The neonatal window of opportunity—early priming for life

Renz, Harald; Adkins, Becky; Bartfeld, Sina; Blumberg, Richard S.; Farber, Donna L.; Garssen, Johan; Ghazal, Peter; Hackam, David J.; Marsland, Benjamin J.; McCoy, Kathy D.; Penders, John; Prinz, Immo; Verhasselt, Valérie; Mutius, Erika von; Weiser, Jeffrey N.; Wesemann, Duane R.; Hornef, Mathias W.

doi:10.1016/j.jaci.2017.11.019

Cited by 89 publications

(83 citation statements)

References 10 publications

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“…While dealing with the continual process of immune education during postnatal development, early life lung-resident immune cells are faced with the distinct challenge of reacting to pathogenic and non-pathogenic exposures in a manner that protects the organ's critical gas exchange machinery. This "neonatal window of opportunity" is such that early life priming can set the stage for life long host-microbial interaction and immune homeostasis (48)(49)(50)(51). Additionally, composition of the early life microbiome may ultimately affect vaccine efficacy (52).…”

Section: Discussionmentioning

confidence: 99%

The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

2020

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Intranasal mucosal vaccines are an attractive approach to induce protective mucosal immune responses. Activation of lung antigen presenting cells (APCs), a phenotypically and functionally heterogeneous cell population located at distinct mucosal sites, may be key to the immunogenicity of such vaccines. Understanding responsiveness of newborn lung APCs to adjuvants may the inform design of efficacious intranasal vaccines for early life, when most infections occur. Here, we characterized and phenotyped APCs from neonatal (7 days of life) and adult (6-8 weeks of age) mice. Neonatal mice demonstrated a relatively high abundance of alveolar macrophages (AMs), with lower percentages of plasmacytoid dendritic cells (pDCs), CD103 + (cDC1), and CD11b + (cDC2) DCs. Furthermore, neonatal CD103 + and CD11b + DC subsets demonstrated a significantly lower expression of maturation markers (CD40, CD80, and CD86) as compared to adult mice. Upon stimulation of lung APC subsets with a panel of pattern recognition receptor (PRR) agonists, including those engaging TLRs or STING, CD11c + enriched cells from neonatal and adult mice lungs demonstrated distinct maturation profiles. Of the agonists tested, the TLR5 ligand, flagellin, was most effective at activating neonatal lung APCs, inducing significantly higher expression of maturation markers on CD103 + (cDC1) and CD11b + (cDC2) subsets. Intranasal administration of flagellin induced a distinct migration of CD103 + and CD11b + DC subsets to the mediastinal lymph nodes (mLNs) of neonatal mice. Overall, these findings highlight age-specific differences in the maturation and responsiveness of lung APC subsets to different PRR agonists. The unique efficacy of flagellin in enhancing lung APC activity suggests that it may serve as an effective adjuvant for early life mucosal vaccines.

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Section: Discussionmentioning

confidence: 99%

The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

2020

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“…Hence, a more personalized precision medicine approach is needed. The neonatal period has lifelong imprinting effects and remains the primary window of opportunity for prevention or intervention [254]. It could be promising to extrapolate the set trajectory of immune development in term infants [255] into the context of preterm birth.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Preterm birth and sustained inflammation: consequences for the neonate

et al. 2020

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Almost half of all preterm births are caused or triggered by an inflammatory process at the feto-maternal interface resulting in preterm labor or rupture of membranes with or without chorioamnionitis (“first inflammatory hit”). Preterm babies have highly vulnerable body surfaces and immature organ systems. They are postnatally confronted with a drastically altered antigen exposure including hospital-specific microbes, artificial devices, drugs, nutritional antigens, and hypoxia or hyperoxia (“second inflammatory hit”). This is of particular importance to extremely preterm infants born before 28 weeks, as they have not experienced important “third-trimester” adaptation processes to tolerate maternal and self-antigens. Instead of a balanced adaptation to extrauterine life, the delicate co-regulation between immune defense mechanisms and immunosuppression (tolerance) to allow microbiome establishment is therefore often disturbed. Hence, preterm infants are predisposed to sepsis but also to several injurious conditions that can contribute to the onset or perpetuation of sustained inflammation (SI). This is a continuing challenge to clinicians involved in the care of preterm infants, as SI is regarded as a crucial mediator for mortality and the development of morbidities in preterm infants. This review will outline the (i) role of inflammation for short-term consequences of preterm birth and (ii) the effect of SI on organ development and long-term outcome.

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“…Regulation of allergy development in murine offspring mediated by maternal and neonatal immune status has been discussed by our group . Recent observations have highlighted the concept of the neonatal window of opportunity and the critical role of early priming for lifelong host‐microbiota and immune homoeostasis . Microbial factors have a strong impact on the development of immune cells, including CD8 + T cells, B cells, invariant natural killer T (iNKT) cells and γδ T cells .…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4][5] Recent observations have highlighted the concept of the neonatal window of opportunity and the critical role of early priming for lifelong host-microbiota and immune homoeostasis. 6 Microbial factors have a strong impact on the development of immune cells, including CD8 + T cells, B cells, invariant natural killer T (iNKT) cells and γδ T cells. [7][8][9] In addition to the neonatal microbiome, antigens encountered by the future mother, such as allergens, may also influence the immune status of the offspring by potentially modulating their T-cell maturation.…”

Section: Introductionmentioning

confidence: 99%

Maternal IgG impairs the maturation of offspring intrathymic IL‐17‐producing γδT cells: Implications for murine and human allergies

de‐Oliveira

Lira

Sgnotto

et al. 2019

Clin Experimental Allergy

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Background The precise mechanism involved in the acquisition of the IL‐17+ profile of γδT cells, the ligands responsible for this change, and whether this default is acquired during intrathymic maturation need to be elucidated. Objective This study aimed to evaluate whether IL‐17‐producing γδT cells are present in the airways of tolerant offspring from allergen‐sensitized mothers and the possible implication of maternal IgG in the generation of these cells. Methods Female mice were immunized or not, and the allergic response, frequency of γδT cell subsets and cytokine production of the offspring were analysed by flow cytometry. The effects of passive in vivo transfer of purified IgG were investigated in offspring. A translational approach was employed to analyse γδT cells in the thymus and PBMCs from humans. Results Maternal immunization reduced the frequency of spontaneous IL‐17‐producing γδT cells in the thymus, spleen and lung of offspring. This effect was mimicked by the in vivo treatment of females with purified IgG. IgG directly interacted with γδT cell membranes. The modulatory effect of human IgG on human infant intrathymic and adult peripheral γδT cells showed similarities to murine γδT cells, which is rarely reported in the literature. Conclusions & Clinical Relevance Together, our results reveal that IgG from potentially tolerant atopic mothers can influence offspring thymic IL‐17‐producing γδT cell maturation. Furthermore, we suggest that IgG is an unprecedented modulatory factor of murine and human γδT cells. These observations may support the future development of IgG‐based immunoregulatory therapeutic strategies.

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The neonatal window of opportunity—early priming for life

Cited by 89 publications

References 10 publications

The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

The TLR5 Agonist Flagellin Shapes Phenotypical and Functional Activation of Lung Mucosal Antigen Presenting Cells in Neonatal Mice

Preterm birth and sustained inflammation: consequences for the neonate

Maternal IgG impairs the maturation of offspring intrathymic IL‐17‐producing γδT cells: Implications for murine and human allergies

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