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Abstract

Contact with farm animals and their subsequent microbes have been shown to reduce the risk of allergy and asthma, although the effect of traditional versus industrialized farming methods is not well understood. In a recent study Stein et al (N Engl J Med 2016;375:411-21; doi: http://dx.doi.org/10.1056/NEJMoa1508749) characterized the immune profiles of 2 genetically similar US farming populations, 30 Amish and 30 Hutterite schoolchildren, who differ in their farming practices. The authors found that the Amish, who practice traditional family farming and are exposed to an environment rich in microbes, had exceedingly low levels of asthma despite increased levels of endotoxin in their homes compared with the Hutterites, who practice industrialized communal farming methods and have endotoxin exposure and rates of asthma consistent with children assimilated in Western culture. Moreover, using a mouse model of asthma, the authors showed that intranasal administration of dust extracts of Amish but not Hutterite homes significantly reduced airway hyperreactivity and eosinophilia. The authors demonstrate that mice deficient in myeloid differentiation primary response gene–88 and Trif (molecules critical for innate immune signaling) abrogated the protective effects of the Amish house dust. Although this study used a small number of children, the significant differences between these 2 groups of farmers is compelling and suggests that innate immune pathways are critical in the development of asthma prevention strategies. (Image used via Creative Commons license BY-SA 2.0, with credit to user “Anoldent” [CC BY-SA 2.0 (http://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons.)Exceedingly low levels of asthma despite increased levels of endotoxin in homes Exceedingly low levels of asthma despite increased levels of endotoxin in homes Parasitic helminths and allergens are well known to induce the type 2 immune response, which leads to changes in tissue pathology, including tuft cell hyperplasia. However, the function of tuft cells is not completely understood, leading von Moltke et al (Nature 2016;529:221-5; doi: http://dx.doi.org/10.1038/nature16161) to demonstrate that tuft cells constitutively express IL-25, a cytokine that favors the type 2 immune response, to sustain type 2 innate lymphoid cell (ILC2) homeostasis in the resting lamina propria in mice. After helminth infection of these mice, tuft cell–derived IL-25 further activated ILC2s to secrete IL-13, ultimately leading to the differentiation and accumulation of tuft and goblet cells. In the absence of IL-25, ILC2s were activated by other signals to mediate worm clearance. In spite of this, the authors show that tuft cells appear to be the primary source of IL-25 in the gut and are a crucial component of a response circuit with ILC2s and progenitors that mediate epithelial remodeling, making tuft cells a key player in the physiologic host response against helminths. Given that the authors provide data that tuft cells appear to be the primary source of IL-25 in the lung as well, these cells might be implicated in allergic conditions and airway disease and provide therapeutic potential for these afflictions.A crucial component of a response circuit with ILC2s and progenitors that mediate epithelial remodeling A crucial component of a response circuit with ILC2s and progenitors that mediate epithelial remodeling Asthma and atopic conditions are known to be associated with reduced levels of forkhead box P3–positive regulatory T (Treg) cells; however, the mechanisms underlying the cause are unclear. Massoud et al (Nat Med 2016; 22:1013-22; doi: http://dx.doi.org/10.1038/nm.4147) show that a polymorphism encoding the IL-4 receptor alpha chain (Il4raR576), which is associated with asthma exacerbations and severity, promotes the skewing of induced Treg (iTreg) cells to a TH17 cell lineage through recruitment of the adaptor protein growth factor receptor–bound protein 2. Furthermore, the Treg cell–specific deletion of genes that regulate TH17 cell differentiation prevented exacerbated airway inflammation in mice expressing Il4raR576. Notably, treatment with a neutralizing IL-6–specific antibody prevented iTreg cell preprogramming into TH17 cells and prevented severe airway inflammation in this mouse model. These results indicate that subversion of Il4raR576 iTreg cells into TH17-like cells is IL-4 directed and IL-6 dependent and might be a critical factor in asthma severity. Thus therapeutics that block the IL-4 receptor or IL-6 receptor might prevent the subversion of iTreg cells into TH2 and/or TH17 cells, respectively.Treatment with a neutralizing IL-6–specific antibody prevented iTreg cell preprogramming into TH17 cells Treatment with a neutralizing IL-6–specific antibody prevented iTreg cell preprogramming into TH17 cells Studies that identify the root causes of asthma are limited compared with those that identify asthma triggers. This is especially true during fetal and early-life development, during which external stimuli can lead to permanent changes in genetic expression and disease susceptibility. A rapid decrease in temperature and a lack of wind-collected airborne pollutants formed a thick layer of fog over London for 5 days in December of 1952, an event now known as the Great Smog. Bharadwaj et al (Am J Respir Crit Care Med 2016; doi: http://dx.doi.org/10.1164/rccm.201603-0451OC) analyzed 2916 respondents to the Life History portion of the English Longitudinal Study on Aging who were born from 1945-1955 and determined that exposure to the Great Smog in the first year of life increased the likelihood of childhood asthma by 19.87% (95% CI, 3.37% to 36.38%). Furthermore, early exposure led to a 9.53% increase (95% CI, −4.85% to 23.91%) in adult asthma, whereas exposure in utero led to an increase of 7.91% (95% CI, −2.39% to 18.20%) in the rate of childhood asthma. This study uncovered evidence that early-life exposure to air pollution can contribute to the development of asthma, potentially leading to new insights on how to prevent this condition. (Image used via Creative Commons license BY-SA 2.0, with credit to user N T Stobbs. N T Stobbs [CC BY-SA 2.0 (http://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons.)Evidence that early-life exposure to air pollution can be a root cause of asthma Evidence that early-life exposure to air pollution can be a root cause of asthma We asked author Jamie Mullins of the University of Massachusetts, Amherst, for comment: “This work provides some of the first evidence strongly linking environmental conditions in early life to the development of asthma, and also underscores the need to consider long term—as well as immediate—health costs of air pollution. Leveraging the Great Smog of London as a natural experiment, we show that the event’s legacy continues to reverberate more than 60 years on, a finding with particularly ominous implications for many around the globe that continue to face regular bouts of extreme air pollution.”News items were written by medical writer Kristina Bielewicz, MS.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. News items were written by medical writer Kristina Bielewicz, MS. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.