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

Airway infections with fungi, such as molds and yeasts, are important drivers of allergic asthma. In contrast to molds, which rely on proteinase activity, Wu et al (Immunity 2021;54:2595-610.e7; https://doi.org/10.1016/j.immuni.2021.08.009) identified that the yeast Candida albicans promotes allergic airway inflammation through the soluble peptide toxin candidalysin. Candidalysin activated the von Willebrand factor receptor glycoprotein 1b alpha (GP1bα) on the extracellular membrane of platelets to induce release of the Wnt antagonist peptide dickkopf 1 (Dkk-1). This led to subsequent robust type 2 (TH2) and TH17 inflammation, rather than thrombotic responses, that promoted experimental murine allergic airway disease and decreased both pulmonary fungal burden and mycosis-induced pulmonary hemorrhage. Overall, this study identifies a novel proallergic, antifungal pathway involving candidalysin and platelets. We asked first author David Corry of Baylor College of Medicine, Houston, Texas, for comment. He writes, “For decades, a major basic research effort has been to understand the molecular pathways that common causes of asthma, such as fungi, activate to drive TH2 and TH17 responses. Our findings reveal a highly specific pathway mediated through the candidalysin-GP1bα-Dkk-1 axis and suggest that inhibition of platelets or Dkk-1 may be beneficial in asthma and related disorders.” Asher et al (Lancet 2021;398:1569-80; https://doi.org/10.1016/s0140-6736(21)01450-1) reported findings from the Global Asthma Network (GAN), a cross-sectional study that utilized questionnaire-based surveys from almost 120,000 participants to assess trends in the prevalence and severity of pediatric asthma globally over the past 30 years. Approximately 10% of school-age children (ages 6-7) and adolescents (ages 13-14) reported asthma symptoms within the past year, for whom almost half were severe. Asthma symptom prevalence at most sites changed over the past 30 years by at least 2 standard deviations, inconsistent with random variation. Finally, significant variation in prevalence and severity of symptoms was observed based on age, country income, and region. In addition to characterizing trends in pediatric asthma prevalence over the past few decades, these findings underscore the need for implementation of strategies to improve symptom control worldwide. We asked first author M. Innes Asher of the Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand, for comment. She writes, “To our knowledge, the Global Asthma Network Phase I study, adopting the same methods as ISAAC, produced the first comparable estimates of prevalence and severity of asthma symptoms in school-aged children over nearly 3 decades (1993–2020), from 27 centers in 14 countries in the Africa and Eastern Mediterranean, America, Europe, and South-East Asia and Western Pacific regions. Asthma is a major worldwide public health problem in school-aged children. Implementing strategies to reduce the prevalence and severity of asthma symptoms (and the associated avoidable asthma morbidity and mortality and subsequent burden of related diseases, including chronic obstructive pulmonary disease) should be a priority for the 21st century.”Symptom prevalence at most sites changed over the past 30 years Symptom prevalence at most sites changed over the past 30 years Boothby et al (Nature 2021 Oct 27; https://doi.org/10.1038/s41586-021-04044-7) discovered that inducing neonatal inflammation by transiently decreasing regulatory T cells causes accumulation of TH2 cells within murine skin that persist into adulthood due to interaction with skin TH2-interacting fascial fibroblasts (TIFFs) that form subcutaneous fibrous bands in response to TH2 cytokine stimulation. Neonatal cutaneous inflammation activates the TH2-TIFF niche and enhances wound repair responses later in life. Finally, fibroblasts exhibiting a TIFF transcriptional signature are present in human skin during homeostasis and are at higher levels in patients with eosinophilic fasciitis. In total, these findings identify the importance of the TH2-TIFF niche in cutaneous wound repair and represent a novel mechanism by which early-life inflammation influences peripheral immune responses later in life. We asked senior author Michael D. Rosenbloom of the Department of Dermatology, University of California at San Francisco, San Francisco, California, to comment on the study. He writes, “I’m hoping this body of work will enhance our understanding of how immune cell niches are established and maintained in peripheral nonlymphoid tissues.” The ability of IL-23 to stimulate TH17 immunity makes it an attractive therapeutic target in severe asthma. Brightling et al (N Engl J Med 2021;385:1669-79. https://doi.org/10.1056/nejmoa2030880) examined the efficacy of risankizumab, a mAb directed against the p19 chain of IL-23, in a placebo-controlled phase 2a randomized trial in adult patients with severe asthma. Unexpectedly, risankizumab worsened both the time to first asthma worsening and the annualized rate of asthma worsening as compared to placebo. However, the rate of severe exacerbations did not differ between the 2 treatment groups. Genome-wide transcriptomic analysis of sputum samples did confirm biologic responses to risankizumab with down-regulation of IL-23-related gene expression. Overall, these results did not show an identifiable clinical benefit of blocking the IL-23-TH17 axis with risankizumab in severe asthma.These results did not show an identifiable clinical benefit These results did not show an identifiable clinical benefit IL-33 is an epithelium-derived cytokine promotes TH2 immune responses in response to cellular damage with increasingly appreciated roles in the pathogenesis of chronic pulmonary diseases. Two randomized controlled clinical trials were performed assessing the efficacy of the anti-IL-33 monoclonal itepekimab in chronic obstructive pulmonary disease (COPD) and asthma, respectively. After identifying that asthma-associated variants in the genes encoding IL-33 (IL33) or its receptor (IL1RL1) similarly modify the risk of COPD, Rabe et al (Lancet Respir Med 2021;9:1288-98; https://doi.org/10.1016/s2213-2600(21)00167-3) performed a phase 2 placebo-controlled trial in patients with moderate-to-severe COPD. Itepekimab did not reduce the annualized rate of exacerbations overall but did so in a prespecified subgroup analysis of former smokers. Wechsler et al (N Engl J Med 2021;385:1656-68; https://doi.org/10.1056/nejmoa2024257) performed a phase 2 placebo-controlled trial assessing itepekimab in combination with dupilumab, which inhibits the downstream signaling pathways of both IL-4 and IL-13, in patients with moderate-to-severe asthma. Interestingly, the combination of itepekimab and dupilumab reduced the incidence of loss of asthma control and improved lung function but surprisingly were not superior to either agent alone. Collectively, these studies highlight the potential of targeting IL-33 in COPD and asthma and support further investigation. Figure attribution: Courtesy of user DataBase Center for Life Science (DBCLS), CC BY 4.0 https://creativecommons.org/licenses/by/4.0, via Wikimedia Commons.The potential of targeting IL-33 in COPD and asthmaNews items were written by medical writer Jared Travers, MD, PhD. The potential of targeting IL-33 in COPD and asthma News items were written by medical writer Jared Travers, MD, PhD.