News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2021)

Long-lived resident connective tissue mast cells (CTMCs) and mucosal mast cells (MMCs), which are recruited to mucosal tissues during type 2 inflammation, have primarily been studied histologically. Derakhshan et al (J Exp Med 2021;218:e20200321; https://doi.org/10.1084/jem.20200321) identified distinct roles for these mast cell populations in type 2 immunity. During airway allergic inflammation, constitutive CTMCs, characterized by low expression of the integrin β7, remained static. In contrast, MMCs, which highly expressed β7, markedly expanded and matured with induction of a distinct inflammatory transcriptional program. Overall, this study has furthered our understanding of the differences between these 2 distinct murine mast cell lineages and identified inducible MMCs as a potential therapeutic target in the prevention of mast cell allergic responses. We asked senior author Daniel Dwyer, PhD, of the Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, to comment on the study. He writes, “We noted distinct transcriptional signatures associated with constitutive and inflammation-induced mast cells, which tells us that protease expression profiles are just the tip of the iceberg in what separates these 2 lineages. Our findings also build on prior studies that suggest an active role for structural cells in regulating mast cell maturation and function.” Utilizing a birth cohort, Depner et al (Nat Med 2020;26:1766-75; https://doi.org/10.1038/s41591-020-1095-x) examined how changes in gut microbiota composition during the first year of life mediate the poorly understood association between growing up on a farm and protection from asthma. Previous farm exposure decreased the risk of childhood asthma as compared to non-farm rural children, and alterations in the gut microbiome mediated approximately 20% of this protective effect. Asthma protection was associated with increased levels of fecal butyrate, and abundance of bacterial taxa that produce butyrate and of an enzyme critical to butyrate metabolism. Collectively, these results demonstrate how the maturation of the gut microbiome through the first year of life protects against childhood asthma and is likely mediated at least in part through enhanced butyrate production. (Figure reproduced under Creative Commons license CC BY 4.0, attribution: DataBase Center for Life Science (DBCLS), CC BY 4.0 https://creativecommons.org/licenses/by/4.0, via Wikimedia Commons.) We asked senior author Markus J. Ege, MD, MA, MPH, of the Institute for Asthma and Allergy Prevention, Helmholtz Zentrum Munich and the German Research Center for Environmental Health, Neuherberg, Germany, to comment on the study. He writes, “We were surprised by the rather large proportion of the well-known farm effect on childhood onset asthma that was mediated by the maturation of the gut microbiome. It will be exciting to study the cross-maturation of the microbiome and the mucosal immunity in the gut but also at other mucosal surfaces such as the upper and lower airways” Because there currently are no FDA-approved therapies for eosinophilic gastritis or duodenitis, Dellon et al (N Engl J Med 2020;383:1624-34; https://doi.org/10.1056/NEJMoa2012047) performed a phase 2 placebo-controlled randomized controlled trial to assess the efficacy of AK002, an anti-Siglec-8 mAb that selectively depletes eosinophils and prevents mast cell activation. Treatment with AK002 reduced tissue eosinophil counts and improved symptom control. Notably, symptomatic improvement was observed within a week of treatment initiation and persisted throughout the course of the 4-month trial. In total, this study identifies AK002 as a promising treatment for eosinophilic gastritis and duodenitis, though longer-term studies are still required. We asked first author Evan Dellon, MD, MPH, of the University of North Carolina, Chapel Hill, North Carolina, to comment on the study. He writes, “This study is important for several reasons. It’s the first randomized trial in eosinophilic gastritis/duodenitis, which are understudied conditions for which there is a pressing need for new patient treatments. Second, the medication has a novel mechanism of action via the Siglec-8 receptor, and this study now shows proof of concept in eosinophilic gastrointestinal diseases (EGID) of the utility of targeting this pathway. Finally, the results demonstrate efficacy. Patients not only had prominent decreases in their tissue eosinophil counts, but also had a substantial symptom improvement compared to placebo. Given the promising results, the medication has moved on to a phase 3 study in EG/EoD and a phase 2/3 study in eosinophilic esophagitis (EoE).” Intravenous magnesium improves respiratory status and decreases hospitalizations in pediatric acute asthma but has a significant side effect profile, including hypotension. Because administration of magnesium through nebulization is noninvasive and reduces systemic exposure, Schuh et al (JAMA 2020;324:2038-47; https://doi.org/10.1001/jama.2020.19839) performed a randomized controlled trial examining its effectiveness in pediatric patients who presented to the emergency department with acute asthma attack. Addition of nebulized magnesium to ongoing albuterol treatment did not significantly reduce hospitalization rate or improve respiratory status as compared to addition of placebo. These results do not support the use of nebulized magnesium in pediatric patients with acute asthma. (Figure reproduced under Creative Commons license CC-BY_SA 4.0, attribution: user BruceBlaus https://creativecommons.org/licenses/by/4.0, via Wikimedia Commons.) We asked first author Suzanne Schuh, MD, of the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada, to comment on the study. She writes, “Intravenous administration of magnesium sulfate in children with refractory acute asthma in the emergency department is invasive and carries a risk of hypotension. This has led to recent interest in examining the benefit of inhaled magnesium, with an expected favorable safety profile. In this randomized clinical trial, 3 treatments with a high dose of magnesium sulfate plus albuterol delivered via a highly efficient pre-tested nebulizer in children remaining in moderate-to-severe respiratory distress despite optimized initial therapy provided no additional hospitalization or clinical benefit compared to placebo plus albuterol.” Two recent landmark trials of translational science have been performed that illustrate the exciting potential of gene therapy in the treatment of genetic diseases. Both studies targeted the BCL11A gene, which encodes a known inhibitor of Hemoglobin F production, for treatment of sickle cell disease. Esrick et al (N Engl J Med 2020 Dec 5; https://doi.org/10.1056/nejmoa2029392) utilized a gene silencing strategy using RNA interference technology. Hematopoietic stem cells were transduced with a lentiviral vector expressing a short hairpin RNA (shRNA) that inhibited erythrocyte-specific expression of BCL11A. Frangoul et al (N Engl J Med 2020 Dec 5; https://doi.org/10.1056/nejmoa2031054) utilized CRISPR-Cas9 gene editing to alter a BCL11A erythroid enhancer in hematopoietic stem cells. In both studies, infusion of these edited hematopoietic stem cells led to robust induction of Hemoglobin F and improved disease control. It will be of great interest in the future to apply these cutting-edge techniques for the treatment of allergic and immune-related diseases.News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.