Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood

Wit, Dominique De; Tonon, Sandrine; Olislagers, Véronique; Goriely, Stanislas; Boutriaux, Michaël; Goldman, Michel; Willems, Fabienne

doi:10.1016/j.jaut.2003.08.003

Cited by 141 publications

(130 citation statements)

References 24 publications

(24 reference statements)

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“…Moreover, neither LPS nor poly(I:C) induced the release of IFN-␣ or IFN-in plasma. Although conflicting results have been published regarding the release of type I IFNs in poly(I:C)-stimulated whole blood (58,59), our observations appear to be in line with those of Yang et al (60), who found that human PBMC did not produce IFN-␣ or IFN-␤ in response to LPS and produced only tiny amounts of IFN-␣ in response to poly(I:C). Since IFN-␣/␤ is readily produced by murine blood leukocytes and macrophages in response to LPS or poly(I:C) (52-54, 61), these findings indicate that species-specific differences influence the secretion of type I IFNs in response to TLR3 and TLR4 ligands and add to the notion that human and mouse TLR systems are not completely equivalent (62).…”

Section: Discussionsupporting

confidence: 92%

In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands

Vos

Pater

Pangaart

et al. 2009

The Journal of Immunology

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In vitro and in vivo experiments in mice have shown that exposure of cells to the TLR4 ligand LPS induces tolerance toward a second exposure to LPS and induces cross-tolerance to certain other TLR ligands. Recently, we found that LPS tolerance in experimental human endotoxemia and Gram-negative sepsis is associated with elevated levels of IL-1R-associated kinase M, an intracellular negative regulator of MyD88-dependent TLR signaling. In the present study, we investigated whether in vivo exposure of humans to LPS induces tolerance in circulating leukocytes to other TLR agonists that rely either on MyD88- dependent or on MyD88-independent signaling. Analysis of TNF, IL-1β, IL-6, and IL-10 levels in whole blood demonstrated that leukocytes were hyporesponsive to ex vivo LPS restimulation 3–8 h after i.v. LPS injection (4 ng/kg). Reduced cytokine release during the same interval was also observed in whole blood further stimulated with MyD88-dependent ligands for TLR2, TLR5, and TLR7 or with whole bacteria. Strikingly, blood leukocytes were also tolerant to a ligand for TLR3, which signals solely through a MyD88-independent (Toll IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent) pathway. The hyporesponsiveness of leukocytes to TLR3 ligation was associated with reduced rather than increased levels of the recently identified TRIF inhibitor SARM. Taken together, these data indicate that systemic LPS challenge of human volunteers induces cross-tolerance to multiple TLR ligands that signal in a MyD88-dependent or MyD88-independent manner and suggest that LPS exposure of human blood leukocytes may hamper the inflammatory response to various microbial components.

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Section: Discussionsupporting

confidence: 92%

In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands

Vos

Pater

Pangaart

et al. 2009

The Journal of Immunology

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“…IL-12p35 is the rate limiting subunit of IL-12p70, the predominant cytokine driving Th1 cell development. These data are in line with previous work showing that human cord blood DCs (De Wit et al, 2003;Goriely et al, 2001;Tonon et al, 2002) and mouse splenic DCs (Lee et al, 2008) are deficient in IL-12 production. In neonatal lung DCs, IL-12p35 deficiency was strongest in CD11b + cDCs and CD64 + moDCs, the two main HDM-presenting DC subsets.…”

Section: (Legend Continued On Next Page)supporting

confidence: 93%

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

et al. 2016

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“…In another study, neonatal pDCs (Lin − /HLA-DR + /CD11c − /CD123 + ) exhibited incomplete maturation after stimulation with the TLR9 agonist CpG, as demonstrated by the lower expression of CD80, CD83, CD86, and CD40 in comparison to stimulated adult pDCs [44]. Similarly, upregulation of CD40 and CD80 on CB-mDCs in response to LPS and the TLR3 agonist poly (I:C) was significantly lower compared to that of adult mDCs [45]. Of note, in contrast to their lower level on neonatal monocytes, protein expression of TLR2 and TLR4 is normal in neonatal mDCs [41].…”

Section: Cord Blood Dendritic Cellsmentioning

confidence: 91%

“…Interestingly, the latter study showed that the number of expressing cells was equivalent, but the level of expression per individual cell was lower. In addition, IFN-α secretion by unseparated CB cells is decreased in response to the TLR3 agonist poly (I:C) [45]. Since the expression of TLR3 is limited to mDCs, this result suggests again a defect in the response of these cells to viral products.…”

Section: Cord Blood Dendritic Cellsmentioning

confidence: 95%

Defective antigen-presenting cell function in human neonates

Velilla¹,

Rugeles²,

Chougnet³

2006

Clinical Immunology

152

132

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Immaturity of the immune system has been suggested as an underlying factor for the high rate of morbidity and mortality from infections in newborns. Functional impairment of neonatal T cells is frequently quoted as the main underlying mechanism for such immaturity. However, recent studies suggest that neonatal antigen-presenting cells (APCs) also exhibit functional alterations, which could lead to secondary defects of adaptive T cell responses. In this review, we summarize what is known on the functionality of APC at birth and during early childhood. Compared to adults, neonatal APCs display markers of immaturity and produce low levels of cytokines. Multiple factors could be involved in neonatal APC alteration, such as intrinsic immaturity, defective interaction between APCs and T cells, and regulatory T cell-mediated inhibition. Characterization of the relative contribution of each mechanism is clearly needed to better understand the functional capability of the neonatal immune system.

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Impaired responses to toll-like receptor 4 and toll-like receptor 3 ligands in human cord blood

Cited by 141 publications

References 24 publications

In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands

In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

Defective antigen-presenting cell function in human neonates

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