Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells | Science


HomeScienceVol. 349, No. 6252Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells
No access
Report

Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells

Science
4 Sep 2015
Vol 349, Issue 6252
pp. 1106-1110
2,220405

Metrics

Total Downloads2,220

  • Last 6 Months360
  • Last 12 Months775

Total Citations405

  • Last 6 Months3
  • Last 12 Months27

How farming protects against allergies

People who grow up on dairy farms only rarely develop asthma or allergies. This is probably because as children, they breathe air containing bacterial components, which reduce the overall reactivity of the immune system. Schuijs et al. chronically exposed mice to bacterial endotoxin before they received an allergic stimulus. The protocol indeed protected them from developing an allergic response. Protection relied on a particular enzyme: A20. In humans, a variant of A20 correlates with increased susceptibility to asthma and allergy in children growing up on farms.
Science, this issue p. 1106

Abstract

Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)–rich environment with protection has remained elusive. Here we show that chronic exposure to low-dose endotoxin or farm dust protects mice from developing house dust mite (HDM)–induced asthma. Endotoxin reduced epithelial cell cytokines that activate dendritic cells (DCs), thus suppressing type 2 immunity to HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished the protective effect. A single-nucleotide polymorphism in the gene encoding A20 was associated with allergy and asthma risk in children growing up on farms. Thus, the farming environment protects from allergy by modifying the communication between barrier epithelial cells and DCs through A20 induction.

Get full access to this article

View all available purchase options and get full access to this article.

ALREADY A SUBSCRIBER OR AAAS MEMBER? Sign in as an individual or via your institution

Supplementary Material

Summary

Materials and Methods
Figs. S1 to S5
Tables S1 and S2

Resources

File (schuijs.sm.pdf)

References and Notes

1
Lambrecht B. N., Hammad H., The immunology of asthma. Nat. Immunol. 16, 45–56 (2015).
2
Hammad H., Chieppa M., Perros F., Willart M. A., Germain R. N., Lambrecht B. N., House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat. Med. 15, 410–416 (2009).
3
Riedler J., Braun-Fahrländer C., Eder W., Schreuer M., Waser M., Maisch S., Carr D., Schierl R., Nowak D., von Mutius E.ALEX Study Team, Exposure to farming in early life and development of asthma and allergy: A cross-sectional survey. Lancet 358, 1129–1133 (2001).
4
Ege M. J., Mayer M., Normand A. C., Genuneit J., Cookson W. O., Braun-Fahrländer C., Heederik D., Piarroux R., von Mutius E.GABRIELA Transregio 22 Study Group, Exposure to environmental microorganisms and childhood asthma. N. Engl. J. Med. 364, 701–709 (2011).
5
von Mutius E., Vercelli D., Farm living: Effects on childhood asthma and allergy. Nat. Rev. Immunol. 10, 861–868 (2010).
6
Illi S., Depner M., Genuneit J., Horak E., Loss G., Strunz-Lehner C., Büchele G., Boznanski A., Danielewicz H., Cullinan P., Heederik D., Braun-Fahrländer C., von Mutius E.GABRIELA Study Group, Protection from childhood asthma and allergy in alpine farm environments—The GABRIEL Advanced Studies. J. Allergy Clin. Immunol. 129, 1470–1477 (2012).
7
Braun-Fahrländer C., Riedler J., Herz U., Eder W., Waser M., Grize L., Maisch S., Carr D., Gerlach F., Bufe A., Lauener R. P., Schierl R., Renz H., Nowak D., von Mutius E.Allergy and Endotoxin Study Team, Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).
8
Lauener R. P., Birchler T., Adamski J., Braun-Fahrländer C., Bufe A., Herz U., von Mutius E., Nowak D., Riedler J., Waser M., Sennhauser F. H.ALEX study group, Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 360, 465–466 (2002).
9
Simpson A., John S. L., Jury F., Niven R., Woodcock A., Ollier W. E., Custovic A., Endotoxin exposure, CD14, and allergic disease: An interaction between genes and the environment. Am. J. Respir. Crit. Care Med. 174, 386–392 (2006).
10
Ege M. J., Frei R., Bieli C., Schram-Bijkerk D., Waser M., Benz M. R., Weiss G., Nyberg F., van Hage M., Pershagen G., Brunekreef B., Riedler J., Lauener R., Braun-Fahrländer C., von Mutius E.PARSIFAL Study team, Not all farming environments protect against the development of asthma and wheeze in children. J. Allergy Clin. Immunol. 119, 1140–1147 (2007).
11
Hammad H., Plantinga M., Deswarte K., Pouliot P., Willart M. A., Kool M., Muskens F., Lambrecht B. N., Inflammatory dendritic cells—not basophils—are necessary and sufficient for induction of Th2 immunity to inhaled house dust mite allergen. J. Exp. Med. 207, 2097–2111 (2010).
12
Plantinga M., Guilliams M., Vanheerswynghels M., Deswarte K., Branco-Madeira F., Toussaint W., Vanhoutte L., Neyt K., Killeen N., Malissen B., Hammad H., Lambrecht B. N., Conventional and monocyte-derived CD11b+ dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity 38, 322–335 (2013).
13
Nathan A. T., Peterson E. A., Chakir J., Wills-Karp M., Innate immune responses of airway epithelium to house dust mite are mediated through β-glucan–dependent pathways. J. Allergy Clin. Immunol. 123, 612–618 (2009).
14
Llop-Guevara A., Chu D. K., Walker T. D., Goncharova S., Fattouh R., Silver J. S., Moore C. L., Xie J. L., O’Byrne P. M., Coyle A. J., Kolbeck R., Humbles A. A., Stämpfli M. R., Jordana M., A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure. PLOS ONE 9, e88714 (2014).
15
Willart M. A., Deswarte K., Pouliot P., Braun H., Beyaert R., Lambrecht B. N., Hammad H., Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33. J. Exp. Med. 209, 1505–1517 (2012).
16
McAlees J. W., Whitehead G. S., Harley I. T., Cappelletti M., Rewerts C. L., Holdcroft A. M., Divanovic S., Wills-Karp M., Finkelman F. D., Karp C. L., Cook D. N., Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation. Mucosal Immunol. 8, 863–873 (2015).
17
Vereecke L., Beyaert R., van Loo G., The ubiquitin-editing enzyme A20 (TNFAIP3) is a central regulator of immunopathology. Trends Immunol. 30, 383–391 (2009).
18
Boone D. L., Turer E. E., Lee E. G., Ahmad R. C., Wheeler M. T., Tsui C., Hurley P., Chien M., Chai S., Hitotsumatsu O., McNally E., Pickart C., Ma A., The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat. Immunol. 5, 1052–1060 (2004).
19
Lee E. G., Boone D. L., Chai S., Libby S. L., Chien M., Lodolce J. P., Ma A., Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science 289, 2350–2354 (2000).
20
Vereecke L., Sze M., Mc Guire C., Rogiers B., Chu Y., Schmidt-Supprian M., Pasparakis M., Beyaert R., van Loo G., Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor–induced toxicity and experimental colitis. J. Exp. Med. 207, 1513–1523 (2010).
21
Perl A. K., Wert S. E., Loudy D. E., Shan Z., Blair P. A., Whitsett J. A., Conditional recombination reveals distinct subsets of epithelial cells in trachea, bronchi, and alveoli. Am. J. Respir. Cell Mol. Biol. 33, 455–462 (2005).
22
Peters M., Kauth M., Schwarze J., Körner-Rettberg C., Riedler J., Nowak D., Braun-Fahrländer C., von Mutius E., Bufe A., Holst O., Inhalation of stable dust extract prevents allergen induced airway inflammation and hyperresponsiveness. Thorax 61, 134–139 (2006).
23
Ege M. J., Strachan D. P., Cookson W. O., Moffatt M. F., Gut I., Lathrop M., Kabesch M., Genuneit J., Büchele G., Sozanska B., Boznanski A., Cullinan P., Horak E., Bieli C., Braun-Fahrländer C., Heederik D., von Mutius E.GABRIELA Study Group, Gene-environment interaction for childhood asthma and exposure to farming in Central Europe. J. Allergy Clin. Immunol. 127, 138–144 (2011).
24
Musone S. L., Taylor K. E., Lu T. T., Nititham J., Ferreira R. C., Ortmann W., Shifrin N., Petri M. A., Kamboh M. I., Manzi S., Seldin M. F., Gregersen P. K., Behrens T. W., Ma A., Kwok P.-Y., Criswell L. A., Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062–1064 (2008).
25
Kadota K., Mori M., Yanagimachi M., Miyamae T., Hara T., Kanetaka T., Nozawa T., Kikuchi M., Hara R., Imagawa T., Kaneko T., Yokota S., Analysis of gender differences in genetic risk: Association of TNFAIP3 polymorphism with male childhood-onset systemic lupus erythematosus in the Japanese population. PLOS ONE 8, e72551 (2013).
26
Yazdanbakhsh M., Kremsner P. G., van Ree R., Allergy, parasites, and the hygiene hypothesis. Science 296, 490–494 (2002).
27
Eder W., Ege M. J., von Mutius E., The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).
28
Pearce N., Asher I., Billo N., Bissell K., Ellwood P., El Sony A., García-Marcos L., Chiang C. Y., Mallol J., Marks G., Strachan D., Asthma in the global NCD agenda: A neglected epidemic. Lancet Respir Med 1, 96–98 (2013).
29
Chang Y.-J., Kim H. Y., Albacker L. A., Lee H. H., Baumgarth N., Akira S., Savage P. B., Endo S., Yamamura T., Maaskant J., Kitano N., Singh A., Bhatt A., Besra G. S., van den Elzen P., Appelmelk B., Franck R. W., Chen G., DeKruyff R. H., Shimamura M., Illarionov P., Umetsu D. T., Influenza infection in suckling mice expands an NKT cell subset that protects against airway hyperreactivity. J. Clin. Invest. 121, 57–69 (2011).
30
Wang J., Ouyang Y., Guner Y., Ford H. R., Grishin A. V., Ubiquitin-editing enzyme A20 promotes tolerance to lipopolysaccharide in enterocytes. J. Immunol. 183, 1384–1392 (2009).
31
Li X., Ampleford E. J., Howard T. D., Moore W. C., Torgerson D. G., Li H., Busse W. W., Castro M., Erzurum S. C., Israel E., Nicolae D. L., Ober C., Wenzel S. E., Hawkins G. A., Bleecker E. R., Meyers D. A., Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. J. Allergy Clin. Immunol. 130, 861–868 (2012).
32
El Bakkouri K., Wullaert A., Haegman M., Heyninck K., Beyaert R., Adenoviral gene transfer of the NF-κB inhibitory protein ABIN-1 decreases allergic airway inflammation in a murine asthma model. J. Biol. Chem. 280, 17938–17944 (2005).
33
Hammad H., Lambrecht B. N., Barrier epithelial cells and the control of type 2 immunity. Immunity 43, 29–40 (2015).

(0)eLetters

eLetters is a forum for ongoing peer review. eLetters are not edited, proofread, or indexed, but they are screened. eLetters should provide substantive and scholarly commentary on the article. Embedded figures cannot be submitted, and we discourage the use of figures within eLetters in general. If a figure is essential, please include a link to the figure within the text of the eLetter. Please read our Terms of Service before submitting an eLetter.

Log In to Submit a Response

No eLetters have been published for this article yet.

Advertisement

Sign up for ScienceAdviser

Subscribe to ScienceAdviser to get the latest news, commentary, and research, free to your inbox daily.

Subscribe

Advertisement

Related Jobs

More jobs ▶

Advertisement