Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease

Treating autoimmune diseases: Beating the clock

4 June 2018

Disruption to molecular clock gene expression may affect how we respond to autoimmune disease 

Many of our genes operate on 24-hour cycles. These ‘clock genes’ are expressed at varying levels throughout the day, and even across different seasons, helping to balance processes such as metabolism and immune responses. However, our artificially-lit world is increasingly disrupting our circadian rhythms, which could have profound effects on health. 

“We are uncovering links between disruption to circadian clock genes and the body’s immune responses to diseases and infections. For example, a recent study showed that people who work shifts as teenagers are at increased risk of developing multiple sclerosis (MS) as they get older,” says Annie Curtis at the Royal College of Surgeons in Dublin, Ireland, who led the project with Kingston Mills and Caroline Sutton at Trinity College Dublin “Our latest study is the first to show a direct link between clock gene expression and the initial stages of experimental autoimmune encephalomyelitis (EAE) in mice, which is essentially a model for MS in humans.” 

The clock gene Bmal1 is highly expressed during the day, but suppressed at night when we sleep. Cells without Bmal1 lack a functional molecular clock, meaning that multiple downstream mechanisms are also affected. Curtis and co-workers examined Bmal1‘s role in the initial stages of autoimmune disease, using mice that lacked Bmal1 in myeloid (bone marrow-derived) immune cells.  The team found that mice lacking myeloid Bmal1 were more susceptible to autoimmune disease.

“We also found dramatic differences in immune response and disease outcome when we induced EAE in the mice during the day or at night,” says Mills. “When we induced EAE in the middle of the day (when the mice were sleeping), the disease was significantly more severe than when it was induced at night-time (when they were awake).” Taken together, this implies that Bmal1 is responsible for sensing ‘time-of-day’ cues and suppressing inflammation accordingly. 

“It might be that getting the timing of drug administration right could vastly improve treatment for diseases like MS,” says Curtis. “We already know of seasonal variations in the symptoms of MS and other diseases — this could also be linked to clock gene disruption.”     

Curtis notes that scientists may be missing a trick having spent years working with nocturnal animal models. “If our immune systems peak at certain times during the 24-hour period, it would be worth investigating the links between disease and immunity at times when the mice are naturally awake.”

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References

1. Nature Communications 8, 1923 (2017) doi: 10.1038/s41467-017-02111-0