Sanne Hoeks

Chapter 1 18 IMMUNE PROGRAMMING, ENVIRONMENTAL STIMULI AND EPIGENETICS The drastic changes across immune components after birth seem to follow a stereotypic pattern. This was first shown in a model using preterm pigs. Irrespective of postconceptional age, immune maturation started after birth and the postnatal age was the main predictor for the stage of immune maturation. 40 This finding was confirmed in human in more recent studies using multiplex techniques. 41, 42 Of interest, immune developmental pathways are shared by children of different levels of maturity and postnatal environmental conditions. The microbiome and the environment contribute to the development of immunity after birth. The quick colonization by microbiota directly upon birth is a crucial trigger to set of immune developmental pathways. The important role of microbiota-derived factors, particularly in immune development and maturation, is best illustrated in animals raised in germ-free environments. 43 Germ-free mice exhibit a number of significant differences in their immune system, including the cellular composition and maturation status at mucosal sites. Interestingly, the phenotype of germ-free mice is only partially rescued by bacterial colonization after weaning, demonstrating the critical role of early-life exposure for life-long immune homeostasis. 44 Consequently an altered microbiome or microbial deprivation increases the risk for various immune dysregulation and inflammatory diseases. 45, 46 For example, birth by caesarean section increases the risk for asthma, particularly in children of allergic parents. 47 Microbial dysbiosis during the first 100 days of life was associated with the development of asthma in a human birth cohort, 48 a finding that is in line with the hygiene hypothesis. 49 Studies in neonatal mice have shown that antibiotic treatment in the perinatal period alters intestinal microbiota, results in smaller numbers of Tregs cells, elevated serum IgE and increased susceptibility to allergic asthma in adulthood. 50, 51 Well-known are the epidemiological studies that show that growing up on a dairy farm protects children from allergy, hay fever, and asthma. High endotoxin concentrations in animal feces and the farm environment were identified as functional triggers of regulatory mechanisms and immune homeostasis. The strongest protective effect of such exposure was exerted during fetal and early postnatal life. The molecular substrate of the environmental effects on immune development is found in epigenetic changes in gene expression of immune cells. Epigenetic changes in gene expression are functional changes without changes in basepair order of the DNA. 52, 53 This plasticity in gene expression enables fast phenotypical adaptations upon environmental changes and these adaptations can be passed on to new cells to preserve these epigenetic