Vaccines are the most effective means available for preventing infectious diseases. However, vaccine-induced immune responses are highly variable between individuals and between populations in ...different regions of the world. Understanding the basis of this variation is, thus, of fundamental importance to human health. Although the factors that are associated with intra- and inter-population variation in vaccine responses are manifold, emerging evidence points to a key role for the gut microbiome in controlling immune responses to vaccination. Much of this evidence comes from studies in mice, and causal evidence for the impact of the microbiome on human immunity is sparse. However, recent studies on vaccination in subjects treated with broad-spectrum antibiotics have provided causal evidence and mechanistic insights into how the microbiota controls immune responses in humans.
All circulating immunoglobulin G (IgG) antibodies in human newborns are of maternal origin
and transferred across the placenta to provide passive immunity until newborn IgG production takes over 15 ...weeks after birth
. However, maternal IgG can also negatively interfere with newborn vaccine responses
. The concentration of IgG increases sharply during the third trimester of gestation and children delivered extremely preterm are believed to largely lack this passive immunity
. Antibodies to individual viruses have been reported
, but the global repertoire of maternal IgG, its variation in children, and the epitopes targeted are poorly understood. Here, we assess antibodies against 93,904 epitopes from 206 viruses in 32 preterm and 46 term mother-child dyads. We find that extremely preterm children receive comparable repertoires of IgG as term children, albeit at lower absolute concentrations and consequent shorter half-life. Neutralization of the clinically important respiratory syncytial virus (RS-virus) was also comparable until three months of age. These findings have implications for understanding infectious disease susceptibility, vaccine development, and vaccine scheduling in newborn children.
Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span ...has been difficult to determine. By measuring nuclear bomb test-derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31- naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.
Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells ...and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.
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•Mass cytometry data analysis after allogeneic stem cell transplantation•Perturbed co-regulation patterns of cells and proteins are associated with complications•Topological data analyses allow for the integration of cell, protein, and metadata•Cytomegalovirus has a profound impact on the regenerating immune system
Lakshmikanth et al. conduct a systems analysis of immune reconstitution after stem cell transplantation. Using topological data analysis, combinations of cells and proteins associated with CMV and graft-versus-host disease were revealed and illustrate the potential of systems immunomonitoring to improve the development and evaluation of cancer immunotherapies.
The process of immune system regeneration after allogeneic stem cell transplantation is slow, complex, and insufficiently understood. An entire immune system with all of its cell populations must ...regenerate from infused donor hematopoietic stem cells over the course of weeks and months post-transplantation. Both innate and adaptive arms of the immune system differ in their capacity and speed to reconstitiute in the recipient, which contributes to inadequacy in global immunity during the delayed reconstitution period. Systems-level analyses of immune systems in human patients have been made possible by high-throughput and high-dimensional, state-of-the-art, single-cell methodologies such as mass cytometry. Mass cytometry has revolutionized our ability to comprehensively profile all immune cell populations simultaneously in blood or tissue samples, providing signatures of differentially regulated cells in a range of clinical conditions. Such kind of systems immunology analyses promise not only for more accurate descriptions of variation between patients but also within individual patients over time, inter-dependencies between cell populations and the inference of developmental trajectories for specific cell populations. Here, we took advantage of a recently performed longitudinal mass cytometry analysis in 26 patients with hematological malignancies followed during the first 12 months following allogeneic stem cell transplantation. We present a proof-of-principle analysis to understand the evolution of individual immune cell populations. By applying non-linear dimensionality reduction and feauture extraction algorithms, we infer trajectories for individual immune cell populations, and map continuous marker expression changes occuring during immune cell regeneration that add novel information about this developmental process.
Epidemiological data suggest that early life exposures are key determinants of immune-mediated disease later in life. Young children are also particularly susceptible to infections, warranting more ...analyses of immune system development early in life. Such analyses mostly have been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. Here, we performed longitudinal analyses in 100 newborn children, sampled up to 4 times during their first 3 months of life. From 100 μL of blood, we analyze the development of 58 immune cell populations by mass cytometry and 267 plasma proteins by immunoassays, uncovering drastic changes not predictable from cord blood measurements but following a stereotypic pattern. Preterm and term children differ at birth but converge onto a shared trajectory, seemingly driven by microbial interactions and hampered by early gut bacterial dysbiosis.
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•Cord blood is not representative of postnatal immunity•Preterm and term children differ at birth but rapidly converge thereafter•Immune system development follows a stereotypic pattern early in life•Dynamic parameters imply microbial interactions during early immune development
Longitudinal profiling of blood immune cells from 100 newborns provides a systemic view on the ontogeny of the human neonatal immune system.
Immune-microbe interactions early in life influence the risk of allergies, asthma, and other inflammatory diseases. Breastfeeding guides healthier immune-microbe relationships by providing nutrients ...to specialized microbes that in turn benefit the host’s immune system. Such bacteria have co-evolved with humans but are now increasingly rare in modern societies. Here we show that a lack of bifidobacteria, and in particular depletion of genes required for human milk oligosaccharide (HMO) utilization from the metagenome, is associated with systemic inflammation and immune dysregulation early in life. In breastfed infants given Bifidobacterium infantis EVC001, which expresses all HMO-utilization genes, intestinal T helper 2 (Th2) and Th17 cytokines were silenced and interferon β (IFNβ) was induced. Fecal water from EVC001-supplemented infants contains abundant indolelactate and B. infantis-derived indole-3-lactic acid (ILA) upregulated immunoregulatory galectin-1 in Th2 and Th17 cells during polarization, providing a functional link between beneficial microbes and immunoregulation during the first months of life.
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•An ordered sequence of immune changes after birth driven by microbial interactions•Lack of gut bifidobacteria and HMO-utilization genes correlates with systemic inflammation•Feeding B. infantis EVC001 upregulates IFNβ and silences intestinal Th2 and Th17•EVC001-associated indole-3-lactic acid upregulates inhibitory galectin-1 in T cells
A lack of bifidobacteria and/or their genes required for the utilization of human milk oligosaccharides from breast milk is associated with systemic inflammation and immune imbalance early in life. Infant supplementation of Bifidobacterium infantis EVC001 shows promise in mitigating this by reducing Th2 and Th17 cytokines in the intestine through upregulation of the immunoregulatory factor galectin-1.
Antisecretory Factor (AF) is a protein present in breastmilk that regulates inflammatory processes. We aimed to investigate the level of AF in mothers' own milk (MOM) in relation to sepsis and other ...neonatal morbidities in preterm infants.
Samples of breastmilk and infant plasma were collected at 1, 4, and 12 weeks after birth from 38 mothers and their 49 infants born before 30 weeks gestation. AF-compleasome in MOM was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) and inflammatory markers in infant plasma by a panel of 92 inflammatory proteins. Neonatal treatments and outcomes were recorded.
The level of AF in MOM week 1 was lower for infants with later sepsis compared to no sepsis (p = 0.005). Corrected for nutritional intake of MOM, higher levels of AF decreased the risk for sepsis, OR 0.24. AF in MOM week 1 was negatively correlated to inflammatory proteins in infant plasma week 4, markedly IL-8, which was also associated with infant sepsis. Overall, higher AF levels in MOM was associated with fewer major morbidities of prematurity.
Mother's milk containing high levels of antisecretory factor is associated with reduced risk for sepsis and inflammation in preterm infants.
High level of antisecretory factor (AF) in mothers' own milk is associated with less risk for later sepsis in preterm infants. Receiving mothers' milk with low AF levels during the first week after birth is correlated with more inflammatory proteins in infant's plasma 2-4 weeks later. Human breastmilk has anti-inflammatory properties, and antisecretory factor in mothers' own milk is a component of potential importance for infants born preterm. The findings suggest that food supplementation with AF to mothers of preterm infants to increase AF-levels in breastmilk may be a means to decrease the risk of inflammatory morbidities of prematurity.
Background
Changes in immune cell composition during the immunological window within the first years after birth are not fully understood, especially the effect that different lifestyles might have ...on immune cell functionality.
Methods
Peripheral blood mononuclear cells from mothers and their children at birth and at two anvd five years were analyzed by mass cytometry. Immune cell composition and functionality was analyzed according to family lifestyle (anthroposophic and non‐anthroposophic).
Results
We found no significant differences in the proportions of major immune lineages between anthroposophic and non‐anthroposophic children at each time point, but there were clear changes over time in the proportions of mononuclear leukocytes, especially in B‐cells and T lymphocytes. Phenotypic distances between cord blood and maternal blood were high at birth but decreased sharply the first two years, indicating strong phenotypic convergence with maternal cells. We found that children exhibited similar stimulation responses at birth, but subsequently segregated into two discrete functional trajectories. Trajectory 1 was associated with a decrease in tumor necrosis factor alpha (TNFa) production by CD4+ T‐ and NK‐cells, while Trajectory 2 depicted an increase in the production of IL‐2 and interferon gamma (INFg) by T‐cells. In both trajectories, there was an increase in IL‐17A production by T‐cells resulting in prominent differences at five years of age.
Conclusions
This exploratory study suggests that leukocyte frequencies and cell phenotypes change with age in the same way across all children, while functional development follows one of two discrete trajectories that largely segregate by family lifestyle, supporting the hypothesis that early environmental exposures imprint immune cell function which may contribute to IgE sensitization. Our results also support that the first two years are critical for the environmental exposures to imprint the immune cells. Further studies with larger sample sizes are required to validate our findings.
This study identifies environmental and lifestyle‐related factors during pregnancy and early childhood. NK cells and monocytes are more abundant in cord blood and decrease with age, while B cells peak at two years of age. Children exhibit similar stimulation responses at birth, but subsequently segregate into two discrete functional trajectories. The largest differences seen at age five years between children in trajectory 1 and trajectory 2 are in the ability of the CD4+ T‐cell population to produce IFN‐γ, IL‐2, and TNF‐α.Abbreviations: ALADDIN, Assessment of Lifestyle and Allergic Disease During Infancy; DC, dendritic cell; IL‐2, interleukin 2; INF‐γ, interferon gamma; NK, natural killer cell; PC, principal component; TNF‐α, tumor necrosis factor alpha.
The human immune system varies extensively between individuals, but variation within individuals over time has not been well characterized. Systems-level analyses allow for simultaneous ...quantification of many interacting immune system components and the inference of global regulatory principles. Here, we present a longitudinal, systems-level analysis in 99 healthy adults 50 to 65 years of age and sampled every third month for 1 year. We describe the structure of interindividual variation and characterize extreme phenotypes along a principal curve. From coordinated measurement fluctuations, we infer relationships between 115 immune cell populations and 750 plasma proteins constituting the blood immune system. While most individuals have stable immune systems, the degree of longitudinal variability is an individual feature. The most variable individuals, in the absence of overt infections, exhibited differences in markers of metabolic health suggestive of a possible link between metabolic and immunologic homeostatic regulation.
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•Longitudinal variation in immune cell composition during 1 year•Interindividual variation can be described along a principal curve•Immune cell and protein relationships are inferred•Variability over time correlates with markers of metabolic health
Human immune system variation over time within an individual is unclear. Lakshmikanth et al. performed a longitudinal, systems-level analysis of immune cells and plasma proteins in healthy adults. They show that longitudinal variability over time is an individual feature, with the most variable individuals exhibiting markers of metabolic dysregulation.
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