News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2019)

Polymorphisms at the orosomucoid-like 3 (ORMDL3) locus confer genetic susceptibility to childhood-onset asthma and human rhinovirus–induced exacerbations. The ORMDL3 gene product is a known regulator of de novo sphingolipid synthesis, but the mechanisms underlying its genetic association with asthma risk are not well understood. Zhang et al (Am J Respir Crit Care Med 2018; https://doi.org/10.1164/rccm.201803-0438OC) characterized pleiotropic effects of this protein on the responses of lung epithelial cells to IL-1β stimulation. On ORMDL3 gene silencing, the authors observed dysregulated expression of genes involved in stress responses, host-pathogen interactions, and ubiquitination. Notably, loss of expression of ORMDL3 decreased the expression of proinflammatory cytokines and ICAM1, a known receptor for human rhinovirus. Additionally, ORMDL3 gene silencing altered levels of metabolites integral to glycolysis and increased levels of the bioactive lipids ceramides and sphinosine-1-phosphate. The authors conclude that ORMDL3 exerts diverse effects on lung epithelial cells that likely underlie its genetic association with asthma and propose that ORMDL3-regulated pathways are potential therapeutic targets in childhood-onset asthma.ORMDL3 exerts diverse effects on lung epithelial cells that likely underlie its genetic association with asthma ORMDL3 exerts diverse effects on lung epithelial cells that likely underlie its genetic association with asthma We asked author Youming Zhang, MB, DPhil, at Imperial College London, London, United Kingdom, to comment on the study. He writes, “Our study reveals the depth of mechanisms for ORMDL3 modulation of inflammation in epithelial cells. These include cellular stress responses and glycolysis, as well as modifiers of viral and bacterial infection. The results will allow us to identify novel therapeutic targets for severe asthma.” IL-13 is well recognized as a principal driver of the pathogenesis of eosinophilic esophagitis (EoE) and is a prime target for therapeutic manipulation. Hirano et al (Gastroenterology 2018; https://doi.org/10.1053/j.gastro.2018.10.051) performed a multicenter, phase 2, randomized controlled trial (HEROES) to assess the efficacy of RPC4046, a recombinant mAb directed against IL-13, in adults with active EoE. Ninety-nine subjects were randomized to receive RPC4046 or placebo once a week for 16 weeks. RPC4046 decreased mean esophageal eosinophil counts compared with placebo (P < .0001). Compared with placebo, subjects in the high-dose RPC4046 group exhibited decreased disease severity, as determined based on endoscopic, histologic, and clinical global assessments. Overall, these results indicate that RPC4046 decreases disease severity in patients with EoE and provide a strong rationale for further investigation into anti–IL-13 as a treatment for this disease. Image attribution: Figure by user Nephron [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) from Wikimedia Commons.RPC4046 decreases disease severity in patients with EoE RPC4046 decreases disease severity in patients with EoE We asked author Evan Dellon, MD, MPH, of the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, to comment on the study. He writes, “This medication is very promising because it targets one of the key cytokines in EoE pathogenesis. It was effective for decreasing esophageal eosinophil counts (the primary end point for the study) and esophageal endoscopic severity. Patients’ symptoms also improved, and although this finding was not statistically significant, there was a strong trend, and the study was not powered for a symptom outcome. Importantly, the medication was also well tolerated. Taken together, these results merit ongoing study of RPC4046 in a more definitive phase 3 trial. Achieving desensitization through oral immunotherapy with repeated escalating doses of allergen is a promising potential therapeutic strategy for patients with peanut allergy. Vickery et al (N Engl J Med 2018;379:1991-2001; https://doi.org/10.1056/NEJMoa1812856) performed a phase 3, double-blind, randomized, placebo-controlled trial (PALISADE) to evaluate the efficacy of oral immunotherapy with AR101, a preparation of defatted peanut flour, in patients with a history of peanut allergy, including those with previously severe reactions. Five hundred fifty-one subjects (496 pediatric and 55 adult subjects) had an allergic reaction at or before the 100 mg dose of peanut protein (approximately one-third of a single peanut) during a food challenge at screening and were randomized to receive AR101 or placebo daily, with escalating doses until a 24-week maintenance phase with 300 mg. At the end of the study, an exit food challenge was performed. Treatment with AR101 increased the proportion of patients able to tolerate ingestion of at least 600 mg of peanut protein compared with placebo in pediatric subjects (67% vs 4%, P < .001), but no statistically significant difference was identified among adult patients. The AR101 treatment group also showed a lower rate of severe symptoms during the exit challenge compared with the placebo group. Adverse events were common in both groups, but compared to placebo, the subjects in the AR101 treatment group more commonly had adverse events affecting the skin, GI tract, and respiratory tract and 14% experienced systemic allergic reactions. Collectively, these findings show that AR101 induces desensitization in pediatric patients with severe peanut allergy, but that this efficacy is associated with an allergic adverse event profile typical of oral immunotherapy.AR101 induces desensitization in pediatric patients with peanut allergy AR101 induces desensitization in pediatric patients with peanut allergy Exposure of IgE-sensitized mast cells (MCs) to circulating allergens within the bloodstream triggers anaphylactic reactions, although the mechanism by which extravascular MCs sense circulatory allergens is unclear. Choi et al (Science 2018;362; https://doi.org/10.1126/science.aao0666) have recently elucidated a critical role for perivascular CD301b+ dendritic cells (DCs) in facilitating this process. This specific DC population resides in the perivascular space–lining dermal blood vessels and entraps circulating antigens through dendrites that penetrate the endothelial wall. These cell surface–bound antigens are subsequently released on the surfaces of microvesicles to neighboring immune cells, including MCs. Shedding of microvesicles by DCs involves the action of vacuolar protein sorting–associated protein 4 (VPS4). Contact of allergen-containing microvesicles with IgE-bound MCs in the perivascular space results in MC degranulation, and when this occurs simultaneously all along the vasculature, anaphylaxis follows. In total, the authors have identified that early sampling of circulatory allergens and microvesicle formation by DCs leads to MC degranulation, a process that might serve as a future target for prevention of anaphylaxis.Sampling of circulatory allergens and microvesicle formation by DCs leads to mast cell degranulationHae Woong ChoiView Large Image Figure ViewerDownload Hi-res image Download (PPT) Sampling of circulatory allergens and microvesicle formation by DCs leads to mast cell degranulation We asked first author Hae Woong Choi, PhD, of Duke University Medical Center, Durham, North Carolina, to comment on the study. He writes, “Perivascular DCs continuously sample the borne allergens and then shuttle these antigens to neighboring perivascular MCs, resulting in MC degranulation. When these events occur simultaneously throughout the vasculature, anaphylaxis results.”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.