In this study, we sought to fill an important gap in fundamental immunology research by conducting a comprehensive systems immunology analysis of daily variation in the normal human peripheral immune system. Although variation due to circadian rhythmicity was not a significant source of variation in daily B-cell levels or any CD4+ functional subset, it accounted for more than 25% of CD4+ regulatory T-cell variation and over 50% of CD8+ central memory variation. circadian rhythmicity demonstrated phase alignment within functional phenotypes. In addition, we observed that previouslydescribed mechanistic relationships can also appear in the peripheral system as phase shifting in rhythmic patterns. We identified a set of immune factors which are ubiquitously correlated with other factors and further analysis also identified a tightly-correlated "core" set whose relational structure persisted after analytically removing circadian-related variation. This core set consisted of CD8+ and its subpopulations and the NK population. In sum, the peripheral immune system can be conceptualized as a dynamic, interconnected wave-field repeating its pattern on a daily basis. Our data provide a comprehensive inventory of synchronization and correlation within this wave-field and we encourage use of our data to discover unknown mechanistic relationships which can then be tested in the laboratory.Immune variation, in both circulating cell frequency and phenotype, have been associated with multiple autoimmune diseases 1 . For example, variations in subsets of immune cells have been correlated to metabolic changes in type 1 diabetes 2,3 and found predictive of disease progression in multiple sclerosis 4 . Additionally, peripheral blood immune cell variations were demonstrated to be predictive of a post-vaccination response 5 . Over the long-term, variation within an individual appears to be relatively stable compared to variation between-individuals 6 .Shorter-term variation occurring within the course of a day (i.e., circadian) is now a well-established characteristic of human immunity in circulation 7-15 . The presence of a "master clock", entraining the organism to external light cues via the suprachiasmic nuclei of the neuroendocrine system, is thought to be a major but not exclusive driver of the circadian behavior seen in certain components of the human immune system. Circadian changes in immune cell function and abundance within the circulatory system are also thought to result from transcriptional and posttranslational feedback loops generated by a set of interplaying clock proteins and time-keeping clock genes 16 . These "peripheral clocks" and their transcription/translation are now believed to function in nearly every human cell 17 . Immune factors such as cytokines can also influence the circadian clock, providing bidirectional flow of circadian information between the neuroendocrine and immune system 18 . Mavroudis 18 hypothesized that this network of neuroendocrine-immune interactions consist of complex and integrated mole...
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