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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 cum. 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., QC 20200819

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 env

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.

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