Neonatal Innate TLR-Mediated Responses Are Distinct from Those of Adults

Division of Infectious and Immunological Diseases, Department of Pediatrics, University of British Columbia, CFRI, 950 West 28th Avenue, Vancouver, BC, V5Z4H4, Canada.
The Journal of Immunology (Impact Factor: 5.36). 11/2009; 183(11):7150-60. DOI: 10.4049/jimmunol.0901481
Source: PubMed

ABSTRACT The human neonate and infant are unduly susceptible to infection with a wide variety of microbes. This susceptibility is thought to reflect differences from adults in innate and adaptive immunity, but the nature of these differences is incompletely characterized. The innate immune response directs the subsequent adaptive immune response after integrating information from TLRs and other environmental sensors. We set out to provide a comprehensive analysis defining differences in response to TLR ligation between human neonates and adults. In response to most TLR ligands, neonatal innate immune cells, including monocytes and conventional and plasmacytoid dendritic cells produced less IL-12p70 and IFN-alpha (and consequently induced less IFN-gamma), moderately less TNF-alpha, but as much or even more IL-1beta, IL-6, IL-23, and IL-10 than adult cells. At the single-cell level, neonatal innate cells generally were less capable of producing multiple cytokines simultaneously, i.e., were less polyfunctional. Overall, our data suggest a robust if not enhanced capacity of the neonate vs the adult white-blood cell TLR-mediated response to support Th17- and Th2-type immunity, which promotes defense against extracellular pathogens, but a reduced capacity to support Th1-type responses, which promote defense against intracellular pathogens.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Almost 7 million children under the age 5 die each year, and most of these deaths are attributable to vaccine-preventable infections. Young infants respond poorly to infections and vaccines. In particular, dendritic cells secrete less IL-12 and IL-18, CD8(pos) T cells and NK cells have defective cytolysis and cytokine production, and CD4(pos) T cell responses tend to bias towards a Th2 phenotype and promotion of regulatory T cells (Tregs). The basis for these differences is not well understood and may be in part explained by epigenetic differences, as well as immaturity of the infant's immune system. Here we present a third possibility, which involves active suppression by immune regulatory cells and place in context the immune suppressive pathways of mesenchymal stromal cells (MSC), myeloid-derived suppressor cells (MDSC), CD5(pos) B cells, and Tregs. The immune pathways that these immune regulatory cells inhibit are similar to those that are defective in the infant. Therefore, the immune deficiencies seen in infants could be explained, in part, by active suppressive cells, indicating potential new avenues for intervention.
    Virology: Research and Treatment 01/2014; 2014(5):1-9. DOI:10.4137/VRT.S12248
  • [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptor 1 (TLR1) recognizes lipopeptides with TLR2, and affects immune response to Mycobacterium tuberculosis infection. Here, we report results of the first case-control pediatric study of the TLR1 single-nucleotide polymorphisms and susceptibility to tuberculosis (TB). A pediatric case-control study enrolled 340 TB patients and 366 healthy controls, all Han Chinese from North China. Significant differences of the allelic and genotypic distributions of rs5743618 in TLR1 gene were observed between TB group and control group and, G allele of rs5743618 was associated with increased risk for TB (OR: 2.40, 95%CI: 1.41-4.07, P = 0.0009). TLR1 rs5743618 -GT genotype was related to reduction in surface expression of TLR1 in monocytes and granulocytes regardless of stimulation with inactivated H37Rv. In addition, after stimulated with inactivated lysate of M. tuberculosis strain H37Rv, samples of peripheral blood mononuclear cells (PBMCs) from children with the rs5743618 GT genotypes showed a decreased level of Tumor Necrosis Factor-a (TNF-a) and CXC chemokine ligand 10 (CXCL10) production, invariable production of interleukin-6 (IL-6) and IL-8 and increased production of IL-10 ex vivo. To conclude, TLR1 rs5743618 G allele was found associated to susceptibility to TB in Han Chinese pediatric population. TLR1 rs5743618-GT genotype carriers may have reduced immune response to MTB infection although further study is warranted to test this conclusion. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Tuberculosis (Edinburgh, Scotland) 12/2014; 95(2). DOI:10.1016/ · 2.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background By comparing fibroblasts collected from animals at 5-months or 16-months of age we have previously found that the cultures from older animals produce much more IL-8 in response to lipopolysaccharide (LPS) stimulation. We now expand this finding by examining whole transcriptome differences in the LPS response between cultures from the same animals at different ages, and also investigate the contribution of DNA methylation to the epigenetic basis for the age-dependent increases in responsiveness.ResultsAge-dependent differences in IL-8 production by fibroblasts in response to LPS exposure for 24 h were abolished by pretreatment of cultures with a DNA demethylation agent, 5-aza-2¿deoxycytidine (AZA). RNA-Seq analysis of fibroblasts collected from the same individuals at either 5 or 16 months of age and exposed in parallel to LPS for 0, 2, and 8 h revealed a robust response to LPS that was much greater in the cultures from older animals. Pro-inflammatory genes including IL-8, IL-6, TNF-¿, and CCL20 (among many other immune associated genes), were more highly expressed (FDR < 0.05) in the 16-month old cultures following LPS exposure. Methylated CpG island recovery assay sequencing (MIRA-Seq) revealed numerous methylation peaks spread across the genome, combined with an overall hypomethylation of gene promoter regions, and a remarkable similarity, except for 20 regions along the genome, between the fibroblasts collected at the two ages from the same animals.Conclusions The fibroblast pro-inflammatory response to LPS increases dramatically from 5 to 16 months of age within individual animals. A better understanding of the mechanisms underlying this process could illuminate the physiological processes by which the innate immune response develops and possibly individual variation in innate immune response arises. In addition, although relatively unchanged by age, our data presents a general overview of the bovine fibroblast methylome as a guide for future studies in cattle epigenetics utilizing this cell type.
    BMC Genomics 01/2015; 16(1):30. DOI:10.1186/s12864-015-1223-z · 4.04 Impact Factor

Full-text (2 Sources)

Available from
Dec 11, 2014