Seasonal disease outbreaks are perennial features of human infectious disease but the factors generating these patterns are unclear. Here we investigate seasonal and daytime variability in multiple immune parameters in 329,261 participants in UK Biobank and test for associations with a wide range of environmental and lifestyle factors, including changes in day length, outdoor temperature and vitamin D at the time the blood sample was collected. Seasonal patterns were evident in lymphocyte and neutrophil counts, and C-reactive protein CRP, but not monocytes, and these were independent of lifestyle, demographic, and environmental factors. All the immune parameters assessed demonstrated significant daytime variation that was independent of confounding factors. At a population level, human immune parameters vary across season and across time of day, independent of multiple confounding factors. Both season and time of day are fundamental dimensions of immune function that should be considered in all studies of immuno-prophylaxis and disease transmission.
INTRODUCTIONAnnual cycles in vulnerability to infectious disease are an established feature of human epidemiology: most respiratory viruses cause winter-time infection and polio is principally a summer-time disease (Dowell and Shang Ho, 2004). Childhood infectious diseases (meningitis, mumps, pertussis, and varicella) (Shah et al., 2006), and many of the contagious diseases that affect domestic animals (Poljak et al., 2014) (Jactel et al., 1990 are seasonal as are relapses in autoimmune diseases (Harding et al., 2017;Mori et al., 2019). The factors that mediate this seasonality are poorly understood and circannual patterns are simply an assumed component of the dynamics of infectious diseases. In addition to seasonality, animals and humans are more susceptible to infectious disease during the resting phase of their daily cycle (Tognini et al., 2017), adding a further circadian dimension to disease vulnerability.The axial and orbital rotations of the Earth generate predictable seasonal and daily rhythms of light and darkness. These conditions in turn generate circadian and seasonal oscillations in ambient temperature, food availability, predation, and risk of infection. Evolution has equipped animals with innate timing mechanisms, or ''clocks'', that synchronize physiology to these recurring periods of increased risk. The circadian clock is generated by a series of interconnected transcription-translation feedback loops that regulate the expression of a panel of clock-controlled genes (Takahashi, 2017). Most mammalian cells contain a molecular clock and overall rhythmicity is maintained by a master clock located in the suprachiasmatic nuclei of the hypothalamus, conferring time dependence on most physiological parameters through hormonal and neural signals (Takahashi, 2017). Mice deficient in the cryptochrome clock genes (Cry1 and Cry2), show elevated proinflammatory cytokines (Narasimamurthy et al., 2012), and an autoimmune phenotype (Cao et al., 2017), while loss of ...