title: Reduced frequency of a CD14+ CD16+ monocyte subset with high Toll-like receptor 4 expression in cord blood compared to adult blood contributes to lipopolysaccharide hyporesponsiveness in newborns.
abstract: The human innate immune response to pathogens is not fully effective and mature until well into childhood, as exemplified by various responses to Toll-like receptor (TLR) agonists in newborns compared to adults. To better understand the mechanistic basis for this age-related difference in innate immunity, we compared tumor necrosis factor alpha (TNF-α) production by monocytes from cord blood (CB) and adult blood (AB) in response to LAM (lipoarabinomannan from Mycobacterium tuberculosis, a TLR2 ligand) and LPS (lipopolysaccharide from Escherichia coli, a TLR4 ligand). LPS or LAM-induced TNF-α production was 5 to 18 times higher in AB than in CB monocytes, whereas interleukin-1α (IL-1α) stimulated similar levels of TNF-α in both groups, suggesting that decreased responses to LPS or LAM in CB are unlikely to be due to differences in the MyD88-dependent signaling pathway. This impaired signaling was attributable, in part, to lower functional TLR4 expression, especially on CD14(+) CD16(+) monocytes, which are the primary cell subset for LPS-induced TNF-α production. Importantly, the frequency of CD14(+) CD16(+) monocytes in CB was 2.5-fold lower than in AB (P < 0.01). CB from Kenyan newborns sensitized to parasite antigens in utero had more CD14(+) CD16(+) monocytes (P = 0.02) and produced higher levels of TNF-α in response to LPS (P = 0.004) than CB from unsensitized Kenyan or North American newborns. Thus, a reduced CD14(+) CD16(+) activated/differentiated monocyte subset and a correspondingly lower level of functional TLR4 on monocytes contributes to the relatively low TNF-α response to LPS observed in immunologically naive newborns compared to the response in adults.
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Sigifredo
authors.initials: S
authors.lastname: Pedraza-Sánchez
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Ramachandra
authors.forename: Fabian
authors.initials: F
authors.lastname: Arechavaleta-Velasco
authors.forename: Christopher L
authors.initials: CL
authors.lastname: King
mesh_terms: D000328:Adult; D004926:Escherichia coli / Q000737:chemistry / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000032:analysis; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D018950:Lipopolysaccharide Receptors / Q000032:analysis*; D008070:Lipopolysaccharides / Q000276:immunology* / Q000302:isolation & purification; D009000:Monocytes / Q000737:chemistry / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000276:immunology; D011247:Pregnancy; D017452:Receptors, IgG / Q000032:analysis*; D051197:Toll-Like Receptor 4 / Q000032:analysis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D017452:Receptors, IgG; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C050016:lipoarabinomannan