Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children

被引:695
作者
Stein, Michelle M. [1 ]
Hrusch, Cara L. [2 ,3 ]
Gozdz, Justyna [7 ,8 ,13 ,14 ]
Igartua, Catherine [1 ]
Pivniouk, Vadim [9 ,13 ,14 ]
Murray, Sean E. [13 ,14 ]
Ledford, Julie G. [10 ,13 ,14 ]
dos Santos, Mauricius Marques [11 ]
Anderson, Rebecca L. [1 ]
Metwali, Nervana [15 ]
Neilson, Julia W. [12 ]
Maier, Raina M. [12 ]
Gilbert, Jack A. [4 ,5 ,6 ]
Holbreich, Mark [16 ]
Thorne, Peter S. [15 ]
Martinez, Fernando D. [13 ,14 ]
von Mutius, Erika [17 ]
Vercelli, Donata [9 ,13 ,14 ]
Ober, Carole [1 ]
Sperling, Anne I. [2 ,3 ]
机构
[1] Univ Chicago, Dept Human Genet, 920 E 58th St,CLSC 425, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, Chicago, IL 60637 USA
[3] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA
[4] Univ Chicago, Dept Ecol & Evolut, Chicago, IL 60637 USA
[5] Univ Chicago, Dept Surg, Chicago, IL 60637 USA
[6] Argonne Natl Lab, Inst Genom & Syst Biol, 9700 S Cass Ave, Argonne, IL 60439 USA
[7] Univ Arizona, NIEHS Training Program Environm Toxicol, Tucson, AZ 85721 USA
[8] Univ Arizona, Grad Program Cellular & Mol Med, Tucson, AZ 85721 USA
[9] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85721 USA
[10] Univ Arizona, Dept Med, Tucson, AZ 85721 USA
[11] Univ Arizona, Dept Chem & Environm Engn, Tucson, AZ 85721 USA
[12] Univ Arizona, Dept Soil Water & Environm Sci, Tucson, AZ 85721 USA
[13] Arizona Resp Ctr, Tucson, AZ USA
[14] Bio5 Inst, Tucson, AZ USA
[15] Univ Iowa, Dept Occupat & Environm Hlth, Iowa City, IA USA
[16] Allergy & Asthma Consultants, Indianapolis, IN USA
[17] Univ Munich, Dr von Hauner Childrens Hosp, Munich, Germany
基金
美国国家卫生研究院;
关键词
EXPOSURE; ENDOTOXIN; DISEASE; SUSCEPTIBILITY; NEUTROPHILS; PREVALENCE; RECEPTORS; INDUCTION; RESPONSES; GENETICS;
D O I
10.1056/NEJMoa1508749
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:411 / 421
页数:11
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