Abstract
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 previously-described 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.
Highlights
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
Systems biology[20] has been used to better understand the mechanisms of circadian rhythmicity within specific cell populations[21], to the best of our knowledge there has not yet been published the type of systems immunology analysis as suggested by Davis et al focused on the cell and cytokine as the basic unit in the human circadian immune system
Our work meets a need to address the synchrony of the human immune system since previously published data have largely been comprised of “reductionist” studies focused on the mechanistic interactions of isolated subsets resulting in a disjointed understanding of human immunity[18]
Summary
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. 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 be tested in the laboratory Immune variation, in both circulating cell frequency and phenotype, have been associated with multiple autoimmune diseases[1]. Circadian changes in immune cell function and abundance within the circulatory system are 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 believed to function in nearly every human cell[17]. We sought to analytically separate observed circadian-based variation from what we hypothesize to be an underlying circulatory immune profile that is not significantly influenced by time-related external or internal factors
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