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: 4.92). 11/2009; 183(11):7150-60. DOI: 10.4049/jimmunol.0901481
Source: PubMed


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.

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Available from: Pascal M Lavoie, Dec 11, 2014
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    • "Innate immune responses in early life are also distinct from those in adulthood. In particular, triggering of most toll-like receptors (TLR) ligands in neonatal leukocyte populations yields less IL-12, type 1 IFN, and TNFα, but enhanced levels of IL-1, IL-6, IL-23, and IL-10 relative to corresponding adult cells; overall, the neonatal innate response profile supports robust Th-2 and Th-17 immunity while Th-1 immunity is attenuated (74). "
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    ABSTRACT: Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1-6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis.
    Frontiers in Immunology 09/2014; 5:447. DOI:10.3389/fimmu.2014.00447
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    • "Isolated neonatal T cells have a lower proliferative capacity and secrete lower amounts of IFN-gamma after polyclonal stimulation in vitro. In vivo, the ability of neonatal T cells to mount effective responses is likely influenced by the lower expression of B7 family molecules on antigen-presenting cells (APCs) [39] and the defective cytokine production by these cells [40]. T cell responses induced by several routine vaccines are less polyfunctional, less proliferative and produce lower IFN-gamma in infants compared to adults [41]–[47]. "
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    ABSTRACT: Over 4 million infants die each year from infections, many of which are vaccine-preventable. Young infants respond relatively poorly to many infections and vaccines, but the basis of reduced immunity in infants is ill defined. We sought to investigate whether myeloid-derived suppressor cells (MDSC) represent one potential impediment to protective immunity in early life, which may help inform strategies for effective vaccination prior to pathogen exposure. We enrolled healthy neonates and children in the first 2 years of life along with healthy adult controls to examine the frequency and function of MDSC, a cell population able to potently suppress T cell responses. We found that MDSC, which are rarely seen in healthy adults, are present in high numbers in neonates and their frequency rapidly decreases during the first months of life. We determined that these neonatal MDSC are of granulocytic origin (G-MDSC), and suppress both CD4+ and CD8+ T cell proliferative responses in a contact-dependent manner and gamma interferon production. Understanding the role G-MDSC play in infant immunity could improve vaccine responsiveness in newborns and reduce mortality due to early-life infections.
    PLoS ONE 09/2014; 9(9):e107816. DOI:10.1371/journal.pone.0107816 · 3.23 Impact Factor
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    • "Age dependent differences in human immunity are implied by the clinical observation of altered disease susceptibility and substantiated by differences in immune cell activities. Newborns are more susceptible to several diseases when compared to adults; this appears to be at least partially due to a lack of acquired immune memory and differential regulation of innate immune responses (7, 8). This altered immunological priming is not maladaptive, rather, the fetus and neonate are challenged with balancing defense against infection, minimizing potentially harmful inflammation, and mitigating colonization by microbes as it develops and transitions from the relatively protected womb to the external world (9). "
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    ABSTRACT: The concept of immunological memory stipulates that past exposures shape present immune function. These exposures include not only specific antigens impacting adaptive immune memory but also conserved pathogen or danger associated molecular patterns that mold innate immune responses for prolonged periods of time. It should thus not come as a surprise that there is a vast range of external or environmental factors that impact immunity. The importance of environmental factors modulating immunity is most readily recognized in early life, a period of rapidly changing environments. We here summarize available data on the role of environment shaping immune development and from it derive an overarching hypothesis relating the underlying molecular mechanisms and evolutionary principles involved.
    Frontiers in Immunology 09/2014; 5:434. DOI:10.3389/fimmu.2014.00434
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