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      Stereotypic Immune System Development in Newborn Children

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          Summary

          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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          Highlights

          • 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

          Abstract

          Longitudinal profiling of blood immune cells from 100 newborns provides a systemic view on the ontogeny of the human neonatal immune system.

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          Most cited references 25

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          Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans.

          A major challenge in vaccinology is to prospectively determine vaccine efficacy. Here we have used a systems biology approach to identify early gene 'signatures' that predicted immune responses in humans vaccinated with yellow fever vaccine YF-17D. Vaccination induced genes that regulate virus innate sensing and type I interferon production. Computational analyses identified a gene signature, including complement protein C1qB and eukaryotic translation initiation factor 2 alpha kinase 4-an orchestrator of the integrated stress response-that correlated with and predicted YF-17D CD8(+) T cell responses with up to 90% accuracy in an independent, blinded trial. A distinct signature, including B cell growth factor TNFRS17, predicted the neutralizing antibody response with up to 100% accuracy. These data highlight the utility of systems biology approaches in predicting vaccine efficacy.
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            Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero.

            As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.
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              Pyogenic bacterial infections in humans with MyD88 deficiency.

              MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                23 August 2018
                23 August 2018
                : 174
                : 5
                : 1277-1292.e14
                Affiliations
                [1 ]Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, 17121 Solna, Sweden
                [2 ]Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 14152 Solna, Sweden
                [3 ]Department of Neonatology, Karolinska University Hospital, 17176 Solna, Sweden
                [4 ]Science for Life Laboratory, School of Biotechnology, KTH, Royal Institute of Technology, 17121 Stockholm, Sweden
                Author notes
                []Corresponding author petter.brodin@ 123456ki.se
                [5]

                These authors contributed equally

                [6]

                Lead Contact

                Article
                S0092-8674(18)30848-1
                10.1016/j.cell.2018.06.045
                6108833
                30142345
                © 2018 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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