IL-33–Dependent Type 2 Inflammation during Rhinovirus-induced Asthma Exacerbations In Vivo
15 Dec 2014-American Journal of Respiratory and Critical Care Medicine (American Thoracic Society)-Vol. 190, Iss: 12, pp 1373-1382
TL;DR: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo and relate to exacerbation severity, which is a novel therapeutic approach for asthma exacerbations.
Abstract: Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays ...
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TL;DR: 15 years of discoveries on IL‐33 protein are highlighted, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases.
Abstract: Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8+ T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.
504 citations
TL;DR: The cytokine networks driving asthma are reviewed, placing these in cellular context and incorporating insights from cytokine-targeting therapies in the clinic, to argue that the development of new and improved therapeutics will require understanding the diverse mechanisms underlying the spectrum of asthma pathologies.
501 citations
TL;DR: To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5), a large number of patients with severe, eosinophilic asthma were enrolled in 81 multinational centers.
Abstract: ID Pavord, S Korn, P Howarth. Lancet. 2012;380(9842):651–659
To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5). Previous small, proof-of-concept studies in subjects with severe, eosinophilic asthma revealed that mepolizumab decreased exacerbation rates.
From 81 multinational centers, 621 pa-tients were enrolled. Major inclusion criteria included: age 12 to 74 years, asthma diagnosis with objective measures, ≥2 asthma exacerbations requiring oral corticosteroids in the last year, refractory asthma as defined by the American …
387 citations
TL;DR: This article attempts to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.
Abstract: SUMMARY Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.
332 citations
Cites background from "IL-33–Dependent Type 2 Inflammation..."
...models of infection, such as rhinovirus-induced asthma exacerbations that have been reported (41) (Fig....
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...Most notable is the recent discovery of the RSV-induced interleukin 33 (IL-33)–IL-13 axis that may potentiate the development of long-term hyperreactivity in the airway (41, 42), which we discuss below in more detail in “A Causal Link between RSV Infection and Asthma....
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TL;DR: Evidence is reviewed of how air pollutants can affect different immune cell types such as particle-clearing macrophages, inflammatory neutrophils, dendritic cells that orchestrate adaptive immune responses and lymphocytes that enact those responses, and of the capacity of air pollutants to stimulate pro-inflammatory immune responses across multiple classes of immune cell.
284 citations
References
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TL;DR: The identification and functional characterization of a new innate type-2 immune effector leukocyte that is named the nuocyte is presented, which represents a critically important innate effector cell in type- 2 immunity.
Abstract: Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity-responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma-consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity.
1,896 citations
TL;DR: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.
Abstract: Objective: To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. Design: Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. Subjects: 108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. Setting: Southampton and surrounding community. Main outcome measures: Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. Results: Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 1/min. The most commonly identified virus type was rhinovirus. Conclusions: This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children. Key messages Key messages In this study common cold viruses were found in 80-85% of reported exacerbations of asthma in children Rhinoviruses, which cause most common colds, accounted for two thirds of viruses detected Analysis of diary cards also showed large numbers of similar but less severe episodes that may also be viral in origin
1,889 citations
TL;DR: Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma.
1,765 citations
TL;DR: A few common alleles are associated with disease risk at all ages and suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation in asthma.
Abstract: A b s t r ac t Background Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. Methods We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. Results We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P =3×10 −9 ); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7×10 −14 ); rs1342326 on chromosome 9, flanking IL33 (P = 9×10 −10 ); rs744910 on chromosome 15 in SMAD3 (P = 4×10 −9 ); and rs2284033 on chromosome 22 in IL2RB (P = 1.1×10 −8 ). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6×10 −23 ). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. Conclusions Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
1,764 citations
"IL-33–Dependent Type 2 Inflammation..." refers background in this paper
...Polymorphisms in IL-33 and its receptor are associated with increased risk of asthma (17)....
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TL;DR: The results of this study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population.
Abstract: BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)
1,674 citations
"IL-33–Dependent Type 2 Inflammation..." refers background in this paper
...It is also unknown whether respiratory viral infection in asthma leads to amplification of type 2 inflammation in vivo, as measuring type 2 cytokines in human airway samples is difficult, leading to reliance upon indirect measures such as RNA levels (20), eosinophils (for IL-5) (5, 6), or periostin (for IL-13) (7)....
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...Recent trials of anti-IgE (31), anti–IL-4 (4), anti–IL-5 (5, 6, 8), and anti–IL-13 (7) therapies have shown the potential of blocking individual type 2 molecules to reduce asthma exacerbations....
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