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

Abstract: 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.