of IL-33 during virus-driven exacerbation in humans and mice, respectively. By blocking ST2 we demonstrated that IL-33 and not TSLP was necessary to drive exacerbations. IL-33 enhanced AHR and airway inflammation by suppressing innate and adaptive anti-viral responses and by instructing epithelial cells and dendritic cells (DCs) of HDM-sensitized mice to dampen IFN-β expression and prevent the Th1-promoting DCs phenotype. IL-33 also boosted luminal NETosis and halted cytolytic anti-viral activities, but did not affect the Th2-response. CONCLUSION: Interventions targeting the IL-33/ST2 axis could prove an effective acute, short-term therapy for virus-induced asthma exacerbation

Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers.

Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue‐residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue‐resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44− ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL‐13 when exposed to IL‐33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR‐3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment

Dopaminergic Regulation of Innate Immunity: a Review

Dopamine (DA) is a neurotransmitter in the central nervous system as well as in peripheral tissues. Emerging evidence however points to DA also as a key transmitter between the nervous system and the immune system as well as a mediator produced and released by immune cells themselves. Dopaminergic pathways have received so far extensive attention in the adaptive branch of the immune system, where they play a role in health and disease such as multiple sclerosis, rheumatoid arthritis, cancer, and Parkinson\ue2\u80\u99s disease. Comparatively little is known about DA and the innate immune response, although DA may affect innate immune system cells such as dendritic cells, macrophages, microglia, and neutrophils. The present review aims at providing a complete and exhaustive summary of currently available evidence about DA and innate immunity, and to become a reference for anyone potentially interested in the fields of immunology, neurosciences and pharmacology. A wide array of dopaminergic drugs is used in therapeutics for non-immune indications, such as Parkinson\ue2\u80\u99s disease, hyperprolactinemia, shock, hypertension, with a usually favorable therapeutic index, and they might be relatively easily repurposed for immune-mediated disease, thus leading to innovative treatments at low price, with benefit for patients as well as for the healthcare systems