Many organisms have synchronised with the 24-hour day. The circadian rhythm of the immune system, one example of this, indicates the best times for vaccination. Photo credit: Steven Cornfield via Unsplash
What is the circadian rhythm?
Have you ever felt immensely lethargic after coming off a long-haul flight and travelling across different time zones? We all know it as “jet lag” but what causes this profound sense of fatigue? Jet lag happens when there is a mismatch between environmental cues and your inner biological clockwork, which results in your body wanting to sleep in the middle of the day. Our bodies optimise their biological processes to synchronise with the 24-hour period of a day. This 24-hour synchronisation is known as the circadian rhythm, originating from the Latin words circa diem, which means “around a day”.
This feature is not unique to humans—we also see it in animals and plants. In fact, Jean Jacques d’Ortous de Mairan made the initial observations of the circadian rhythm back in the 18th century when he discovered that the opening and closing of the leaves of the mimosa plant continued to follow their normal daily patterns even when the plant was placed in constant darkness. As for animals, day-night oscillations in metabolism have been observed in non-human primates, such as monkeys and baboons.
Until the 1980s, when work in Drosophila fruit flies shed more light on the mechanisms governing the body’s internal circadian rhythm, the body’s internal clock was largely shrouded in mystery. Some suggested that the internal clock mechanism acts via negative feedback loops within individual cells. In this theory, the relevant proteins involved in circadian control, such as period circadian protein homolog 1 (PER) and protein timeless homolog (TIM), negatively regulate their own production, resulting in a near-24-hour oscillation of protein levels, dictating the internal clock. On top of intrinsic control, external factors can greatly affect the circadian rhythm, with the most prominent example being light.
In humans, a region of the brain known as the suprachiasmatic nucleus (SCN) takes in information regarding the lengths of day and night. It passes these messages onto the pineal gland, which secretes the hormone melatonin that promotes sleep. This external information establishes the circadian rhythm by promoting alertness and sleep with the day-night cycle.
Perhaps the most crucial function of the circadian rhythm is its contribution to the regulation of the immune system, our body’s natural defence mechanism.
Now, how important is this rhythm? What happens when we disrupt it, especially in this era when it is difficult to get a good night’s sleep? It goes without saying that the circadian rhythm is crucial in virtually all mental and physical systems of the body. For example, it regulates the endocrine system to produce hormones at specific points during the day to match energy expenditure. Consequently, circadian misalignment has major repercussions on health. In shift workers who have developed circadian rhythm disruption due to their working patterns, this has led to the development of metabolic syndrome, including heart diseases, neuropsychiatric problems, such as depression, and an increased risk of some cancers. But perhaps the most crucial function of the circadian rhythm is its contribution to the regulation of the immune system, our body’s natural defence mechanism.
Circadian control of the immune system—how does this work?
The immune system is a complex network of organs, tissues, and cells that work together to defend against external threats to the human body—it is the second most complex bodily system after the nervous system. The main orchestrators of the immune system are white blood cells, also known as leukocytes. These white blood cells patrol the body or stay resident within tissues and organs—their location determines their functions. Tissue-resident cells mainly function to sense damage at their niche and initiate immune responses by producing chemicals that recruit patrolling leukocytes (chemokines).
When there is a breach in our physical barriers, such as the skin or digestive tract, or when an infection has taken hold, the patrolling leukocytes will mobilise to the site of insult following the chemokine gradient to neutralise any external threats using a plethora of effector functions. The immune system is categorised into two types of immunity based on its speed and specificity of function, namely the innate and adaptive immune systems. The innate immunity is responsible for the immediate and rapid containment of the infection foci, buying time for the adaptive immunity to customise their “weapons” to target the specific pathogens. Both systems complement each other and work hand-in-hand to protect our bodies. Failure or aberrant activation of the immune system can have deleterious effects on human health, such as autoimmunity (where the body’s immune system attacks its own cells), inflammatory disorders (inflammation that chronically persists), or immunodeficiencies (impairment of the immune system).
Like all other systems, the immune system follows a circadian rhythm regarding cellularity, migration, and function. Previous studies have demonstrated that the number of circulating leukocytes in the blood oscillates throughout the day, most notably peaking during the behavioural “active phase” of the organism. Since we typically have increased social interactions during the day, our body has evolved a diurnal pattern of immune activity to defend us against bacteria and pathogens.
The migratory patterns of immune cells, too, exhibit a molecular rhythmic signature depending on the time of day by altering the expression of adhesion molecules and receptors required for effective migration. Studies have demonstrated that dendritic cells, a key immune cell that connects innate and adaptive immunity, have a circadian migration pattern into the lymphatics. The lymphatics are a circulatory system that collects immune cells to allow them to crosstalk so the immune system can mount the appropriate response based on the threat. Dendritic cells tend to show greater migration during the day than at night, owing to the rhythmic expression of relevant molecules, which means they may be able to activate the adaptive immune response faster when we are awake. This increase in dendritic cell migration coincides with the peak in circulating leukocytes, indicating that humans have a stronger immunity during the day.
Even the activation and functions of leukocytes depend on the time of day! T-cells are white blood cells that are key to the adaptive immune system and are responsible for coordinating immune responses. These cells exhibit rhythmicity in proliferation and cytokine production (chemicals produced by immune cells to initiate crosstalk and modulate immune responses), such as interleukin-2, interleukin-4, and interferon-γ. As a result, if the body encounters bacteria during the day when immune cells have heightened functions and increased numbers, we will get a much better adaptive immune response.
Disruptions to the circadian rhythm, such as pulling an all-nighter or not eating on time, can drastically affect immune cell functions, which has been shown to cause T-cell exhaustion. Exhausted T-cells aren’t actually tired per se. Instead, the term “exhausted” is mainly associated with T-cell dysfunction, whereby the immune cells have a partial or inefficient response to threats.
Based on the evidence presented, we can safely conclude that the circadian rhythm profoundly influences immune functions. Following on from that, say if we disrupt this biological clock, it should also affect the immune system’s ability to defend us. Indeed, sleep deprivation (<6 hours of sleep) before vaccination has been shown to acutely decrease influenza vaccine efficacy in rodents and was also correlated with an increased susceptibility to respiratory infections in humans.
Perhaps another worrying issue is the risk of cancer development. Cancerous cells are actively held at bay by the immune system, as immune cells constantly survey the body for any mutated cells and eradicate them. A disrupted circadian rhythm will significantly reduce the immune system’s effectiveness in maintaining surveillance, increasing the risk of cancerous growth. There have been studies to suggest that women in shift work for 30 years or more have an increased risk of developing breast cancer, and mice models of chronic jet lag have demonstrated much faster development of liver cancer.
Harnessing the power of the “immune clock”
Given the importance of the circadian rhythm on the immune system, medical interventions involving the immune system should take this into account to maximise its therapeutic advantage. Vaccination has been an effective way of protecting the general population against infectious diseases by artificially introducing immunological memory in the host towards the pathogen of interest so that it is ready for incoming infections. However, vaccine efficacy has varied across individuals, with immunocompromised people, such as the elderly, facing difficulties in mounting a robust immune response towards vaccines.
Given the importance of the circadian rhythm on the immune system, medical interventions involving the immune system should take this into account to maximise its therapeutic advantage.
There have been many efforts to optimise vaccine efficacy from vaccine design, such as adjuvants (ingredients added to a vaccine that helps create a more robust immune response) to further stimulate the immune system. Still, progress has been rather sluggish due to safety concerns. Based on our knowledge of the “immune clock”, perhaps we can look into the timing of immunisation to coincide with one’s circadian rhythm to boost vaccine responses further. This idea has been termed “chronovaccination”, and research has begun to address the clinical efficacy of such vaccination protocols.
Studies involving Chinese healthcare workers have shown that morning vaccination (between 9 AM and 11 AM) may produce a better neutralising antibody response against SARS-CoV-2, possibly due to the immune system being more active and able to mount a stronger response during the day, as previously discussed. A similar observation was also seen with the Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis and Staphylococcus aureus, whereby morning vaccinations resulted in a better immune response.
These studies and others have provided preliminary evidence that chronovaccination might be an exciting avenue to explore, but whether this approach is feasible in clinical practice remains to be seen. Chronovaccination may vary across vaccine types and the level of protective response it induces, not to mention that different people may have a distinct optimal biological time depending on their lifestyle and environment. Nonetheless, these optimisation protocols may be implemented for certain at-risk populations, rather than the general population, to reduce the logistical complexity.
There has been a new field in vaccine immunology, known as “chronovaccination”, which looks at the effect of vaccination timing on the immune response generated.
The circadian rhythm plays an indispensable role in every aspect of our lives, but few understand its importance in the functioning of the immune system. The cellularity, migration, and function of immune cells exhibit rhythmicity based on the circadian rhythm, and disruption to this pattern can have adverse impacts. With this idea in mind, there has been a new field in vaccine immunology, known as “chronovaccination”, which looks at the effect of vaccination timing on the immune response generated. Although preliminary results have been positive, more work must be done to better illustrate the mechanistic overview and science of it all. In light of all this information, perhaps the best antidote to our miserable flu is a good night’s sleep.
