期刊
JOURNAL OF INFECTIOUS DISEASES
卷 202, 期 11, 页码 1754-1763出版社
OXFORD UNIV PRESS INC
DOI: 10.1086/657143
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资金
- Canadian Child Health Clinician Scientist Program
- SickKids Foundation
- Child & Family Research Institute (British Columbia)
- Women and Children's Health Research Institute (Alberta)
- Manitoba Institute of Child Health
- Burroughs Wellcome Fund
- Division of Neonatology at Children's & Women's Health Centre of British Columbia
- British Columbia Lung Association
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [N01 AI50023]
- AllerGen Networks of Centres of Excellence of Canada [07-A1A, 07-B2B]
- Canadian Institutes for Health Research [MOP-53269]
Background. Infants born prematurely are highly vulnerable to infections and also exhibit a high susceptibility to organ damage due to inflammation. Methods. To investigate homeostatic immune control early in life, we used advanced multiparameter flow cytometry to compare responses to multiple Toll-like receptor (TLR) ligands in single cells and mononuclear cell populations in term neonates versus preterm neonates born before 29 weeks of gestation. Results. Preterm neonates had globally attenuated TLR-stimulated interleukin (IL)-6, interferon-alpha, and, to a lesser extent, tumor necrosis factor-alpha responses but demonstrated relative preservation of anti-inflammatory IL-10 responses in monocytes and dendritic cell subtypes. Remarkably, preterm neonates were also profoundly deficient in the common IL-12 and IL-23 cytokines' p40 subunit, which is critical for immunity against a wide variety of microbial pathogens in mice. Consistent with the increased susceptibility to infections resulting from the lack of IL-12/IL-23 in human newborns, significantly lower serum p40 concentrations were observed at birth in infants who developed early-onset sepsis. Conclusion. To our knowledge, this study is the first detailed analysis of multiple TLR function in neonates born extremely premature. Although attenuation of proinflammatory pathways may protect against tissue-damaging immunity early in life, this previously unrecognized p40 immune deficiency appears to result in considerably increased susceptibility to infection in human preterm newborns.
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