The Circadian Rhythm of the Immune System

Sleeping with a cold is a horrible experience, no matter how much cough syrup you down or vaporizers you install in your room, you know the quality and amount of sleep will be diminished. It is possible this is due to poor draining of sinuses/lymph nodes from lack of movement or decreased blood pressure and temperature during the night. This paper published in Cell in February titled The Circadian Clock Controls Toll-Like Receptor 9-Mediated Innate and Adaptive Immunity, may provide answers. This paper suggests that the innate immune response, specifically through TLR9, may exhibit circadian behavior and is mediated by a well-known circadian rhythm pathway.  This could provide reasoning as to why sleeping with a cold is such an unpleasant experience.

They hypothesized that the immune system may exhibit circadian rhythms to better respond to pathogens that one may be more likely to encounter at certain points in the day. To see if the innate immune system does display circadian behavior they used mice with a mutation in a well-known circadian protein, Period2 (Per2^Brdm1). They isolated macrophages from mice and used various PAMPs to stimulate their corresponding PRR. When using CpG oligodeoxynucleotides (CpG ODNs), a PAMP that is specific to bacterial and viral DNA, to stimulate TLR9, the cytokines released from the Per2^Brdm1 macrophages were significantly reduced when compared to wildtype. They found that the mRNA levels of TLR9 in macrophages fluctuate throughout a 24hr period with the lowest at hour 7 (ZT7) and highest at hour 19 (ZT19). They later show that well-known circadian regulators, CLOCK and BMAL1, also regulate TLR9 transcriptionally by using ChIP analysis.

With the idea that TLR9 levels fluctuate throughout the day, they were curious to see what implications this has on the adaptive immune system. They vaccinated mice with the CpG ODNs as an adjuvant at either ZT7 or ZT19 and then gave them a booster at their respective time four weeks later. They found the mice vaccinated at ZT19 had the highest levels of IFN-g indicating a higher Th1 response. They used a model of sepsis in mice at either ZT7 or ZT19. The mice with sepsis induction at ZT19 had decreased survival as well as increased pro-inflammatory cytokines. This indicated at the time-point with higher TLR9 expression, the immune system response is greater and therefore could propagate and exacerbate disease.

There are various implications that the immune system does in fact display circadian behavior. It has been shown that in the humans the expression of pro-inflammatory cytokines is especially higher at night (Scheff et al., 2010). The mortality rate in septic patients is highest between the hours of 2AM and 6AM (Hrushesky and Wood, 1997). It has been suggested that the immune system fluctuates throughout the day due to exposure of pathogens being higher at certain points of time. If this is true, could a pathogen take advantage of the rhythmicity and infect at times where the immune system is at its’ diminished levels? This as well as other studies are suggesting that many genes display circadian behavior and therefore that we need to be aware of timing of treatments, such as chronotherapy which is becoming a new idea. Another question that arises is what happens when this rhythmicity is disrupted-like for example night shift workers. Could they be more susceptible to disease? The answer to a lot of these questions remains unsolved and therefore needs further investigation. Nonetheless, this paper as well as others may provide a new perspective on science as a whole and improve treatments in humans suffering from various diseases.

Silver AC, Arjona A, Walker WE, Fikrig E. “The Circadian Clock Controls Toll-Like Receptor 9-Mediated Innate and Adaptive Immunity” Cell. 2011. Feb 24; 36(2): 251-261.