title: Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848.
abstract: Newborns are at increased risk of overwhelming infection, yet the mechanisms underlying this susceptibility are incompletely defined. In this study we report a striking 1- to 3-log decrease in sensitivity of monocytes in human neonatal cord blood, compared with monocytes in adult peripheral blood, to the TNF-alpha-inducing effect of multiple TLR ligands, including bacterial lipopeptides (BLPs), LPS, and the imidazoquinoline compound, imiquimod. In marked contrast, TNF-alpha release in response to R-848, a TLR ligand that is a congener of imiquimod, was equivalent in newborn and adult blood. Differences in ligand-induced TNF-alpha release correlated with divergent ligand-induced changes in monocyte TNF-alpha mRNA levels. Newborn and adult monocytes did not differ in basal mRNA or protein expression of TLRs or mRNA expression of functionally related molecules. Newborn monocytes demonstrated diminished LPS-induced, but equivalent R-848-induced, phosphorylation of p38 mitogen-activated protein kinase and altered BLP- and LPS-induced acute modulation of cognate receptors, suggesting that the mechanism accounting for the observed differences may be localized proximal to ligand recognition by surface TLRs. Remarkably, newborn plasma conferred substantially reduced BLP-, LPS-, and imiquimod-induced TNF-alpha release on adult monocytes without any effect on R-848-induced TNF-alpha release, reflecting differences in a plasma factor(s) distinct from soluble CD14. Impaired response to multiple TLR ligands may significantly contribute to immature neonatal immunity. Conversely, relative preservation of responses to R-848 may present unique opportunities for augmenting innate and acquired immunity in the human newborn.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Boston, MA 02115, USA. ofer.levy@childrens.harvard.edu
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
authors.forename: Kol A
authors.initials: KA
authors.lastname: Zarember
authors.forename: Rene M
authors.initials: RM
authors.lastname: Roy
authors.forename: Colette
authors.initials: C
authors.lastname: Cywes
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Godowski
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wessels
mesh_terms: D000328:Adult; D000634:Aminoquinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D005260:Female; D005312:Fetal Blood / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000077271:Imiquimod; D007108:Immune Tolerance; D007113:Immunity, Innate; D007231:Infant, Newborn; D007369:Interferon Inducers / Q000494:pharmacology; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood* / Q000502:physiology; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000634:Aminoquinolines; D007093:Imidazoles; D007369:Interferon Inducers; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077271:Imiquimod; C402365:resiquimod