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Cited by 939Asthma and respiratory diseasesAllergic Rhinitis and SensitizationIndoor Air Quality and Microbial Exposure

Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children

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Stein, Michelle M., Hrusch, Cara L., Gozdz, Justyna, Igartua, Catherine, Pivniouk, Vadim, Murray, Sean E., Ledford, Julie G., Marques dos Santos, Mauricius +12 more·2016·New England Journal of Medicine
DOI 10.1056/nejmoa1508749PMC PMC5137793
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Abstract

BACKGROUND: The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities. METHODS: We studied environmental exposures, genetic ancestry, and immune profiles among 60 Amish and Hutterite children, measuring levels of allergens and endotoxins and assessing the microbiome composition of indoor dust samples. Whole blood was collected to measure serum IgE levels, cytokine responses, and gene expression, and peripheral-blood leukocytes were phenotyped with flow cytometry. The effects of dust extracts obtained from Amish and Hutterite homes on immune and airway responses were assessed in a murine model of experimental allergic asthma. RESULTS: Despite the similar genetic ancestries and lifestyles of Amish and Hutterite children, the prevalence of asthma and allergic sensitization was 4 and 6 times as low in the Amish, whereas median endotoxin levels in Amish house dust was 6.8 times as high. Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes. Profound differences in the proportions, phenotypes, and functions of innate immune cells were also found between the two groups of children. In a mouse model of experimental allergic asthma, the intranasal instillation of dust extracts from Amish but not Hutterite homes significantly inhibited airway hyperreactivity and eosinophilia. These protective effects were abrogated in mice that were deficient in MyD88 and Trif, molecules that are critical in innate immune signaling. CONCLUSIONS: The results of our studies in humans and mice indicate that the Amish environment provides protection against asthma by engaging and shaping the innate immune response. (Funded by the National Institutes of Health and others.).

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  • Mechanistically, farming and rural exposures are thought to exert effects on immune regulatory pathways essentially via microbial taxa, microbial metabolites and specific carrier-proteins like beta-lactoglobulin present in the stable environment and milk.

    “Mechanistically, these exposures are thought to exert effects on the immune regulatory pathways essentially via microbial taxa, microbial metabolites [22, 23, 24] and specific carrier‐proteins like beta‐lactoglobulin present in the stable environment and milk [25, 26].”

    From <scp>EAACI</scp> Guidelines on the Importance of Green Space in Urban Environments for Allergy and Asthma Prevention (2026) · cites this paper as [23]

    The Results (Exposures to Allergens, Microbes, and Microbial Products; page unavailable) report differences in dust bacteria and substantially higher endotoxin levels in Amish homes. The Discussion links sustained microbial exposure to altered innate immune responses, but the paper does not identify microbial metabolites as mediators. The beta-lactoglobulin clause has separate citations and is not attributed to this source. (LLM, conf=0.86)

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Research works printed but not linked: 30

  1. [2]Meyers DA Bleecker ER Holloway JW Holgate ST Asthma genetics and personalised medicine Lancet Respir Med 2014 2 405 15 24794577 PMC4768462
  2. [3]Bach JF The effect of infections on susceptibility to autoimmune and allergic diseases N Engl J Med 2002 347 911 20 12239261
  3. [4]Braun-Fahrländer C Riedler J Herz U Environmental exposure to endotoxin and its relation to asthma in school-age children N Engl J Med 2002 347 869 77 12239255
  4. [5]Ege MJ Mayer M Normand AC Exposure to environmental microorganisms and childhood asthma N Engl J Med 2011 364 701 9 21345099
  5. [6]Ege MJ Frei R Bieli C Not all farming environments protect against the development of asthma and wheeze in children J Allergy Clin Immunol 2007 119 1140 7 17349684
  6. [7]Ege MJ Strachan DP Cookson WO Gene-environment interaction for childhood asthma and exposure to farming in Central Europe J Allergy Clin Immunol 2011 127 138 44 21211648
  7. [8]Hostetler JA Hutterite society 1974 Johns Hopkins University Press Baltimore
  8. [9]Hostetler JA Amish society 1993 Johns Hopkins University Press Baltimore 4th ed
  9. [10]Holbreich M Genuneit J Weber J Braun-Fahrländer C Waser 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 22513133
  10. [11]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 21840584 PMC3401412
  11. [12]Adachi O Kawai T Takeda K Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function Immunity 1998 9 143 50 9697844
  12. [13]Yamamoto M Sato S Hemmi H Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway Science 2003 301 640 3 12855817
  13. [15]Cann HM de Toma C Cazes L A human genome diversity cell line panel Science 2002 296 261 2 11954565
  14. [16]Kim-Schulze S Scotto L Vlad G Recombinant Ig-like transcript 3-Fc modulates T cell responses via induction of Th anergy and differentiation of CD8+ T suppressor cells J Immunol 2006 176 2790 8 16493035
  15. [17]Velten FW Duperrier K Bohlender J Metharom P Goerdt S A gene signature of inhibitory MHC receptors identifies a BDCA3(+) subset of IL-10-induced dendritic cells with reduced allostimulatory capacity in vitro Eur J Immunol 2004 34 2800 11 15368296
  16. [18]Lluis A Depner M Gaugler B Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood J Allergy Clin Immunol 2014 133 551 9 23993223
  17. [19]Schaub B Liu J Höppler S Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells J Allergy Clin Immunol 2009 123 4 774 82.e5 19348917
  18. [20]Ma A Malynn BA A20: linking a complex regulator of ubiquitylation to immunity and human disease Nat Rev Immunol 2012 12 774 85 23059429 PMC3582397
  19. [21]Schuijs MJ Willart MA Vergote K Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells Science 2015 349 1106 10 26339029
  20. [22]Bosco A Ehteshami S Panyala S Martinez FD Interferon regulatory factor 7 is a major hub connecting interferon-mediated responses in virus-induced asthma exacerbations in vivo J Allergy Clin Immunol 2012 129 88 94 22112518 PMC3246116
  21. [23]Loss GJ Depner M Hose AJ The early development of wheeze: environmental determinants and genetic susceptibility at 17q21 Am J Respir Crit Care Med 2016 193 889 97 26575599
  22. [24]Calışkan M Bochkov YA Kreiner-Møller E Rhinovirus wheezing illness and genetic risk of childhood-onset asthma N Engl J Med 2013 368 1398 407 23534543 PMC3755952
  23. [25]Li Q Yan J Mao AP Tripartite motif 8 (TRIM8) modulates TNFα- and IL-1β-triggered NF-κB activation by targeting TAK1 for K63-linked polyubiquitination Proc Natl Acad Sci U S A 2011 108 19341 6 22084099 PMC3228454
  24. [26]Meisel C Schefold JC Pschowski R Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multi-center trial Am J Respir Crit Care Med 2009 180 640 8 19590022
  25. [27]Gomez HG Gonzalez SM Londoño JM Immunological characterization of compensatory anti-inflammatory response syndrome in patients with severe sepsis: a longitudinal study Crit Care Med 2014 42 771 80 24365860
  26. [28]Fortunati E Kazemier KM Grutters JC Koenderman L Van den Bosch J Human neutrophils switch to an activated phenotype after homing to the lung irrespective of inflammatory disease Clin Exp Immunol 2009 155 559 66 19077082 PMC2669533
  27. [29]Orden S De Pablo C Rios-Navarro C Efavirenz induces interactions between leucocytes and endothelium through the activation of Mac-1 and gp150,95 J Antimicrob Chemother 2014 69 995 1004 24275118
  28. [30]Devi S Wang Y Chew WK Neutrophil mobilization via plerixafor-mediated CXCR4 inhibition arises from lung demargination and blockade of neutrophil homing to the bone marrow J Exp Med 2013 210 2321 36 24081949 PMC3804935
  29. [31]Yamada M Kubo H Kobayashi S The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury Cell Mol Immunol 2011 8 305 14 21460863 PMC4002449
  30. [32]Netea MG Wijmenga C O'Neill LAJ Genetic variation in toll-like receptors and disease susceptibility Nat Immunol 2012 13 535 42 22610250

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Authors
Stein, M. M., Hrusch, C. L., Gozdz, J., Igartua, C., Pivniouk, V., Murray, S. E., Ledford, J. G., Marques dos Santos, M., Anderson, R. L., Metwali, N., Neilson, J. W., Maier, R. M., Gilbert, J. A., Holbreich, M., Thorne, P. S., Martinez, F. D., von Mutius, E., Vercelli, D., Ober, C., & Sperling, A. I.
Affiliations
University of Iowa (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2016-08-04
Volume
375
Issue
5
Pages
411-421
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1508749
PMC
PMC5137793
OpenAlex
W2484915396
Cited by
939
References
2
Citations by year
2026: 50 · 2025: 62 · 2024: 65 · 2023: 91 · 2022: 91 · 2021: 118 · 2020: 109 · 2019: 117 · 2018: 112 · 2017: 108 · 2016: 15
FWCI
94.48
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UA Campus Repository (The University of Arizona) (acceptedVersion)
Funders
  • American Academy of Allergy Asthma and Immunology
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL125602, R00HL111151, R01HL085197, T32HL007605)
  • National Cancer Institute (P30CA014599)
  • National Institute of Allergy and Infectious Diseases (U19AI095230)
  • National Institute of Environmental Health Sciences (P30ES005605, T32ES007091, P30ES006694)
Topics
  • Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
  • Health Sciences › Medicine › Immunology and Allergy › Allergic Rhinitis and Sensitization
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Indoor Air Quality and Microbial Exposure
Keywords
asthma, innate immunity, Amish, Hutterites, house dust, endotoxin, microbial community composition, allergen sensitization, serum IgE, cytokine response, leukocyte phenotyping, airway hyperresponsiveness, eosinophilia, MyD88, TRIF, traditional agriculture, genetic ancestry
MeSH terms
Adolescent, Agriculture, Animals, Asthma, Child, Christianity, Cross-Sectional Studies, Disease Models, Animal, Dust, Environmental Exposure, Female, Humans, Immunoglobulin E, Immunity, Innate, Leukocyte Count, Leukocytes, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Gene Expression, Prevalence, Cytokines, Models, Animal, Adaptor Proteins, Vesicular Transport, Mice, Myeloid Differentiation Factor 88

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