News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2022)

In order to clarify the contributions of mast cells to severe asthma, Tiotiu et al (Am J Respir Crit Care Med 2021 Nov 23; https://doi.org/10.1164/rccm.202102-0355oc) assessed the presence of different mast cell activation transcriptional signatures in sputum samples obtained from subjects from the U-BIOPRED asthma cohort. Multiple mast cell signatures were enriched in subjects with asthma compared to control individuals. Notably, sputa from subjects with eosinophilic asthma exhibited enrichment in Fc epsilon RI (FcεRI)- IgE-stimulated mast cell signatures. Conversely, both IL-33- and bacterial lipopolysaccharides (LPS)-stimulated mast cell signatures were enriched in subjects with neutrophilic asthma. Overall, these results show that mast cells can be induced to take on distinct transcriptional phenotypes that reflect the local microenvironment and are associated with distinct endotype-specific activated mast cell phenotypes in severe asthma. We asked corresponding author Kian Fan Chung, MD, DSc, of the National Heart and Lung Institute, Imperial College London, United Kingdom, for comment. He writes, “This novel approach of identifying the level of activation of mast cells through their transcriptional signatures has confirmed the important contribution of the mast cell in driving either neutrophilic or eosinophilic asthma, dependent on the composition of its immediate environment. This has implications with regards to determining the endotypes and the delivery of precision medicine in severe asthma.” Mayer et al (Nat Immunol 2021;22:1538-50; https://doi.org/10.1038/s41590-021-01067-0) identified homeostatic factors regulating the development of type 2 dendritic cells (DC2s) in the skin. More specifically, the differentiation of dermis-specific CD11blo DCs required homeostatic STAT6-dependent IL-13 production by dermal innate lymphoid cells. In contrast, both lung- and small intestine-resident DCs were CD11bhi and did not require STAT6 activity. Finally, in the absence of homeostatic IL-13 signaling, dermal DC2s remained CD11bhi, with impaired activation after allergen exposure and skewing of naive CD4+ T cells to a TH17 rather than TH2 phenotype. Collectively, these findings demonstrate that steady-state IL-13 expression induces a noninflammatory, skin-specific niche that promotes both the differentiation of dermal DC2s and atopy. We asked corresponding author Franca Ronchese, PhD, of the Malaghan Institute of Medical Research in Wellington, New Zealand, to comment on the study. She writes, “We found that IL-13 is made in skin at steady state, independently of microbiota, IL-33, and TSLP, and conditions type 2 dendritic cells to foster TH2 responses. These observations may be relevant to the allergic march and help explain why skin barrier defects such as filaggrin deficiencies are associated with increased risk of all types of allergic disease, including airway and food allergy.” Bruton tyrosine kinase (BTK) is required for both FcεRI-induced mast cell activation and B cell autoantibody production in chronic spontaneous urticaria (CSU). Therefore, Metz et al (Nat Med 2021;27:1961-9; https://doi.org/10.1038/s41591-021-01537-w) assessed the efficacy of the oral BTK inhibitor fenebrutinib in a placebo-controlled phase 2 trial in adult patients with antihistamine-refractory CSU. Urticaria activity score decreased after 8 weeks with multiple fenebrutinib doses compared to placebo. Safety assessment revealed nonserious, reversible liver transaminase elevations in a minority of subjects. In total, the results from this trial support further investigation into the use of BTK inhibitors, including fenebrutinib, in patients with CSU. We asked first author Martin Metz, MD, of Charité - Universitätsmedizin Berlin, Berlin, Germany, to comment on the study. He writes, “For patients with CSU who do not respond adequately to antihistamines, therapeutic alternatives to anti-IgE treatment are urgently needed. This is especially true for patients with autoimmune CSU who are known to respond less well to anti-IgE therapy. The results of our trial indicate that BTK inhibitors could be such an alternative new treatment option for antihistamine-refractory CSU patients.” Dupilumab, a mAb directed against the alpha subunit of the IL-4 receptor that inhibits both IL-4 and IL-13, is FDA-approved for treatment of adults, adolescents, and now children as young as 6 years with asthma. Bacharier et al (N Engl J Med 2021;385:2230-40; https://doi.org/10.1056/nejmoa2106567) performed a phase 3 randomized, placebo-controlled trial (Liberty Asthma VOYAGE) to assess the efficacy of add-on dupilumab therapy in children aged 6-11 years with moderate-to-severe asthma. Over the course of the yearlong trial, the annualized rate of severe exacerbations was significantly lower in dupilumab-treated children compared to placebo. Notably, dupilumab also improved the secondary outcomes of lung function and symptom control. Overall, these results extend the use of dupilumab in moderate-to-severe asthma to the pediatric population, particularly those with evidence of type 2 inflammation. Image attribution Wikimedia by user BruceBlaus, CC BY-SA 4.0, https://creativecommons.org/licenses/by-sa/4.0, via Wikimedia Commons. We asked first author Leonard B. Bacharier, MD, of the Monroe Carell Jr Children’s Hospital at Vanderbilt University Medical Center, Nashville, Tennessee, to comment on the study. He writes, “We found that children 6-11 years with uncontrolled moderate-severe asthma and evidence of type 2 inflammation significantly benefit from the addition of dupilumab in terms of fewer severe asthma exacerbations, along with rapid and sustained improvements in lung function and asthma control. These findings provide support for the use of dupilumab in children whose asthma remains uncontrolled despite standard therapies.” In order to understand the contributions of IgA in host defense against lower respiratory tract viral pathogens, Oh et al (Sci Immunol 2021;6:eabj5129; https://doi.org/10.1126/sciimmunol.abj5129) characterized the cellular sources of influenza-induced murine pulmonary IgA production. IgA was released from a heterogeneous population of memory B cells, plasmablasts, and plasma cells after live influenza infection or protein-based vaccination. In both instances, enhanced IgA production and antiviral immunity occurred after intranasal administration when compared to intramuscular or intraperitoneal systemic immunization. Finally, intranasal but not systemic immunization protected against secondary challenge with different influenza strains. Collectively, these results illustrate the ability of local immunization-induced IgA to provide robust defense against influenza and support further investigation into mucosal vaccination strategies against respiratory viruses. We asked corresponding author Akiko Iwasaki, PhD, of the Yale University School of Medicine, New Haven, Connecticut, to comment on the study. She writes, “This study determined the cellular sources of secreted IgA in the respiratory tract, and the potency of mucosal IgA in conferring protection against heterologous virus. Our work shows that intranasally instilled vaccine, which does not require needles, can elicit long-lasting cross-reactive immune responses against respiratory viruses, and development of safe nasal vaccines may be useful in combating future variants of SARS-CoV-2.”News items were written by medical writer Jared Travers, MD, PhD. News items were written by medical writer Jared Travers, MD, PhD.