The development of the human immune system during the first five years of life

Systems immunology is a scientific field combining high-throughput analytic technologies and integrative data analysis to study the immune system from a holistic perspective. As the immune system is a complex integrated network of cells and proteins interacting in order to produce higher-level emergent behavior, the more traditional approach to immunological research is not fully capable of adequately describing these interactions. Systems immunology presents an alternative methodology and has already lead to new insight into mechanisms of human immunity. In the past century, to a large extent due to the introduction of sanitation, antibiotics, and vaccination, there has been a drastic decrease in the prevalence and severity of infectious disease. In parallel, the western world has experienced a dramatic increase in the incidence of immune-related diseases such as diabetes, asthma, allergies, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. This is often attributed to changes in lifestyle and children exhibit increased susceptibility to immune modulation by environmental factors. Although many such factors have been identified in epidemiological studies, the immunological mechanisms affected by these environmental factors and how they mediate an increased susceptibility to disease remain to be explored. The purpose of this thesis is to use systems immunology to study the development of the human immune system during the first years of life and identify connections between environmental and lifestyle exposures and the resulting immune phenotype. We identified a stereotypic pattern of change in immune cell composition over time that was consistent over all studies. The immune phenotypes of preterm and term children were different at birth but converged later in life, partially driven by environmental factors. We observed that the antibody repertoire and neutralization efficiency was similar for preterm and term children. We identified many environmental modulators of immune phenotype including gut microbiota composition, maternal antibody concentration, vaccination, and prenatal antibiotics. We are still in the early days of systems immunology. These studies hopefully represent only the beginning of a more rigorous and extensive application of systems immunology to the development of the human immune system. While many improvements in the collection and analysis of data have to be made, the initial results are encouraging. Hopefully, continued work in this area will reveal further connections between the environment and the immune system, as well as how the resulting phenotype leads to immunologic disease

Gut bacteria at 6 months of age are associated with immune cell status in 1-year-old children

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Integration of molecular profiles in a longitudinal wellness profiling cohort

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine

Cellular metabolism constrains innate immune responses in early human ontogeny

Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny

Mass Cytometry and Topological Data Analysis Reveal Immune Parameters Associated with Complications after Allogeneic Stem Cell Transplantation

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

Stereotypic Immune System Development in Newborn Children

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 mu L 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.QC 20180914</p

Cell generation dynamics underlying naive T-cell homeostasis in adult humans

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 C-14 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 kappa B (NF-kappa B) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-kappa B signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-kappa B 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.De 2 första författarna delar förstaförfattarskapet.</p