Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis.
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-α, and, to a lesser extent, tumor necrosis factor-α 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.


CONCLUSIONS
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.
Child & Family Research Institute, Vancouver, British Columbia, Canada. plavoie@cw.bc.ca
Pascal M
PM
Lavoie
Qing
Q
Huang
Elyse
E
Jolette
Mihoko
M
Whalen
Anne Monique
AM
Nuyt
Francois
F
Audibert
David P
DP
Speert
Thierry
T
Lacaze-Masmonteil
Hugo
H
Soudeyns
Tobias R
TR
Kollmann
D001955:British Columbia; D005312:Fetal Blood; D005434:Flow Cytometry; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000276:immunology*; D018664:Interleukin-12 / Q000097:blood*; D053762:Interleukin-12 Subunit p40 / Q000097:blood*; D012307:Risk Factors; D018805:Sepsis / Q000276:immunology*; D051193:Toll-Like Receptors / Q000097:blood*
D053762:Interleukin-12 Subunit p40; D051193:Toll-Like Receptors; D018664:Interleukin-12