News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2018)

IL-33 promotes allergy by activating a plethora of innate and adaptive immune cells. Building on previous work showing that IL-33 is processed into mature forms with increased activity by extracellular proteases derived from neutrophils or mast cells, Cayrol et al (Nat Immunol 2018;19:75-385; https://doi.org/10.1038/s41590-018-0067-5) identified that proteases present in environmental allergens, such as pollen, house dust mite, fungi, and bacteria, have this same capability. The cleavage sites overlapped with the previously identified sites for neutrophil- and mast cell–derived proteases and were all present in the same region of the IL-33 protein, termed the central sensor domain. Direct allergen-mediated processing of IL-33 was detected in vivo. Finally, administration of a novel antibody against the protease sensor domain prevented cleavage of full-length IL-33 and diminished aeroallergy induction in vivo. On the basis of these results, the authors propose that IL-33 senses protease activity present in common environmental allergens, and this protease-dependent response maximizes the activity of IL-33. We asked authors Corinne Cayrol, PhD, and Jean-Philippe Girard, PhD, of the University of Toulouse, Toulouse, France, to comment on the study. They write, “Genetic data suggest that small changes in IL-33 expression have a critical role in susceptibility to allergic diseases. We believe that regulation of the bioactive forms of IL-33 by allergen proteases is equally important. This IL-33–based protease-sensing mechanism could play an important role in the initiation and severity of asthma and allergic airway disease.” Early-life viral infections are associated with development of recurrent wheeze and asthma later in life, although the underlying mechanisms remain incompletely understood because prior studies have focused on the contribution of individual cytokines. Turi et al (Am J Respir Crit Care Med 2018; https://doi.org/10.1164/rccm.201711-2348OC) characterized immune response profiles in nasal washes from a prospective birth cohort of healthy infants with first-time infection with respiratory syncytial virus (RSV) or human rhinovirus (HRV). Infection with either RSV or HRV induced 2 distinct immune response profiles within the cohort. The profile characterized by lower levels of noninterferon antiviral mediators and increased levels of both type 2 and type 17 cytokines after infection with RSV, but not HRV, was associated with increased risk for recurrent wheeze at age 1 and 2 years. Finally, topological network analysis revealed that production of type 2 and type 17 cytokines were central to the nasal immune response to RSV, whereas the immune response to HRV was driven by growth factors and chemokines. The authors have identified a novel RSV-induced nasal immune response profile that is associated with later onset of recurrent wheeze and might help explain how RSV infection predisposes to later development of asthma. The study was funded by the National Institutes of Health/National Institute of Allergy and Infectious Diseases. Figure used with Creative Commons BY-SA 2.0 license by user Yale Rosen: https://secure.flickr.com/photos/pulmonary_pathology/ Yale Rosen (Yale Rosen collection) [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons. We asked authors Tina Hartert, MD, MPH, and Kedir Turi, PhD, of Vanderbilt University Medical Center, Nashville, Tennessee, to comment on the study. They write, “This study of the infant nasal immune response profile to first infection with RSV characterizes a host and viral subgroup in which there is an inadequate immune response to RSV and a stronger type 2 response that identifies those with recurrent wheeze. Defining patterns of host and viral immune response to infection advances our understanding not only of acute viral pathogenicity but also of the pathways through which systemic immunity develops to RSV and how RSV contributes to asthma development. The Global Initiative for Obstructive Lung Disease criteria recommend inhaled triple therapy, which consists of inhaled corticosteroids, long-acting muscarinic antagonists (LAMAs), and long-acting β-agonists (LABAs) as a step up from dual bronchodilator therapy (either inhaled glucocorticoid-LABA or LAMA-LABA) in patients with severe chronic obstructive pulmonary disease (COPD) and frequent exacerbations. Two recently published studies were conducted to strengthen the evidence underlying this recommendation. Lipson et al (N Engl J Med 2018;378:1671-80; https://doi.org/10.1056/NEJMoa1713901) performed a randomized trial (IMPACT) involving 10,355 subjects with symptomatic COPD and a history of exacerbation within the previous year. Using an Ellipta inhaler, patients received daily inhaled triple therapy (fluticasone furoate, umeclidinium, and vilanterol), inhaled glucocorticoid-LABA (fluticasone furoate–vilanterol), or LAMA-LABA (umeclidinium-vilanterol) for 52 weeks. Triple therapy statistically significantly decreased the rate of moderate or severe exacerbations (0.91 per year) compared with inhaled glucocorticoid-LABA (1.07 per year, P < .001) or LAMA-LABA (1.21 per year, P < .001). However, triple therapy with Ellipta increased risk for pneumonia. In the second study Papi et al (Lancet 2018;391:1076-84; https://doi.org/10.1016/S0140-6736(18)30206-X) compared triple inhaled therapy (beclomethasone dipropionate, glycopyrronium, and formoterol fumarate) with dual therapy with a LABA (indacaterol) and LAMA (glycopyrronium) in a randomized, parallel-group, double-blind, double-dummy study of 1532 subjects (TRIBUTE study). Patients with severe symptomatic COPD and at least 1 exacerbation within the past year were randomized to receive 52 weeks of twice-daily triple inhaled therapy or once-daily dual bronchodilator. Triple inhaled therapy modestly decreased the rate of moderate and severe exacerbations (0.50 vs 0.59 per year, P = .043). Notably, triple inhaled therapy with this combination was not associated with an increased risk of pneumonia. The findings of these 2 trials support use of triple inhaled therapy to prevent COPD exacerbations in patients with severe COPD in whom dual bronchodilator therapy fails. Figure shared under Creative Commons BY-SA 3.0 license, by user James Heilman, MD [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], from Wikimedia Commons.Triple inhaled therapy to prevent COPD exacerbations in patients with severe COPD in whom dual bronchodilator therapy fails Triple inhaled therapy to prevent COPD exacerbations in patients with severe COPD in whom dual bronchodilator therapy fails The stratification of asthma into distinct endotypes has led to more effective treatments for subsets of patients, such as anti–IL-5 biologics for patients with eosinophilic asthma. However, no such disease endotypes have been described for eosinophilic esophagitis (EoE). Shoda et al (Lancet Gastroenterol Hepatol 2018;3: 477-88; https://doi.org/10.1016/S2468-1253(18)30096-7) used endoscopic and histologic scoring systems and a commercially available EoE diagnostic panel, which involves transcriptional profiling of esophageal biopsy specimens for 96 genes, to identify novel disease endotypes. Three clusters of patients with distinct transcriptional profiles and endotypes, termed EoEe1 to EoEe3, were identified in esophageal biopsy specimens from a discovery cohort of 86 patients with active EoE. Patients with EoEe1 exhibited relatively mild histologic, endoscopic, and transcriptional changes. Patients with EoEe2 had the highest degree of endoscopic and histologic inflammation and the highest expression of type 2 immune genes, such as IL4 and TSLP. EoEe3 was a fibrostenotic phenotype resulting in more furrows and edema. These 3 endotypes were also present in an independent validation cohort of 100 patients. Collectively, these results demonstrate the existence of distinct endotypes in patients with EoE. Enhanced understanding of the clinical significance of these endotypes might lead to the development of more targeted and effective treatments. We asked author Dr Tetsuo Shoda, MD, PhD, of the Cincinnati Children’s Hospital Medical Center, Cincinnati, United States, about the study. He writes, “Our study uncovered 3 distinct subtypes of EoE (endotypes) with different clinical and molecular features. However, this is not the end. We hope these finding will allow for developing personalized and precision therapy for specific EoE subpopulations.”News items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.