title: Ontogeny of Toll-like receptor mediated cytokine responses of human blood mononuclear cells.
abstract: Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an 'immature' neonatal to a 'mature' adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation.
authors.affiliation: Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, Vancouver, Canada.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Corbett
authors.forename: Darren
authors.initials: D
authors.lastname: Blimkie
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ho
authors.forename: Bing
authors.initials: B
authors.lastname: Cai
authors.forename: Darren P
authors.initials: DP
authors.lastname: Sutherland
authors.forename: Arlene
authors.initials: A
authors.lastname: Kallos
authors.forename: Juliet
authors.initials: J
authors.lastname: Crabtree
authors.forename: Annie
authors.initials: A
authors.lastname: Rein-Weston
authors.forename: Pascal M
authors.initials: PM
authors.lastname: Lavoie
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Hawkins
authors.forename: Steven G
authors.initials: SG
authors.lastname: Self
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Wilson
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
authors.forename: Edgardo S
authors.initials: ES
authors.lastname: Fortuno
authors.forename: Tobias R
authors.initials: TR
authors.lastname: Kollmann
mesh_terms: D000328:Adult; D000367:Age Factors; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002675:Child, Preschool; D015331:Cohort Studies; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology*; D055815:Young Adult
chemical_list: C513200:CpG-A 2336; D016207:Cytokines; D055666:Lipopeptides; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; C508075:Pam(3)CSK(4) peptide; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors