Innate Immunity in Asthma E d i t o r i a l T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 375;5 nejm.org August 4, 2016 477 Innate Immunity in Asthma Talal A. Chatila, M.D., M.Sc. It is appreciated that the marked increase in the prevalence of asthma over the past few decades reflects changes in environmental exposures and living conditions associated with modern lifestyles.1 Of particular interest is the documen- tation of a protective effect of exposures associ- ated with traditional farming, the influence of which has waned with increased urbanization and the advent of mechanized agriculture.2 On small family-based farms where children are reared in close proximity to farm animals and their sheds, increased exposure to the microbial products found in these environments, including lipopolysaccharides, has been associated with protection against asthma.3,4 It remains unclear how exposure to a traditional farming environ- ment confers protection against asthma and whether such protection also applies in the con- text of large-scale industrialized farming. Stein et al. now advance our knowledge on both ac- counts in this issue of the Journal.5 In their study, Stein et al. took advantage of a lifestyle attribute that differentiates two other- wise closely related U.S. populations in which the incidence of asthma is dissimilar. The Amish and the Hutterites are reproductively isolated farming communities that are linked by ances- try, having originated in German-speaking alpine regions of Europe. They also share a similar lifestyle that includes environmental exposures that often affect the risk of asthma, with one notable exception — whereas the Amish have maintained a traditional farming practice that revolves around single-family dairy farms and eschews mechanization, the Hutterites practice large-scale, highly mechanized communal farm- ing. The prevalence of asthma and allergic sen- sitization among the Amish is low, but among the Hutterites the prevalence of both conditions is strikingly high, similar to that in the U.S. population at large.6,7 As such, these two com- munities are ideally suited for analysis of the influence of environmental exposures on sus- ceptibility to asthma. By studying children from these two commu- nities, Stein et al. confirmed the discrepancy that exists in the communities’ incidences of allergy and asthma. The researchers also estab- lished the presence of a distinct microbial com- position and an increased burden of lipopolysac- charides in dust samples collected from the houses of the Amish as compared with those of the Hutterites. After exposing samples of periph- eral-blood lymphocytes from both populations to lipopolysaccharides, the samples from the Amish expressed more innate immunity-related cytokines than those from the Hutterites. The peripheral-blood lymphocytes of Amish children also exhibited a genetic signature characterized by higher levels of the gene transcripts associ- ated with innate-type immune responses, includ- ing those involved in the innate immune re- sponse to microbial products such as tumor necrosis factor and IRF7. In addition, dust sam- ples collected from Amish households suppressed the induction of airway inflammation in a mouse model of allergic asthma. This protection was abrogated in mice lacking MyD88 and Trif, adaptor proteins that mediate signaling by mi- crobial products through toll-like receptors (TLRs). In agreement with these findings are previous studies on protective bacterial species isolated from farm-dust samples, including the gram-negative bacterium Acinetobacter lwof f ii, whose application to the airways of mice trig- gers local and systemic inflammatory innate The New England Journal of Medicine Downloaded from nejm.org at CARNEGIE-MELLON UNIV on April 5, 2021. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 375;5 nejm.org August 4, 2016478 immune responses in a TLR-dependent manner.8 Overall, the results of the study by Stein et al. are consistent with the idea that the protective effect of Amish dust is related to its distinct microbial composition. What mechanisms account for the protective effect of long-term, innate, immune-cell activa- tion by farming-related microbial products (Fig. 1)? Studies have delineated a network of innate im- mune cells, including epithelial cells, type 2 in- nate lymphoid cells, mast cells, dendritic cells, and others, that are activated by allergens.9 This network programs a proallergic adaptive immune response involving allergen-specific type 2 helper T cells and IgE-producing B cells that sustains disease activity. The findings of Stein et al. sup- port the notion that exposure to microbe-rich farm dust directs an alternative, proinflamma- tory, innate immune response involving tran- scriptional pathways and mediators, including nuclear factor κB and IRF7, that prevents the emergence of asthma. It should be pointed out that microbial products may also act through TLRs and MyD88 to activate the formation of regulatory T cells that enforce tolerance at mu- cosal surfaces.10 Thus, both long-term, low-level activation of innate immune cells and possibly T-cell–related immune regulatory mechanisms may contribute to the protective effects of the Amish farm dust against asthma. Stein et al. also leave several questions unan- swered. It is unclear whether continuous expo- sure to farm dust is required to maintain its protective effect against allergic asthma. In mice, pregnant mothers exposed to A. lwoffii transmit protection against allergic asthma to their off- spring through mechanisms that involve mater- nal TLR activation, which suggests that an epi- genetic effect may be acquired in utero.8 It is also unclear whether the protective effect of mi- crobial exposure requires live microbes that may colonize the airways or can be reproduced with purified microbial products. The answers to these questions will help to harness the insights gleaned from the studies of Stein et al. and others for the purpose of treating and preventing asthma. Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org. From the Division of Immunology, Boston Children’s Hospital, and the Department of Pediatrics, Harvard Medical School, Boston. 1. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006; 355: 2226-35. 2. von Mutius E, Vercelli D. Farm living: effects on childhood asthma and allergy. Nat Rev Immunol 2010; 10: 861-8. 3. Braun-Fahrländer C, Riedler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002; 347: 869-77. 4. Ege MJ, Mayer M, Normand A-C, et al. Exposure to environ- mental microorganisms and childhood asthma. N Engl J Med 2011; 364: 701-9. 5. Stein MM, Hrusch CL, Gozdz J, et al. Innate immunity and asthma risk in Amish and Hutterite farm children. N Engl J Med 2016; 375: 411-21. 6. Holbreich M, Genuneit J, Weber J, Braun-Fahrländer C, Was- er M, von Mutius E. Amish children living in northern Indiana have a very low prevalence of allergic sensitization. J Allergy Clin Immunol 2012; 129: 1671-3. 7. Motika CA, Papachristou C, Abney M, Lester LA, Ober C. Rising prevalence of asthma is sex-specific in a US farming population. J Allergy Clin Immunol 2011; 128: 774-9. Figure 1. Farming Lifestyle, the Activation of Innate Immunity, and Protection against Asthma. Differences in the prevalence of asthma and allergic sensitization in Amish and Hutterite communities are linked to their distinct farming practices. The traditional farming practices in Amish communities protect against asthma by inducing a long-term, low-level, proinflammatory innate immune response. This protection involves the activation by microbial signals, act- ing through MyD88 and Trif and the production of tumor necrosis factor (TNF) and interleukin-1. The Hutterites, who practice mechanized farming and are not exposed to the same microbial influences, are not protected. The New England Journal of Medicine Downloaded from nejm.org at CARNEGIE-MELLON UNIV on April 5, 2021. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved. Edit or i a l s n engl j med 375;5 nejm.org August 4, 2016 479 8. Conrad ML, Ferstl R, Teich R, et al. Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 2009; 206: 2869-77. 9. Pulendran B, Artis D. New paradigms in type 2 immunity. Science 2012; 337: 431-5. 10. Wang S, Charbonnier LM, Noval Rivas M, et al. MyD88 Adaptor-dependent microbial sensing by regulatory T cells pro- motes mucosal tolerance and enforces commensalism. Immu- nity 2015; 43: 289-303. DOI: 10.1056/NEJMe1607438 Copyright © 2016 Massachusetts Medical Society. The New England Journal of Medicine Downloaded from nejm.org at CARNEGIE-MELLON UNIV on April 5, 2021. For personal use only. No other uses without permission. Copyright © 2016 Massachusetts Medical Society. All rights reserved.